Co-reporter:Heidi R. Culver and Nicholas A. Peppas
Chemistry of Materials July 25, 2017 Volume 29(Issue 14) pp:5753-5753
Publication Date(Web):June 20, 2017
DOI:10.1021/acs.chemmater.7b01936
The potential to develop materials with antibody-like molecular recognition properties has helped sustain interest in protein-imprinted polymers over the past several decades. Unfortunately, despite persistent research, the field of noncovalent protein imprinting has seen limited success in terms of achieving materials with high selectivity and high affinity. In this Perspective, important yet sometimes overlooked aspects of the imprinting and binding processes are reviewed to help understand why there has been limited success. In particular, the imprinting and binding processes are viewed through the scope of free radical polymerization and hydrogel swelling theories to underscore the complexity of the synthesis and behavior of protein-imprinted polymers. Additionally, we review the metrics of success commonly used in protein imprinting literature (i.e., adsorption capacity, imprinting factor, and selectivity factor) and consider the relevance of each to the characterization of an imprinted polymer’s recognition characteristics. Throughout, common shortcomings are highlighted, and experiments that could help verify or disprove the efficacy of noncovalent protein imprinting are discussed.
Co-reporter:Heidi R. Culver;Stephanie D. Steichen
Biomacromolecules December 12, 2016 Volume 17(Issue 12) pp:4045-4053
Publication Date(Web):November 4, 2016
DOI:10.1021/acs.biomac.6b01482
Molecularly imprinted polymers (MIPs) are often investigated as lower cost, more environmentally robust alternatives to natural recognitive biomolecules, such as antibodies. When synthesized on the surface of nanomaterial supports, MIPs are capable of quick and effective binding of macromolecular templates when compared to traditional bulk-imprinted polymers. We have developed a method for imprinting proteins on biodegradable nanoparticle supports and have used these materials to investigate the impact of molecular imprinting on adsorption capacity and selectivity for lysozyme, the template protein. The imprinting process increased the adsorption capacity of the polymer for the template, lysozyme, with the MIPs being able to bind up to 83.5% of their dry weight as compared to 55.7% for nonimprinted polymers (NIPs). In noncompetitive binding experiments, where proteins were independently incubated with MIPs, the difference between adsorption capacity for lysozyme and proteins with much lower isoelectric points (pI < 8.0) was statistically significant. However, there was no statistical difference between adsorption capacity for lysozyme and other high-isoelectric point proteins, suggesting that MIPs are semiselective for this class of proteins. In competitive binding experiments, both MIPs and NIPs preferentially bound lysozyme over other high-isoelectric point proteins. This result demonstrated that imprinting alone could not account for the observed selectivity for lysozyme. Analysis of the solvent accessible surface area of lysozyme and its high-isoelectric point competitors revealed why lysozyme is an exceptional binder to the polymer system used in this work, with or without imprinting.
Co-reporter:Heidi R. Culver, John R. Clegg, and Nicholas A. Peppas
Accounts of Chemical Research 2017 Volume 50(Issue 2) pp:
Publication Date(Web):February 7, 2017
DOI:10.1021/acs.accounts.6b00533
ConspectusNature has mastered the art of molecular recognition. For example, using synergistic non-covalent interactions, proteins can distinguish between molecules and bind a partner with incredible affinity and specificity. Scientists have developed, and continue to develop, techniques to investigate and better understand molecular recognition. As a consequence, analyte-responsive hydrogels that mimic these recognitive processes have emerged as a class of intelligent materials. These materials are unique not only in the type of analyte to which they respond but also in how molecular recognition is achieved and how the hydrogel responds to the analyte. Traditional intelligent hydrogels can respond to environmental cues such as pH, temperature, and ionic strength. The functional monomers used to make these hydrogels can be varied to achieve responsive behavior. For analyte-responsive hydrogels, molecular recognition can also be achieved by incorporating biomolecules with inherent molecular recognition properties (e.g., nucleic acids, peptides, enzymes, etc.) into the polymer network. Furthermore, in addition to typical swelling/syneresis responses, these materials exhibit unique responsive behaviors, such as gel assembly or disassembly, upon interaction with the target analyte. With the diverse tools available for molecular recognition and the ability to generate unique responsive behaviors, analyte-responsive hydrogels have found great utility in a wide range of applications.In this Account, we discuss strategies for making four different classes of analyte-responsive hydrogels, specifically, non-imprinted, molecularly imprinted, biomolecule-containing, and enzymatically responsive hydrogels. Then we explore how these materials have been incorporated into sensors and drug delivery systems, highlighting examples that demonstrate the versatility of these materials. For example, in addition to the molecular recognition properties of analyte-responsive hydrogels, the physicochemical changes that are induced upon analyte binding can be exploited to generate a detectable signal for sensing applications. As research in this area has grown, a number of creative approaches for improving the selectivity and sensitivity (i.e., detection limit) of these sensors have emerged. For applications in drug delivery systems, therapeutic release can be triggered by competitive molecular interactions or physicochemical changes in the network. Additionally, including degradable units within the network can enable sustained and responsive therapeutic release. Several exciting examples exploiting the analyte-responsive behavior of hydrogels for the treatment of cancer, diabetes, and irritable bowel syndrome are discussed in detail. We expect that creative and combinatorial approaches used in the design of analyte-responsive hydrogels will continue to yield materials with great potential in the fields of sensing and drug delivery.
Co-reporter:Heidi R. Culver;Ishna Sharma;Marissa E. Wechsler;Eric V. Anslyn
Analyst (1876-Present) 2017 vol. 142(Issue 17) pp:3183-3193
Publication Date(Web):2017/08/21
DOI:10.1039/C7AN00787F
Due to the high cost and environmental instability of antibodies, there is precedent for developing synthetic molecular recognition agents for use in diagnostic sensors. While these materials typically have lower specificity than antibodies, their cross-reactivity makes them excellent candidates for use in differential sensing routines. In the current work, we design a set of charge-containing poly(N-isopropylacrylamide) (PNIPAM) nanogels for use as differential protein receptors in a turbidimetric sensor array. Specifically, NIPAM was copolymerized with methacrylic acid and modified via carbodiimide coupling to introduce sulfate, guanidinium, secondary amine, or primary amine groups. Modification of the ionizable groups in the network changed the physicochemical and protein binding properties of the nanogels. For high affinity protein–polymer interactions, turbidity of the nanogel solution increased, while for low affinity interactions minimal change in turbidity was observed. Thus, relative turbidity was used as input for multivariate analysis. Turbidimetric assays were performed in two buffers of different pH (i.e., 7.4 and 5.5), but comparable ionic strength, in order to improve differentiation. Using both buffers, it was possible to achieve 100% classification accuracy of eleven model protein biomarkers with as few as two of the nanogel receptors. Additionally, it was possible to detect changes in lysozyme concentration in a simulated tear fluid using the turbidimetric sensor array.
Co-reporter:John R. Clegg;Marissa E. Wechsler
Regenerative Engineering and Translational Medicine 2017 Volume 3( Issue 3) pp:166-175
Publication Date(Web):20 March 2017
DOI:10.1007/s40883-017-0028-9
The emerging field of regenerative engineering offers a great challenge and an even greater opportunity for materials scientists and engineers. How can we develop materials that are highly porous to permit cellular infiltration, yet possess sufficient mechanical integrity to mimic native tissues? How can we retain and deliver bioactive molecules to drive cell organization, proliferation, and differentiation in a predictable manner? In the following perspective, we highlight recent studies that have demonstrated the vital importance of each of these questions, as well as many others pertaining to scaffold development. We posit hybrid materials synthesized by molecular decoration and molecular imprinting as intelligent biomaterials for regenerative engineering applications. These materials have potential to present cell adhesion molecules and soluble growth factors with fine-tuned spatial and temporal control, in response to both cell-driven and external triggers. Future studies in this area will address a pertinent clinical need, expand the existing repertoire of medical materials, and improve the field’s understanding of how cells and materials respond to one another.Regenerative engineering seeks to combine our growing understandings of materials, stem cells, and developmental biology to generate therapeutic and curative treatments for a range of diseases. In this perspective, we discuss the utility and limitations of existing materials employed for regenerative engineering applications. These materials balance the dynamic need to provide mechanical strength, present therapeutic biomolecules, permit cell entry, and degrade over time. Then, we present recent developments in the field of materials science, which have generated hybrids of natural and synthetic origin. These blended, conjugated, and/or functionalized materials engage in intelligent and responsive interactions with the biological host. Specific interaction-response examples are discussed for the regeneration of nerve, bone, and cardiac muscle. In the future, intelligent materials for regenerative engineering will respond dynamically to signals produced by a patient’s cells or administered in a clinical intervention to facilitate tissue growth, healing, and recovery.
Co-reporter:
Macromolecular Bioscience 2017 Volume 17(Issue 1) pp:
Publication Date(Web):2017/01/01
DOI:10.1002/mabi.201600266
Hydrogels based upon terpolymers of methacrylic acid, N-vinyl pyrrolidone, and poly(ethylene glycol) are developed and characterized for their ability to respond to changes in environmental pH and to partition protein therapeutics of varying molecular weights and isoelectric points. P((MAA-co-NVP)-g-EG) hydrogels are synthesized with PEG-based cross-linking agents of varying length and incorporation densities. The composition is confirmed using FT-IR spectroscopy and shows peak shifts indicating hydrogen bonding. Scanning electron microscopy reveals microparticles with an irregular, planar morphology. The pH-responsive behavior of the hydrogels is confirmed under equilibrium and dynamic conditions, with the hydrogel collapsed at acidic pH and swollen at neutral pH. The ability of the hydrogels to partition model protein therapeutics at varying pH and ionic strength is evaluated using three model proteins: insulin, porcine growth hormone, and ovalbumin. Finally, the microparticles are evaluated for adverse interactions with two model intestinal cell lines and show minimal cytotoxicity at concentrations below 5 mg mL−1.
Co-reporter:Sarena D. Horava
Drug Delivery and Translational Research 2017 Volume 7( Issue 3) pp:359-371
Publication Date(Web):27 February 2017
DOI:10.1007/s13346-017-0365-8
Hemophilia B is a hereditary bleeding disorder caused by the deficiency in coagulation factor IX. Understanding coagulation and the role of factor IX as well as patient population and diagnosis are all critical factors in developing treatment strategies and regimens for hemophilia B patients. Current treatment options rely on protein replacement therapy by intravenous injection, which have markedly improved patient lifespan and quality of life. However, issues with current options include lack of patient compliance due to needle-based administration, high expenses, and potential other complications (e.g., surgical procedures, inhibitor formation). As a result, these treatment options are also limited to developed countries. Recent advantages in hemophilia B treatment have focused on addressing these pain points. Emerging commercial products based on modified factor IX aim to reduce injection frequency. Exploratory research efforts have focused on novel drug delivery systems for orally administered treatment and gene therapy as a potential cure. Such alternative treatment methods are promising options for hemophilia B patients worldwide.
Co-reporter:Julia E. Vela Ramirez, Lindsey A. Sharpe, Nicholas A. Peppas
Advanced Drug Delivery Reviews 2017 Volume 114(Volume 114) pp:
Publication Date(Web):15 May 2017
DOI:10.1016/j.addr.2017.04.008
While vaccination remains the most cost effective strategy for disease prevention, communicable diseases persist as the second leading cause of death worldwide. There is a need to design safe, novel vaccine delivery methods to protect against unaddressed and emerging diseases. Development of vaccines administered orally is preferable to traditional injection-based formulations for numerous reasons including improved safety and compliance, and easier manufacturing and administration. Additionally, the oral route enables stimulation of humoral and cellular immune responses at both systemic and mucosal sites to establish broader and long-lasting protection. However, oral delivery is challenging, requiring formulations to overcome the harsh gastrointestinal (GI) environment and avoid tolerance induction to achieve effective protection. Here we address the rationale for oral vaccines, including key biological and physicochemical considerations for next-generation oral vaccine design.Download high-res image (123KB)Download full-size image
Co-reporter:Michael Clinton Koetting, Joseph Frank Guido, Malvika Gupta, Annie Zhang, Nicholas A. Peppas
Journal of Controlled Release 2016 Volume 221() pp:18-25
Publication Date(Web):10 January 2016
DOI:10.1016/j.jconrel.2015.11.023
Two potential platform technologies for the oral delivery of protein therapeutics were synthesized and tested. pH-responsive poly(itaconic acid-co-N-vinyl-2-pyrrolidone) (P(IA-co-NVP)) hydrogel microparticles were tested in vitro with model proteins salmon calcitonin, urokinase, and rituximab to determine the effects of particle size, protein size, and crosslinking density on oral delivery capability. Particle size showed no significant effect on overall delivery potential but did improve percent release of encapsulated protein over the micro-scale particle size range studied. Protein size was shown to have a significant impact on the delivery capability of the P(IA-co-NVP) hydrogel. We show that when using P(IA-co-NVP) hydrogel microparticles with 3 mol% tetra(ethylene glycol) dimethacrylate crosslinker, a small polypeptide (salmon calcitonin) loads and releases up to 45 μg/mg hydrogel while the mid-sized protein urokinase and large monoclonal antibody rituximab load and release only 19 and 24 μg/mg hydrogel, respectively. We further demonstrate that crosslinking density offers a simple method for tuning hydrogel properties to variously sized proteins. Using 5 mol% TEGDMA crosslinker offers optimal performance for the small peptide, salmon calcitonin, whereas lower crosslinking density of 1 mol% offers optimal performance for the much larger protein rituximab. Finally, an enzymatically-degradable hydrogels of P(MAA-co-NVP) crosslinked with the peptide sequence MMRRRKK were synthesized and tested in simulated gastric and intestinal conditions. These hydrogels offer ideal loading and release behavior, showing no degradative release of encapsulated salmon calcitonin in gastric conditions while yielding rapid and complete release of encapsulated protein within 1 h in intestinal conditions.
Co-reporter:Amey S. Puranik, Ludovic P. Pao, Vanessa M. White, and Nicholas A. Peppas
Industrial & Engineering Chemistry Research 2016 Volume 55(Issue 40) pp:10576
Publication Date(Web):September 29, 2016
DOI:10.1021/acs.iecr.6b02565
About 70% of pharmaceutical drug candidates are poorly soluble and suffer from low oral bioavailability. Additionally, a large number of therapeutics are also substrates for P-glycoprotein (P-gp) receptors present on the intestinal cell lining and undergo efflux that further reduces their oral bioavailability drastically. Nanoscale hydrogels are promising candidates for oral delivery of hydrophobic therapeutics as they hold immense potential in improving solubility and increasing intestinal permeability of such therapeutics. In this report, we describe the in vitro evaluation and comparison of four novel, pH-responsive poly(methacrylic acid-g-polyethylene glycol-co-hydrophobic monomer) nanoscale hydrogels for their capacity to load and release chemotherapeutic doxorubicin, as well as their ability to modulate permeability in vitro for improving doxorubicin transport. The resulting nanoscale formulations showed appreciable loading, and in vitro release studies demonstrated excellent pH-triggered release kinetics. These nanoscale hydrogels can serve as carriers for oral delivery of doxorubicin, achieving drug loading efficiencies of 56–70%, and releasing up to 95% of drug within 6 h. Powder X-ray diffraction studies revealed a change from the crystalline nature of doxorubicin to an amorphous form when encapsulated within formulations, illustrating their potential of enhancing solubility and stability for oral delivery of the hydrophobic therapeutic. Furthermore, their ability to modulate in vitro intestinal permeability was also studied using transport studies with Caco-2 cells, and was complemented by assessing their antitumor activity against P-gp overexpressing, DOX-resistant H69/LX4 cancer cells. In vitro cell culture tests demonstrated up to 50% reduction in cellular proliferation in the case of poly(methacrylic acid-g-polyethylene glycol-co-methyl methacrylate), suggesting that these carriers are most suitable as hydrophobic drug carriers that can potentially overcome solubility and permeability limitations typically faced by hydrophobic therapeutics in the gastrointestinal (GI) tract.
Co-reporter:Heidi R. Culver, Stephanie D. Steichen, Margarita Herrera-Alonso, and Nicholas A. Peppas
Langmuir 2016 Volume 32(Issue 22) pp:5629-5636
Publication Date(Web):May 20, 2016
DOI:10.1021/acs.langmuir.6b00929
We introduce a general method for the stabilization and surface functionalization of hydrophobic nanoparticles using an amphiphilic copolymer, poly(maleic anhydride-alt-1-octadecene)-poly(ethylene glycol) methacrylate (PMAO-PEGMA). Coating nanoparticles with PMAO-PEGMA results in colloidally stable nanoparticles decorated with reactive carboxylic acid and methacrylate functionalities, providing a versatile platform for chemical reactions. The versatility and ease of surface functionalization is demonstrated by varying both the core material and the chemistry used. Specifically, the carboxylic acid functionalities are used to conjugate wheat germ agglutinin to conducting polymer nanoparticles via carbodiimide-mediated coupling, and the methacrylate groups are used to link cysteamine to the surface of poly(ε-caprolactone) nanoparticles via thiol–ene click chemistry and to link temperature-responsive polymer shells to the surface of gold nanoparticles via free radical polymerization.
Co-reporter:Jennifer M. Knipe, Laura E. Strong, and Nicholas A. Peppas
Biomacromolecules 2016 Volume 17(Issue 3) pp:
Publication Date(Web):January 26, 2016
DOI:10.1021/acs.biomac.5b01518
Inflammatory bowel diseases (IBD) manifest from excessive intestinal inflammation. Local delivery of siRNA that targets these inflammatory cytokines would provide a novel treatment approach. Microencapsulated nanogels are designed and validated as platforms for oral delivery of siRNA targeting TNF-α, a common clinical target of IBD treatments. The preferred platform was designed to (i) protect siRNA-loaded nanogels from the harsh acidic environment of the upper GI tract and (ii) enzymatically degrade and release the nanogels once the carrier has reached the intestinal region. This platform consists of microgels composed of poly(methacrylic acid-co-N-vinyl-2-pyrrolidone) (P[MAA-co-NVP]) cross-linked with a trypsin-degradable peptide linker. The P(MAA-co-NVP) backbone is designed to collapse around and protect encapsulated nanogel from degradation at the low pH levels seen in the stomach (pH 2–4). At pH levels of 6–7.5, as typically observed in the intestine, the P(MAA-co-NVP) matrix swells, potentially facilitating diffusion of intestinal fluid and degradation of the matrix by intestinal enzymes such as trypsin, thus “freeing” the therapeutic nanogels for delivery and cellular uptake within the intestine. TNF-α siRNA-loaded nanogels released from this platform were capable of inducing potent knockdown of secreted TNF-α levels in murine macrophages, further validating the potential for this approach to be used for the treatment of IBD.
Co-reporter:Sarena D. Horava
Annals of Biomedical Engineering 2016 Volume 44( Issue 6) pp:1970-1982
Publication Date(Web):2016 June
DOI:10.1007/s10439-016-1566-x
The oral administration of hematological factor IX (FIX) can offer a convenient prophylactic treatment for hemophilia B patients. pH-Responsive hydrogels based on poly(methacrylic acid)-grafted-poly(ethylene glycol) (P(MAA-g-EG)) have been engineered as delivery vehicles for FIX. In oral delivery, such hydrogel carriers protected FIX from the gastric environment and released it under intestinal conditions as demonstrated by evaluation of the loading and release of FIX. Tailoring of the hydrogel networks improved the loading of FIX within the microcarriers, which is critical for minimizing protein degradation. Optimizing the loading conditions by increasing the incubation time and using a reduced ionic strength buffer further improved the delivery potential of the microcarriers. The presence of the microcarriers significantly enhanced the oral absorption of FIX in vitro. As shown in this work, P(MAA-g-EG) microcarriers are promising candidates for the oral delivery of FIX.
Co-reporter:Brenda R. Carrillo-Conde, Erik Brewer, Anthony Lowman, and Nicholas A. Peppas
Industrial & Engineering Chemistry Research 2015 Volume 54(Issue 42) pp:10197-10205
Publication Date(Web):May 11, 2015
DOI:10.1021/acs.iecr.5b01193
Oral administration of monoclonal antibodies (mAbs) may enable the localized treatment of infections or other conditions in the gastrointestinal tract (GI) as well as systemic diseases. As with the development of oral protein biotherapeutics, one of the most challenging tasks in antibody therapies is the loss of biological activity due to physical and chemical instabilities. New families of complexation hydrogels with pH-responsive properties have demonstrated to be excellent transmucosal delivery vehicles. This contribution focuses on the design and evaluation of hydrogel carriers that will minimize the degradation and maximize the in vivo activity of anti-TNF-α, a mAb used for the treatment of inflammatory bowel disease (IBD) in the GI tract and systemically for the treatment of rheumatoid arthritis. P(MAA-g-EG) and P(MAA-co-NVP) hydrogels systems were optimized to achieve adequate swelling behavior, which translated into improved protein loading and release at neutral pH simulating the small intestine conditions. Additionally, these hydrogel systems preserve antibody bioactivity upon release resulting in the systemic circulation of an antibody capable of effectively performing its biological function. The compatibility if these hydrogels for mAb bioactivity preservation and release makes them candidates for use as oral delivery systems for therapeutic antibodies.
Co-reporter:Bron V. Slaughter;Aaron T. Blanchard;Katie F. Maass
Journal of Applied Polymer Science 2015 Volume 132( Issue 24) pp:
Publication Date(Web):
DOI:10.1002/app.42076
ABSTRACT
Temperature responsive hydrogels based on ionic polymers exhibit swelling transitions in aqueous solutions as a function of shifting pH and ionic strength, in addition to temperature. Applying these hydrogels to useful applications, particularly for biomedical purposes such as drug delivery and regenerative medicine, is critically dependent on understanding the hydrogel solution responses as a function of all three parameters together. In this work, interpenetrating polymer network (IPN) hydrogels of polyacrylamide and poly(acrylic acid) were formulated over a broad range of synthesis variables using a fractional factorial design, and were examined for equilibrium temperature responsive swelling in a variety of solution conditions. Due to the acidic nature of these IPN hydrogels, usable upper critical solution temperature (UCST) responses for this system occur in mildly acidic environments. Responses were characterized in terms of maximum equilibrium swelling and temperature-triggered swelling using turbidity and gravimetric measurements. Additionally, synthesis parameters critical to achieving optimal overall swelling, temperature-triggered swelling, and sigmoidal temperature transitions for this IPN system were analyzed based on the fractional factorial design used to formulate these hydrogels. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42076.
Co-reporter:Jennifer M. Knipe, Frances Chen, and Nicholas A. Peppas
Biomacromolecules 2015 Volume 16(Issue 3) pp:
Publication Date(Web):February 12, 2015
DOI:10.1021/bm501871a
Multiresponsive poly(methacrylic acid-co-N-vinylpyrrolidone) hydrogels were synthesized with biodegradable oligopeptide crosslinks. The oligopeptide crosslinks were incorporated using EDC-NHS zero-length links between the carboxylic acid groups of the polymer and free primary amines on the peptide. The reaction of the peptide was confirmed by primary amine assay and IR spectroscopy. The microgels exhibited pH-responsive swelling as well as enzyme-catalyzed degradation targeted by trypsin present in the small intestine, as demonstrated upon incubation with gastrointestinal fluids from rats. Relative turbidity was used to evaluate enzyme-catalyzed degradation as a function of time, and initial trypsin concentration controlled both the degradation mechanism as well as the extent of degradation. Trypsin activity was effectively extinguished by incubation at 70 °C, and both the microgels and degradation products posed no cytotoxic effect toward two different cell lines. The microgels demonstrated pH-dependent loading of the protein insulin for oral delivery to the small intestine.
Co-reporter:Michael C. Koetting, Jonathan T. Peters, Stephanie D. Steichen, Nicholas A. Peppas
Materials Science and Engineering: R: Reports 2015 Volume 93() pp:1-49
Publication Date(Web):July 2015
DOI:10.1016/j.mser.2015.04.001
Over the past century, hydrogels have emerged as effective materials for an immense variety of applications. The unique network structure of hydrogels enables very high levels of hydrophilicity and biocompatibility, while at the same time exhibiting the soft physical properties associated with living tissue, making them ideal biomaterials. Stimulus-responsive hydrogels have been especially impactful, allowing for unprecedented levels of control over material properties in response to external cues. This enhanced control has enabled groundbreaking advances in healthcare, allowing for more effective treatment of a vast array of diseases and improved approaches for tissue engineering and wound healing. In this extensive review, we identify and discuss the multitude of response modalities that have been developed, including temperature, pH, chemical, light, electro, and shear-sensitive hydrogels. We discuss the theoretical analysis of hydrogel properties and the mechanisms used to create these responses, highlighting both the pioneering and most recent work in all of these fields. Finally, we review the many current and proposed applications of these hydrogels in medicine and industry.
Co-reporter:Nasim Annabi;Ali Tamayol;Jorge Alfredo Uquillas;Mohsen Akbari;Luiz E. Bertassoni;Chaenyung Cha;Gulden Camci-Unal;Mehmet R. Dokmeci;Ali Khademhosseini
Advanced Materials 2014 Volume 26( Issue 1) pp:85-124
Publication Date(Web):
DOI:10.1002/adma.201303233
Hydrogels are hydrophilic polymer-based materials with high water content and physical characteristics that resemble the native extracellular matrix. Because of their remarkable properties, hydrogel systems are used for a wide range of biomedical applications, such as three-dimensional (3D) matrices for tissue engineering, drug-delivery vehicles, composite biomaterials, and as injectable fillers in minimally invasive surgeries. In addition, the rational design of hydrogels with controlled physical and biological properties can be used to modulate cellular functionality and tissue morphogenesis. Here, the development of advanced hydrogels with tunable physiochemical properties is highlighted, with particular emphasis on elastomeric, light-sensitive, composite, and shape-memory hydrogels. Emerging technologies developed over the past decade to control hydrogel architecture are also discussed and a number of potential applications and challenges in the utilization of hydrogels in regenerative medicine are reviewed. It is anticipated that the continued development of sophisticated hydrogels will result in clinical applications that will improve patient care and quality of life.
Co-reporter:Ankur Singh
Advanced Materials 2014 Volume 26( Issue 38) pp:6530-6541
Publication Date(Web):
DOI:10.1002/adma.201402105
For over two decades, immunologists and biomaterials scientists have co-existed in parallel world with the rationale of understanding the molecular profile of immune responses to vaccination, implantation, and treating incurable diseases. Much of the field of biomaterial-based immunotherapy has relied on evaluating model antigens such as chicken egg ovalbumin in mouse models but their relevance to humans has been point of much discussion. Nevertheless, such model antigens have provided important insights into the mechanisms of immune regulation and served as a proof-of-concept for plethora of biomaterial-based vaccines. After years of extensive development of numerous biomaterials for immunomodulation, it is only recently that an experimental scaffold vaccine implanted beneath the skin has begun to use the human model to study the immune responses to cancer vaccination by co-delivering patient-derived tumor lysates and immunomodulatory proteins. If successful, this scaffold vaccine will change the way we approached untreatable cancers, but more importantly, will allow a faster and more rational translation of therapeutic regimes to other cancers, chronic infections, and autoimmune diseases. Most materials reviews have focused on immunomodulatory adjuvants and micro-nano-particles. Here we provide an insight into emerging hydrogel and scaffold based immunomodulatory approaches that continue to demonstrate efficacy against immune associated diseases.
Co-reporter:Diane C. Forbes
Macromolecular Bioscience 2014 Volume 14( Issue 8) pp:1096-1105
Publication Date(Web):
DOI:10.1002/mabi.201400027
Abstract
This work investigates the interactions of a polycationic nanocarrier with siRNA and with cells in order to better understand the capabilities and limitations of the carrier. The polycationic nanocarriers are cross-linked copolymer nanoparticles synthesized in a single-step reaction using ARGET ATRP (activators regenerated by electron transfer atom transfer radical polymerization). The polycationic nanocarriers efficiently bind siRNA for polymer/siRNA mass ratios less than 1. A method to prepare fluorescently labeled polycationic nanocarriers is presented. The fluorescently labeled polycationic nanocarriers are used to investigate cellular internalization with RAW264.7 murine macrophage cells. Flow cytometry demonstrates that the uptake increased with nanoparticle concentration and incubation time. Confocal microscopy confirmed internalization of fluorescently labeled nanoparticles. The investigation of siRNA-induced knockdown demonstrates that higher concentrations of nanoparticles and siRNA are associated with increased knockdown. For the conditions tested in the knockdown experiments, the ARGET ATRP polycationic nanocarriers outperformed a commercially available Lipofectamine control.
Co-reporter:Jennifer M. Knipe;Frances Chen
Journal of Applied Polymer Science 2014 Volume 131( Issue 7) pp:
Publication Date(Web):
DOI:10.1002/app.40098
ABSTRACT
Intelligent, stimuli-responsive hydrogels have great utility in various fields spanning biomedical technology, separations, and catalysis. Their overall response to surrounding fluids may be further tailored to a specific application by incorporation of one or more intelligent responses within one material, known as multiresponsive hydrogels. This is a report on the facile synthesis and characterization of poly(methacrylic acid-co-N-vinylpyrrolidone) microgels encapsulating polycationic nanogels (70–100 nm) to incorporate inverse pH responsive behavior within a single hydrogel. Potentiometric titration and pH swelling studies reveal a swelling response dependent on both pH and crosslinking agent. Additionally, a protein and a small molecule are loaded and released to evaluate the pH-dependent binding affinity. Such a material could exhibit unique protein-binding capacity and pH-responsive behavior for use in separation or drug delivery applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40098.
Co-reporter:Diane C. Forbes and Nicholas A. Peppas
ACS Nano 2014 Volume 8(Issue 3) pp:2908
Publication Date(Web):February 18, 2014
DOI:10.1021/nn500101c
In this work, we develop and evaluate polycationic nanoparticles for the delivery of small interfering RNA (siRNA). Delivery remains a major challenge for translating siRNA to the clinic, and overcoming the delivery challenge requires effective siRNA delivery vehicles that meet the demands of the specific delivery strategy. Cross-linked polycationic nanoparticle formulations were synthesized using ARGET ATRP or UV-initiated polymerization. The one-step, one-pot, surfactant-stabilized monomer-in-water synthesis technique may provide a simpler and faster alternative to complicated, multistep techniques and an alternative to methods that rely on toxic organic solvents. The polymer nanoparticles were synthesized using the cationic monomer 2-(diethylamino)ethyl methacrylate, the hydrophobic monomer tert-butyl methacrylate to tune pH responsiveness, the hydrophilic monomer poly(ethylene glycol) methyl ether methacrylate to improve biocompatibility, and cross-linking agent tetraethylene glycol dimethacrylate to enhance colloidal stability. Four formulations were evaluated for their suitability as siRNA delivery vehicles in vitro with the human embryonic kidney cell line HEK293T or the murine macrophage cell line RAW264.7. The polycationic nanoparticles demonstrated efficient and rapid loading of the anionic siRNA following complexation. Confocal microscopy as well as flow cytometry analysis of cells treated with polycationic nanoparticles loaded with fluorescently labeled siRNA demonstrated that the polycationic nanoparticles promoted cellular uptake of fluorescently labeled siRNA. Knockdown experiments using polycationic nanoparticles to deliver siRNA demonstrated evidence of knockdown, thus demonstrating potential as an alternative route to creating polycationic nanoparticles.Keywords: ARGET ATRP; cationic polymer; drug delivery; siRNA; UV-initiated
Co-reporter:Matilde Durán-Lobato, Brenda Carrillo-Conde, Yasmine Khairandish, and Nicholas A. Peppas
Biomacromolecules 2014 Volume 15(Issue 7) pp:
Publication Date(Web):June 23, 2014
DOI:10.1021/bm500588x
Oral drug delivery is a route of choice for vaccine administration because of its noninvasive nature and thus efforts have focused on efficient delivery of vaccine antigens to mucosal sites. An effective oral vaccine delivery system must protect the antigen from degradation upon mucosal delivery, penetrate mucosal barriers, and control the release of the antigen and costimulatory and immunomodulatory agents to specific immune cells (i.e., APCs). In this paper, mannan-modified pH-responsive P(HEMA-co-MAA) nanogels were synthesized and assessed as carriers for oral vaccination. The nanogels showed pH-sensitive properties, entrapping and protecting the loaded cargo at low pH values, and triggered protein release after switching to intestinal pH values. Surface decoration with mannan as carbohydrate moieties resulted in enhanced internalization by macrophages as well as increasing the expression of relevant costimulatory molecules. These findings indicate that mannan-modified P(HEMA-co-MAA) nanogels are a promising approach to a more efficacious oral vaccination regimen.
Co-reporter:Ali Khademhosseini
Advanced Healthcare Materials 2013 Volume 2( Issue 1) pp:10-12
Publication Date(Web):
DOI:10.1002/adhm.201200444
No abstract is available for this article.
Co-reporter:Cody A. Schoener;Heather N. Hutson
Journal of Biomedical Materials Research Part A 2013 Volume 101A( Issue 8) pp:2229-2236
Publication Date(Web):
DOI:10.1002/jbm.a.34532
Abstract
Amphiphilic polymer carriers were formed by polymerizing a hydrophilic, pH-responsive hydrogel composed of poly(methacrylic–grafted–ethylene glycol) (P(MAA-g-EG)) in the presence of hydrophobic PMMA nanoparticles. These polymer carriers were varied in PMMA nanoparticle content to elicit a variety of physiochemical properties which would preferentially load doxorubicin, a hydrophobic chemotherapeutic, and release doxorubicin locally in the colon for the treatment of colon cancers. Loading levels ranged from 49% to 64% and increased with increasing nanoparticle content. Doxorubicin loaded polymers were released in a physiological model where low pH was used to simulate the stomach and then stepped to more neutral conditions to simulate the upper small intestine. P(MAA-g-EG) containing nanoparticles were less mucoadhesive as determined using a tensile tester, polymer samples, and fresh porcine small intestine. The cytocompatibility of the polymer materials were assessed using cell lines representing the GI tract and colon cancer and were noncytotoxic at varying concentrations and exposure times. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.
Co-reporter:D.C. Forbes, N.A. Peppas
Polymer 2013 Volume 54(Issue 17) pp:4486-4492
Publication Date(Web):2 August 2013
DOI:10.1016/j.polymer.2013.06.047
This work compares material properties of polycationic nanoparticles synthesized using the techniques of UV-initiated polymerization or ARGET ATRP and relates differences in material properties to differences in molecular structure. The nanoparticles are based on the pH-responsive monomer 2-(diethylamino)ethyl methacrylate (DEAEMA) copolymerized with poly(ethylene glycol) methyl ether methacrylate (PEGMA), tert-butyl methacrylate (tBMA), and tetraethylene glycol dimethacrylate (TEGDMA) in a surfactant-stabilized monomer-in-water emulsion to form cross-linked nanoscale hydrogels. ARGET ATRP resulted in a narrower distribution of molecular weight for linear analogs of the polycationic nanoparticles. In addition, ARGET ATRP formulations showed a sharper glass transition than UV-initiated formulations, indicating increased homogeneity. These networks could be used as drug delivery carriers or for other nanogel applications that would benefit from polycationic nanoparticles with high homogeneity.
Co-reporter:Jennifer M. Knipe, Jonathan T. Peters, Nicholas A. Peppas
Nano Today 2013 Volume 8(Issue 1) pp:21-38
Publication Date(Web):February 2013
DOI:10.1016/j.nantod.2012.12.004
Gene therapy is the modification of gene expression to treat a disease. However, efficient intracellular delivery and monitoring of gene therapeutic agents is an ongoing challenge. Use of theranostic agents with suitable targeted, controlled delivery and imaging modalities has the potential to greatly advance gene therapy. Inorganic nanoparticles including magnetic nanoparticles, gold nanoparticles, and quantum dots have been shown to be effective theranostic agents for the delivery and spatiotemporal tracking of oligonucleotides in vitro and even a few cases in vivo. Major concerns remain to be addressed including cytotoxicity, particularly of quantum dots; effective dosage of nanoparticles for optimal theranostic effect; development of real-time in vivo imaging; and further improvement of gene therapy efficacy.Graphical abstractSchematic of gene delivery and imaging by theranostic inorganic nanoparticles.Highlights► Inorganic nanoparticles are effective theranostic agents for gene transfection. ► The response to light or magnetic field imparts noninvasive delivery control and/or spatiotemporal tracking capabilities. ► Further development of in vitro and in vivo testing and increased gene therapy efficacy is necessary for clinical success.
Co-reporter:William B. Liechty, Rebekah L. Scheuerle, Nicholas A. Peppas
Polymer 2013 Volume 54(Issue 15) pp:3784-3795
Publication Date(Web):8 July 2013
DOI:10.1016/j.polymer.2013.05.045
We present the synthesis and characterization of a series of pH-responsive hydrogel nanoparticles based on crosslinked 2-(diethylaminoethyl) methacrylate and poly(ethylene glycol) methyl ether methacrylate (P(DEAEMA-g-PEGMA)). Variants of this polymer were created using t-butyl methacrylate (P(DEAEMA-co-TBMA-g-PEGMA)) or t-butylaminoethyl methacrylate (P(DEAEMA-co-TBAEMA-g-PEGMA)). The synthesis of these materials was accomplished using a facile photoemulsion polymerization. Polymer composition was verified using 1H NMR spectroscopy and closely approximates the copolymer composition estimated from reactivity ratios. Particle formulations possess a dry diameter of 50–65 nm as determined by transmission electron microscopy and collapsed hydrodynamic diameter of 70–100 nm as determined by dynamic light scattering. Dynamic light scattering and pyrene fluorescence spectroscopy were used to probe the pH-dependent phase transition in the hydrogel nanoparticles from collapsed hydrophobe to swollen hydrophile. The inclusion of t-butyl methacrylate served to depress the nanogel pKa and critical pH for phase transition to <6.9 while the inclusion of t-butylamino methacrylate had the opposite effect. We show that these hydrogel nanoparticles possess tunable physicochemical properties that can be adjusted by changing copolymer composition.
Co-reporter:Diane C. Forbes, Nicholas A. Peppas
Journal of Controlled Release 2012 Volume 162(Issue 2) pp:438-445
Publication Date(Web):10 September 2012
DOI:10.1016/j.jconrel.2012.06.037
The promise of short RNA or DNA segments such as siRNAs, antisense oligonucleotides, and transcription factor decoys to treat disease has prompted nearly 40 clinical trials for RNA interference (RNAi)-based therapeutics and more than 100 clinical trials for antisense oligonucleotide-based technologies; in fact, there are promising in vivo and preclinical studies for many hundreds of technologies. Current treatment strategies are largely injection-based, so effective oral delivery platforms for oligonucleotides may result in improved patient comfort and compliance. We analyze recently developed oral delivery methods for short RNA and DNA segments.We analyze six recently developed polymer-based systems for the oral delivery of small RNA and DNA such as siRNA and review nearly 40 clinical trials for RNA interference-based therapeutics.
Co-reporter:David R. Kryscio, Nicholas A. Peppas
Acta Biomaterialia 2012 Volume 8(Issue 2) pp:461-473
Publication Date(Web):February 2012
DOI:10.1016/j.actbio.2011.11.005
Abstract
Molecular recognition is a fundamental and ubiquitous process that is the driving force behind life. Natural recognition elements – including antibodies, enzymes, nucleic acids, and cells – exploit non-covalent interactions to bind to their targets with exceptionally strong affinities. Due to this unparalleled proficiency, scientists have long sought to mimic natural recognition pathways. One promising approach is molecularly imprinted polymers (MIPs), which are fully synthetic systems formed via the crosslinking of organic polymers in the presence of a template molecule, which results in stereo-specific binding sites for this analyte of interest. Macromolecularly imprinted polymers, those synthesized in the presence of macromolecule templates (>1500 Da), are of particular importance because they open up the field for a whole new set of robust diagnostic tools. Although the specific recognition of small-molecular-weight analytes is now considered routine, extension of these efficacious procedures to the protein regime has, thus far, proved challenging. This paper reviews the main approaches employed, highlights studies of interest with an emphasis on recent work, and offers suggestions for future success in the field of macromolecularly imprinted polymers.
Co-reporter:David R. Kryscio, Nicholas A. Peppas
Analytica Chimica Acta 2012 Volume 718() pp:109-115
Publication Date(Web):9 March 2012
DOI:10.1016/j.aca.2012.01.006
Molecularly imprinted polymers are synthetic antibody mimics formed by the crosslinking of organic or inorganic polymers in the presence of an analyte which yields recognitive polymer networks with specific binding pockets for that biomolecule. Surface imprinted polymers were synthesized via a novel technique for the specific recognition of bovine serum albumin (BSA). Thin films of recognitive networks based on 2-(dimethylamino)ethyl methacrylate (DMAEMA) as the functional monomer and varying amounts of either N,N′-methylenebisacrylamide (MBA) or poly(ethylene glycol) (400) dimethacrylate (PEG400DMA) as the crosslinking agent were synthesized via UV free-radical polymerization and characterized. A clear and reproducible increase in recognition of the template BSA was demonstrated for these systems at 1.6–2.5 times more BSA recognized by the MIP sample relative to the control polymers. Additionally, these polymers exhibited selective recognition of the template relative to competing proteins with up to 2.9 times more BSA adsorbed than either glucose oxidase or bovine hemoglobin. These synthetic antibody mimics hold significant promise as the next generation of robust recognition elements in a wide range of bioassay and biosensor applications.Graphical abstractHighlights► We develop a novel surface imprinting technique for the recognition of BSA. ► We address the main obstacles preventing success in the field. ► Reproducible recognition is demonstrated. ► Statistically significant selectivity is shown for the template versus competitors.
Co-reporter:David R. Kryscio;Michael Q. Fleming
Macromolecular Bioscience 2012 Volume 12( Issue 8) pp:1137-1144
Publication Date(Web):
DOI:10.1002/mabi.201200068
Co-reporter:Cody A Schoener;Heather N Hutson;Nicholas A Peppas
Polymer International 2012 Volume 61( Issue 6) pp:874-879
Publication Date(Web):
DOI:10.1002/pi.4219
Abstract
To investigate the delivery of hydrophobic therapeutic agents, a new class of polymer carriers was synthesized. These carriers are composed of two components: (i) a pH-responsive hydrogel composed of methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA-g-EG), and (ii) hydrophobic poly(methyl methacrylate) (PMMA) nanoparticles. Before the P(MAA-g-EG) hydrogel was crosslinked, PMMA nanoparticles were added to the solution and upon exposure to UV light they were photoencapsulated throughout the P(MAA-g-EG) hydrogel structure. The pH-responsive behavior of P(MAA-g-EG) is capable of triggered release of a loaded therapeutic agent, such as a low molecular weight drug or protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). The introduction of PMMA nanoparticles into the hydrogel structure affected the swelling behavior, therapeutic agent loading efficiency, and solute release profiles. In equilibrium swelling conditions the swelling ratio of nanoparticle-containing hydrogels decreased with increasing nanoparticle content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 38% to 51% and increased with increasing hydrophobic content. Release studies from neat P(MAA-g-EG) and the ensuing P(MAA-g-EG) hydrogels containing nanoparticles indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophobicity of the carriers used in these studies. Copyright © 2012 Society of Chemical Industry
Co-reporter:Adam K. Ekenseair, Robert N. Seidel, Nicholas A. Peppas
Polymer 2012 Volume 53(Issue 18) pp:4010-4017
Publication Date(Web):17 August 2012
DOI:10.1016/j.polymer.2012.06.036
The effects of network structure of crosslinked poly(methyl methacrylate) (PMMA) discs on dynamic penetrant transport behavior were investigated through gravimetric integral sorption studies. Samples of P(MMA-co-(EG)xDMA) were synthesized via an iniferter-mediated, thermally-initiated free radical polymerization procedure to produce polymers with controlled variations in network structure by altering the comonomer feed ratios of dimethacrylate crosslinkers and changing the crosslinker interchain bridge length. The front velocity in the Case II transport regime was shown to scale directly with the square root of the crosslinking density over varied thermal and structural conditions, and increasing the crosslinker interchain bridge length moved the observed penetrant transport behavior towards the Fickian regime. The demonstrated ability to tune the dynamic transport behavior through modification of the polymer network structure holds promise as a means to mitigate solvent-induced material failure due to cracking and crazing encountered in many high-tech applications.Graphical abstract
Co-reporter:Adam K. Ekenseair, Richard A. Ketcham, Nicholas A. Peppas
Polymer 2012 Volume 53(Issue 3) pp:776-781
Publication Date(Web):2 February 2012
DOI:10.1016/j.polymer.2011.12.052
High-resolution X-ray computed tomography, a completely non-destructive technique that can be used to visualize features in the interior of opaque solids, was successfully adapted in a novel manner to examine the transport dynamics of methanol into glassy poly(methyl methacrylate) discs synthesized by an iniferter-mediated free radical polymerization. In addition to tracking methanol absorption and dimensional swelling, the time-dependent concentration profiles within the polymer disc were determined with higher resolution, lower scanning times, and no major geometry restrictions compared to previous state-of-the-art techniques. These profiles indicated non-Fickian transport behavior with sharp penetrant fronts and deviations from previously reported swelling profiles.
Co-reporter:Chaenyung Cha, William B. Liechty, Ali Khademhosseini, and Nicholas A. Peppas
ACS Nano 2012 Volume 6(Issue 11) pp:9353
Publication Date(Web):November 8, 2012
DOI:10.1021/nn304773b
As stem cells are a cornerstone of regenerative medicine, research efforts have been extensively focused on controlling their self-renewal and differentiation. It is well-known that stem cells are tightly regulated by a combination of physical and chemical factors from their complex extracellular surroundings; thus, conventional cell culture approaches based purely on using soluble factors to direct stem cell fate have resulted in limited success. To account for the complexities of native stem-cell niches, biomaterials are actively investigated as artificial extracellular matrices in order to mimic the natural microenvironment. This Perspective highlights important areas related to the design of biomaterials to control stem cell behavior, such as cell-responsive ligands, mechanical signals, and delivery of soluble factors.
Co-reporter:Mar Creixell, Nicholas A. Peppas
Nano Today 2012 Volume 7(Issue 4) pp:367-379
Publication Date(Web):August 2012
DOI:10.1016/j.nantod.2012.06.013
There are two main mechanisms by which cells become multidrug resistant (MDR): by increasing drug efflux pumps on the cell membrane and by increasing anti-apoptotic pathways. The use of nanotechnology to develop nanodelivery systems has allowed researchers to overcome limitations of antineoplastic drugs by increasing the solubility of the drug and decreasing the toxicity to healthy tissues. By encapsulating drugs into nanoparticles that bypass the efflux pumps, drug efflux is reduced, hence increasing the intracellular concentration of the drug. siRNA has the ability to disrupt cellular pathways by knocking down genes, opening the door to down regulating anti-apoptotic pathways.The use of nanocarriers to deliver siRNA, prevents both renal clearance and RNase degradation by protecting siRNA chains, increasing their half life in blood. It has been suggested that co-delivering drugs and siRNA together in the same delivery system would be more effective in overcoming resistance of cancer cells than co-treatment of cancer cells with delivery systems carrying either siRNA or drugs. In this study we discuss the progress of nanoscale co-delivery systems in overcoming multidrug cancer resistance.Graphical abstractHighlights► Efflux pumps and apoptotic pathways are the two main mechanisms of cell cancer resistance. ► Nanotechnology helps antineoplastic drugs bypass efflux pumps, increasing the effectivity of the treatment. ► Nanocarriers prevent both renal clearance and RNase degradation of siRNA, increasing their halflife in blood. ► Treatment using co-delivery systems, rather than co-treatment, of drugs and siRNA is more effective in overcoming resistance of cancer cells. ► Double sensitization is a promising strategy to overcome multidrug resistance, but it may increase toxicity to healthy cells.
Co-reporter:David R. Kryscio;Michael Q. Fleming
Biomedical Microdevices 2012 Volume 14( Issue 4) pp:679-687
Publication Date(Web):2012 August
DOI:10.1007/s10544-012-9648-5
Unlike the molecular imprinting of small molecule templates, molecularly imprinted polymers specific to large templates (>1,500 Da), have achieved limited success to date. Conformational stability of these labile macromolecules is one of the main factors that prevent the direct extension of successful procedures from the small molecule regime. We continue our systematic investigation of the effect of common components in macromolecular MIPs on the conformation of protein templates. Circular dichroism was used to show that frequently employed monomers and crosslinkers induce significant changes in the secondary structures of lysozyme and bovine hemoglobin. The extent to which this change occurs, at ligand concentrations far below what are typically used reported work, is cause for concern and provides as rational explanation for the lack of success in this arena. This is because a change in the template structure prior to polymerization would lead to the binding sites formed during polymerization to be specific to this alternate conformation. Subsequent studies with the macromolecule in its native state and the crosslinked network would not be successful. Using this information as a guide, we offer suggestions as to where work in macromolecular imprinted polymers should focus going forward in order for these antibody mimics to reach their vast potential as a new class of biomedical diagnostic devices.
Co-reporter:Mary E. Caldorera-Moore, William B. Liechty, and Nicholas A. Peppas
Accounts of Chemical Research 2011 Volume 44(Issue 10) pp:1061
Publication Date(Web):September 20, 2011
DOI:10.1021/ar2001777
For decades, researchers and medical professionals have aspired to develop mechanisms for noninvasive treatment and monitoring of pathological conditions within the human body. The emergence of nanotechnology has spawned new opportunities for novel drug delivery vehicles capable of concomitant detection, monitoring, and localized treatment of specific disease sites. In turn, researchers have endeavored to develop an imaging moiety that could be functionalized to seek out specific diseased conditions and could be monitored with conventional clinical imaging modalities. Such nanoscale detection systems have the potential to increase early detection of pathophysiological conditions because they can detect abnormal cells before they even develop into diseased tissue or tumors. Ideally, once the diseased cells are detected, clinicians would like to treat those cells simultaneously. This idea led to the concept of multifunctional carriers that could target, detect, and treat diseased cells. The term “theranostics” has been created to describe this promising area of research that focuses on the combination of diagnostic detection agents with therapeutic drug delivery carriers.Targeted theranostic nanocarriers offer an attractive improvement to disease treatment because of their ability to execute simultaneous functions at targeted diseased sites. Research efforts in the field of theranostics encompass a broad variety of drug delivery vehicles, imaging contrast agents, and targeting modalities for the development of an all-in-one, localized detection and treatment system. Nanotheranostic systems that utilize metallic or magnetic imaging nanoparticles can also be used as thermal therapeutic systems. This Account explores recent advances in the field of nanotheranostics and the various fundamental components of an effective theranostic carrier.
Co-reporter:Cody A. Schoener, Heather N. Hutson, Grace K. Fletcher, and Nicholas A. Peppas
Industrial & Engineering Chemistry Research 2011 Volume 50(Issue 22) pp:12556-12561
Publication Date(Web):September 27, 2011
DOI:10.1021/ie201593h
To investigate the delivery of hydrophobic therapeutic agents, a novel class of interpenetrating networks (IPNs) was synthesized and composed of two networks: methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA-g-EG) and poly(n-butyl acrylate) (PBA). The hydrophilic P(MAA-g-EG) networks are pH-responsive hydrogels capable of triggered release of an encapsulated therapeutic agent, such as a low molecular weight drug or a protein, when it passes from the stomach (low pH) to the upper small intestine (neutral pH). PBA is a hydrophobic homopolymer that can affect the IPN swelling behavior, the therapeutic agent loading efficiencies in IPNs, and solute release profiles from IPNs. In dynamic swelling conditions, IPNs had greater swelling ratios than P(MAA-g-EG), but in equilibrium swelling conditions the IPN swelling ratio decreased with increasing PBA content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 21–44%. Release studies from neat P(MAA-g-EG) and the ensuing IPNs indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophilicity of the carriers used in these studies.
Co-reporter:David R. Kryscio, Yue Shi, Pengyu Ren, and Nicholas A. Peppas
Industrial & Engineering Chemistry Research 2011 Volume 50(Issue 24) pp:13877-13884
Publication Date(Web):October 31, 2011
DOI:10.1021/ie201858n
Molecularly imprinted polymers are fully synthetic antibody mimics prepared via the cross-linking of organic monomers in the presence of an analyte. This general procedure is now well developed for small-molecule templates; however, attempts to extend the same techniques to the macromolecular regime have achieved limited success to date. We employ molecular docking simulations to investigate the interactions between albumin, a common protein template, and frequently employed ligands used in the literature at the molecular level. Specifically, we determine the most favorable binding sites for these ligands on albumin and determine the types of noncovalent interactions taking place based on the amino acids present near this binding pocket. Our results show that hydrogen-bonding, electrostatic, and hydrophobic interactions occur between amino acid side chains and ligands. Several interactions are also taking place with the polypeptide backbone, potentially disrupting the protein’s secondary structure. We show that several of the ligands preferentially bind to the same sites on the protein, which indicates that if multiple monomers are used during synthesis, then competition for the same amino acids could lead to nonspecific recognition. Both of these results provide rational explanations for the lack of success to date in the field.
Co-reporter:Diana Snelling VanBlarcom
Biomedical Microdevices 2011 Volume 13( Issue 5) pp:
Publication Date(Web):2011 October
DOI:10.1007/s10544-011-9553-3
Biodegradable, pH-responsive hydrogels composed of poly(methacrylic acid) crosslinked with varying molar percentages of polycaprolactone diacrylate were synthesized. The equilibrium swelling properties of these pH-responsive materials were studied. Methods were developed to incorporate these novel hydrogels as sensing components in silicon-based microsensors. Extremely thin layers of hydrogels were prepared by photopolymerization atop silicon microcantilever arrays that served to transduce the pH-responsive volume change of the hydrogel into an optical signal. Organosilane chemistry allowed covalent adhesion of the hydrogel to the silicon beam. As the hydrogel swelled, the stress generated at the surface between the hydrogel and the silicon caused a beam deflection downward. The resulting sensor demonstrated a maximum sensitivity of 1 nm/5.7×10−5 pH unit. Sensors were tested in protein-rich solutions to mimic biological conditions and found to retain their high sensitivity. The existing theory was evaluated and developed to predict deflection of these composite cantilever beams.
Co-reporter:Omar Z. Fisher, Ali Khademhosseini, Robert Langer and Nicholas A. Peppas
Accounts of Chemical Research 2010 Volume 43(Issue 3) pp:419
Publication Date(Web):December 31, 2009
DOI:10.1021/ar900226q
Although researchers currently have limited ability to mimic the natural stem cell microenvironment, recent work at the interface of stem biology and biomaterials science has demonstrated that control over stem cell behavior with artificial microenvironments is quite advanced. Embryonic and adult stem cells are potentially useful platforms for tissue regeneration, cell-based therapeutics, and disease-in-a-dish models for drug screening. The major challenge in this field is to reliably control stem cell behavior outside the body. Common biological control schemes often ignore physicochemical parameters that materials scientists and engineers commonly manipulate, such as substrate topography and mechanical and rheological properties. However, with appropriate attention to these parameters, researchers have designed novel synthetic microenvironments to control stem cell behavior in rather unnatural ways. In this Account, we review synthetic microenvironments that aim to overcome the limitations of natural niches rather than to mimic them. A biomimetic stem cell control strategy is often limited by an incomplete understanding of the complex signaling pathways that drive stem cell behavior from early embryogenesis to late adulthood. The stem cell extracellular environment presents a miscellany of competing biological signals that keep the cell in a state of unstable equilibrium. Using synthetic polymers, researchers have designed synthetic microenvironments with an uncluttered array of cell signals, both specific and nonspecific, that are motivated by rather than modeled after biology. These have proven useful in maintaining cell potency, studying asymmetric cell division, and controlling cellular differentiation. We discuss recent research that highlights important biomaterials properties for controlling stem cell behavior, as well as advanced processes for selecting those materials, such as combinatorial and high-throughput screening. Much of this work has utilized micro- and nanoscale fabrication tools for controlling material properties and generating diversity in both two and three dimensions. Because of their ease of synthesis and similarity to biological soft matter, hydrogels have become a biomaterial of choice for generating 3D microenvironments. In presenting these efforts within the framework of synthetic biology, we anticipate that future researchers may exploit synthetic polymers to create microenvironments that control stem cell behavior in clinically relevant ways.
Co-reporter:Kristy M. Wood, Gregory M. Stone, Nicholas A. Peppas
Acta Biomaterialia 2010 Volume 6(Issue 1) pp:48-56
Publication Date(Web):January 2010
DOI:10.1016/j.actbio.2009.05.032
Abstract
A novel class of pH-sensitive complexation hydrogels composed of methacrylic acid and functionalized poly(ethylene glycol) (PEG) tethers, referred to as P(MAA-g-EG) WGA, was investigated as an oral protein delivery system. The PEG tethers were functionalized with wheatgerm agglutinin (WGA), a lectin that can bind to carbohydrates in the intestinal mucosa, to improve residence time of the carrier and absorption of the drug at the delivery site. The ability of P(MAA-g-EG) WGA to improve insulin absorption was observed in two different intestinal epithelial models. In Caco-2 cells P(MAA-g-EG) WGA improved insulin permeability 9-fold as compared with an insulin only solution, which was similar to the improvement by P(MAA-g-EG). P(MAA-g-EG) and P(MAA-g-EG) WGA were also evaluated in a mucus-secreting culture that contained Caco-2 and HT29–MTX cells. Insulin permeability was increased 5-fold in the presence of P(MAA-g-EG) and P(MAA-g-EG) WGA. Overall, it is clear that P(MAA-g-EG) WGA enhances insulin absorption and holds great promise as an oral insulin delivery system.
Co-reporter:Justin P. Shofner;Margaret A. Phillips
Macromolecular Bioscience 2010 Volume 10( Issue 3) pp:299-306
Publication Date(Web):
DOI:10.1002/mabi.200900223
Co-reporter:Edgar P. Herrero, Eva M. Martín Del Valle, and Nicholas A. Peppas
Industrial & Engineering Chemistry Research 2010 Volume 49(Issue 20) pp:9811
Publication Date(Web):August 19, 2010
DOI:10.1021/ie101068z
Molecular imprinting is a promising technology that, although successfully used to recognize small molecules, has had many difficulties in recognizing macromolecules such as peptides and proteins. The current technologies used to achieve the macromolecular imprinting are incompatible with diagnosis and recognition in many life sciences applications such as medical devices, food additives, or drug delivery systems that require biocompatible products. We present here a new, biocompatible technology of protein imprinting by means of calcium alginate-based polymer capsules using ionic gelation and without toxic chemicals other than sodium alginate and calcium chloride. These molecular imprinting capsules are capable of recognizing higher quantities of protein than the existing technologies developed until now, with a simple formulation.
Co-reporter:Daniel A. Carr
Journal of Biomedical Materials Research Part A 2010 Volume 92A( Issue 2) pp:504-512
Publication Date(Web):
DOI:10.1002/jbm.a.32395
Abstract
Hydrogels of poly(methacrylic acid-co-N-vinyl pyrrolidone) were synthesized and evaluated for their use as carriers for oral protein delivery. Insulin loading efficiencies were determined to be near 90% for carriers crosslinked with ethylene glycol dimethacrylate with corresponding weight incorporation levels near 12%. Although no insulin was released in gastric conditions, as desired, near instantaneous release occurred when the pH was raised to values typical of the intestinal area. Cytocompatibility studies with Caco-2 and Caco-2/HT29-MTX cultures demonstrated that microparticles did not elicit toxic effects at concentrations up to 5.0 mg/mL. Insulin transport studies revealed that the carriers did not disrupt the cell layer and thus did not change the insulin permeability in the apical-to-basolateral direction. Therefore, microparticles of this system were best suited for oral delivery of therapeutic agents that do not require transport facilitation. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
Co-reporter:Tania Betancourt;Juan Pardo;Ken Soo
Journal of Biomedical Materials Research Part A 2010 Volume 93A( Issue 1) pp:175-188
Publication Date(Web):
DOI:10.1002/jbm.a.32510
Abstract
Effective oral delivery of proteins is impeded by steep pH gradients and proteolytic enzymes in the gastrointestinal tract, as well as low absorption of the proteins into the bloodstream because of their size, charge, or solubility. In this work, pH-responsive complexation hydrogels of poly(itaconic acid) (PIA) with poly(ethylene glycol) (PEG) grafts were synthesized for applications in oral drug delivery. These hydrogels were expected to be in collapsed configuration at low pH because of hydrogen bonding between PIA carboxyl groups and PEG, and to swell with increasing pH because of charge repulsion between deprotonated carboxylic acid groups. Hydrogels were prepared by UV-initiated free radical polymerization using tetraethylene glycol as the crosslinking agent and Irgacure® 2959 as the initiator. The effect of monomer ratios, crosslinking ratio, and solvent amount on the properties of the hydrogels were investigated. The composition of the hydrogels was confirmed by Fourier transform infrared spectroscopy. Equilibrium swelling studies in the pH range of 1.2–7 revealed that the extent of swelling increased with increasing pH up to a pH of about 6, when no further carboxylic acid deprotonation occurred. Studies in Caco-2 colorectal carcinoma cells confirmed the cytocompatibility of these materials at concentrations of up to 5 mg/mL. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res 2010
Co-reporter:Daniel A. Carr, Marta Gómez-Burgaz, Mathilde C. Boudes, and Nicholas A. Peppas
Industrial & Engineering Chemistry Research 2010 Volume 49(Issue 23) pp:11991-11995
Publication Date(Web):September 29, 2010
DOI:10.1021/ie1008025
The hydrogel system of poly(methacrylic acid-co-N-vinyl pyrrolidone) P(MAA-co-NVP) was evaluated for use as an oral delivery system for growth hormone and salmon calcitonin. These proteins were selected because of their therapeutic importance and the insight provided by evaluating the delivery of a therapeutic agent with a high molecular weight (growth hormone) and a drug with a high isoelectric point (salmon calcitonin). Growth hormone loading and release studies were performed for both P(MAA-co-NVP) and P(MAA-g-poly(ethylene glycol)) (P(MAA-g-PEG)). Loading efficiencies for the respective systems were 50.9 ± 1.8% and 57.8 ± 4.1%; weight incorporation of the protein was determined to be 3.5 ± 0.1% and 4.0 ± 0.3%. At pH 7.4, growth hormone release of 90% occurred within 45 min for P(MAA-co-NVP) microparticles; 90% release was not achieved with P(MAA-g-PEG) microparticles until 180 min. At pH 1.2, no release occurred from P(MAA-co-NVP) microparticles, but 10% release occurred from P(MAA-g-PEG) microparticles. Salmon calcitonin loading and release were shown to be affected by the negative charges of deprotonated MAA; for systems with monomer molar feed ratios of 4:1, 1:1, and 1:4 MAA/NVP, loading efficiencies were determined to be 70.6 ± 3.0%, 25.3 ± 1.2%, and 1.6 ± 1.3%. Salmon calcitonin release was minimal from the copolymer with 4:1 MAA/NVP monomer feed at pH 7.4. The release improved when the pH was raised above physiological levels. These studies confirmed that P(MAA-co-NVP) was an effective oral delivery system for high molecular weight drugs, but improvements are needed before the system could be utilized for high isoelectric point therapeutic delivery.
Co-reporter:Steve R. Marek, Charles A. Conn, Nicholas A. Peppas
Polymer 2010 Volume 51(Issue 6) pp:1237-1243
Publication Date(Web):11 March 2010
DOI:10.1016/j.polymer.2010.01.060
The effect of polymer composition and polymerization parameters such as comonomers, crosslinking ratio, and polymerization method, on the surface characteristics, surface chemistry, and swelling response of crosslinked 2-(diethylaminoethyl methacrylate) (DEAEM) and polyethylene glycol monoethyl ether monomethacrylate (PEGMMA) nanogels was studied. A novel inverse emulsion polymerization method was developed, which formed latex nanoparticles on the order of 100–400 nm. The properties of these nanogels were compared to microparticles synthesized via solution polymerization. The new polymerization method allowed the incorporation of PEG surface tethers of lengths 400 Da up to 2000 Da. Surface tethers successfully decreased the ζ-potential of these nanogels from 70 mV to 30 mV in acidic conditions and from −60 mV to 2 mV in basic media. Nanogels swelled from 100 nm in basic media to 800 nm in acidic media due to the protonation of the tertiary amine on DEAEM.
Co-reporter:Margaret A. Phillips, Martin L. Gran, Nicholas A. Peppas
Nano Today 2010 Volume 5(Issue 2) pp:143-159
Publication Date(Web):April 2010
DOI:10.1016/j.nantod.2010.03.003
Nanomaterials for targeted delivery are uniquely capable of localizing delivery of therapeutics and diagnostics to diseased tissues. The ability to achieve high, local concentrations of drugs or image contrast agents at a target site provides the opportunity for improved system performance and patient outcomes along with reduced systemic dosing. In this review, the design of targeted nanodelivery systems is discussed with an emphasis on in vivo performance, the physicochemical properties that affect localization at the target site, and the incorporation of therapeutic drugs into these systems.
Co-reporter:Carolyn L. Bayer;Alper A. Konuk
Biomedical Microdevices 2010 Volume 12( Issue 3) pp:435-442
Publication Date(Web):2010 June
DOI:10.1007/s10544-010-9400-y
Human disease processes are often characterized by a deviation from the normal physiological concentration of critical biomarkers. The detection of disease biomarkers requires the development of novel sensing methods which are sensitive, specific, efficient and low-cost. To address this need, the ability of a device, which incorporates a film of polymer acid doped polyaniline, to respond to proteins at physiological pH and ionic strength was assessed. The conductive polymer was found to respond by changing conductivity in the presence of biomolecules, demonstrating a direct chemical to electronic transduction method. In future work, specificity can be incorporated into the system by integrating the conductive polymer with a protein selective film. The demonstration of a conductive polymer which is responsive to proteins at physiological conditions is a step towards the integration of these materials into implantable sensing systems.
Co-reporter:Bron V. Slaughter;Shahana S. Khurshid;Omar Z. Fisher;Ali Khademhosseini
Advanced Materials 2009 Volume 21( Issue 32-33) pp:3307-3329
Publication Date(Web):
DOI:10.1002/adma.200802106
Abstract
Hydrogels, due to their unique biocompatibility, flexible methods of synthesis, range of constituents, and desirable physical characteristics, have been the material of choice for many applications in regenerative medicine. They can serve as scaffolds that provide structural integrity to tissue constructs, control drug and protein delivery to tissues and cultures, and serve as adhesives or barriers between tissue and material surfaces. In this work, the properties of hydrogels that are important for tissue engineering applications and the inherent material design constraints and challenges are discussed. Recent research involving several different hydrogels polymerized from a variety of synthetic and natural monomers using typical and novel synthetic methods are highlighted. Finally, special attention is given to the microfabrication techniques that are currently resulting in important advances in the field.
Co-reporter:Daniel A. Carr
Macromolecular Bioscience 2009 Volume 9( Issue 5) pp:497-505
Publication Date(Web):
DOI:10.1002/mabi.200800235
Co-reporter:Omar Z. Fisher and Nicholas A. Peppas
Macromolecules 2009 Volume 42(Issue 9) pp:
Publication Date(Web):April 14, 2009
DOI:10.1021/ma801966r
A novel method for synthesizing nanoscale polymer networks that swell in acidic media is described here using photoinitiated emulsion polymerization. These nanomatrices consist of a cross-linked core of poly[2-(diethylamino)ethyl methacrylate] surface grafted with poly(ethylene glycol) (PDGP) with an average diameter of 50−150 nm. Control over mesh size, surface charge, encapsulation efficiency, and in vitro biocompatibility was obtained by varying cross-linking density. The ability to image nanomatrices in their dry state using conventional scanning electron microscopy was made possible by increasing cross-linking density. Theoretical calculations of matrix mesh sizes were supported by the encapsulation of both insulin and colloidal gold 2−5 nm in diameter. The ability to sequester and control the aggregation of an inorganic phase confirmed their use as a nanocomposite matrix material. These networks could be used as imaging agents, drug delivery devices, or components of sensing devices.
Co-reporter:Omar Z. Fisher;Timothy Kim;Stephen R. Dietz
Pharmaceutical Research 2009 Volume 26( Issue 1) pp:
Publication Date(Web):2009 January
DOI:10.1007/s11095-008-9704-2
In this work a novel pH-responsive nanoscale polymer network was investigated for potential applications in nanomedicine. These consisted of a polybasic core surface stabilized with poly(ethylene glycol) grafts. The ability to control swelling properties via changes in core hydrophobicity and crosslinking feed density was assessed. The nanomatrices were also evaluated in vitro as nanocarriers for targeted intracellular delivery of macromolecules.Photo-emulsion polymerization was used to synthesize poly[2-(diethylamino)ethyl methacrylate-co-t-butyl methacrylate-g-poly(ethylene glycol)] (PDBP) nanomatrices. These were characterized using NMR, dynamic and electrophoretic light scattering, electron microscopy. The cytocompatibility and cellular uptake of nanomatrices was measured using the NIH/3T3 and A549 cell lines.PDBP nanomatrices had a dry diameter of 40–60 nm and a hydrodynamic diameter of 70–90 nm in the collapsed state. Maximum volume swelling ratios from 6–22 were obtained depending on crosslinking feed density. Controlling the hydrophobicity of the networks allowed for control over the critical swelling pH without a significant loss in maximal volume swelling. The effect of PDBP nanomatrices on cell viability and cell membrane integrity depended on crosslinking feed density. Cell uptake and cytosolic delivery of FITC-albumin was enhanced from clathrin-targeting nanocarriers. The uptake resulted in nuclear localization of the dye in a cell type dependent fashion.The results of this work indicate that PDBP nanomatrices have tunable swelling properties. The networks were cytocompatible and proved to be suitable agents for intracellular delivery.
Co-reporter:Nicole M. Bergmann, Nicholas A. Peppas
Progress in Polymer Science 2008 Volume 33(Issue 3) pp:271-288
Publication Date(Web):March 2008
DOI:10.1016/j.progpolymsci.2007.09.004
The hierarchical system of recognition in nature is based on interaction between the smallest elements in a matrix such as molecules and the cumulative interactions of larger parts such as the helices and sheets of proteins. The active sites of enzymes are composed of several amino acids, which bind the ligand molecules in a very specific way. However, the activity of the site is dependent on the stabilization of the three-dimensional structure by the interactions of hundreds of other residues. Likewise, a biomimetic polymeric network can be prepared by designing interactions between the building blocks of a biocompatible network and the desired specific analyte and stabilizing these interactions by a three-dimensional structure. This structure is at the same time flexible enough to allow for diffusion of solvent and analytes into and out of the network. This paper reviews advances in molecular recognition systems, and outlines methods of making molecularly imprinted polymer systems that can recognize large molecular weight analytes.
Co-reporter:Carolyn L. Bayer, Nicholas A. Peppas
Journal of Controlled Release 2008 Volume 132(Issue 3) pp:216-221
Publication Date(Web):18 December 2008
DOI:10.1016/j.jconrel.2008.06.021
Recent developments in drug delivery have been directed towards the development of self sustained systems that would be able to recognize various biomarkers and respond to their high concentrations, leading to therapeutic action. While such systems are diagnostic in nature, their use as therapeutic delivery systems is being expanded most through work done in academic institutions and small biotech companies. Here, we examine the basis of such recognitive delivery systems and we identify their main mechanisms and transducing action, especially in terms of conductive studies. Selected experimental results are given to indicate the importance and success of these methods.
Co-reporter:Nicole M. Bergmann and Nicholas A. Peppas
Industrial & Engineering Chemistry Research 2008 Volume 47(Issue 23) pp:9099
Publication Date(Web):August 7, 2008
DOI:10.1021/ie071270u
Using a configurational biomimetic imprinting technique, we prepared a family of molecularly imprinting polyacrylamide polymers with recognition for the template protein chicken egg white lysozyme in aqueous solution. We showed the formation of a network with specific recognitive sites for the template. To determine the overall macroscopic properties of protein-imprinted gel, we utilized a variety of tools. When gels were examined using scanning electron microscopy, definite morphological differences were observed between the CBIP polymers and the controls. Additionally, Fourier transform infrared spectroscopy determined that the presence of template had no effect upon the overall gel composition, whereas differential scanning calorimetry showed no significant change in the molecular weight between cross-links between CBIP polymers and nonimprinted polymers. Using these results, a theory of gel formation was proposed to try to elucidate gel formation in the presence of a macromolecule.
Co-reporter:Terry G. Farmer Jr., Thomas F. Edgar and Nicholas A. Peppas
Industrial & Engineering Chemistry Research 2008 Volume 47(Issue 24) pp:10053
Publication Date(Web):November 12, 2008
DOI:10.1021/ie070957b
A mathematical model describing glucose-dependent pH swelling and insulin release is developed for pH-sensitive cationic hydrogels in which glucose oxidase and catalase have been immobilized and insulin imbibed. Glucose-based swelling and insulin release are simulated for intravenously injected particles at various design conditions. The effects of particle size, the number of injected particles, insulin loading, enzyme loading, monomer functional group loading and pKa, and hydrogel cross-linking ratio on insulin release and glucose sensitivity are investigated to optimally design the device for use. Increased insulin infusion is shown to result from increasing the number of circulating gels, increasing the collapsed particle size, or decreasing the cross-linking ratio of the system. Release duration is shown to be dependent only upon the particle size and the achievable diffusion coefficient of the system. Glucose sensitivity, as measured by gluconic acid production and by the system pH, is a function of glucose oxidase loading and the concentration and pKa of the monomer used in the hydrogel. The necessary submicrometer particle size results in very rapid device insulin depletion. When the device is designed without considering constraints, the resulting release profile resembles that of an on/off switching mechanism. Future work will focus on simulations of swelling and release when the device is implanted in an alternative administration site.
Co-reporter:Kristy M. Wood, Gregory M. Stone and Nicholas A. Peppas
Biomacromolecules 2008 Volume 9(Issue 4) pp:
Publication Date(Web):March 11, 2008
DOI:10.1021/bm701274p
Insulin was loaded into hydrogel microparticles after two hours with loading efficiencies greater than 70% for both poly(methacrylic acid-grafted-ethylene glycol) (P(MAA-g-EG)) and poly(methacrylic acid-grafted-ethylene glycol) functionalized with wheat germ agglutinin (P(MAA-g-EG) WGA). The pH-responsive release results demonstrated that the pH shift from the stomach to the small intestine can be used as a physiologic trigger to release insulin from P(MAA-g-EG) and P(MAA-g-EG) WGA microparticles, thus limiting release of insulin into the acidic environment of the stomach. Microplates were successfully treated with PGM to create a surface that allowed for specific binding between mucins and lectins. The 1% PGM treatment followed by a 2 h BSA blocking step gave the most consistent results when incubated with F-WGA. In addition, the PGM-treated microplates were shown to create specific interactions between F-WGA and the PGM by use of a competitive carbohydrate. The 1% PGM treated microplates were also used to show that adhesion was improved in the P(MAA-g-EG) WGA microparticles over the P(MAA-g-EG) microparticles. The interaction between the PGM-treated microplate and P(MAA-g-EG) WGA was again shown to be specific by adding a competitive carbohydrate, whilethe interaction between P(MAA-g-EG) and the PGM-treated microplate was nonspecific. Cellular monolayers were used as another method for demonstrating that the functionalized microparticles increase adhesion over the nonfunctionalized microparticles. This work has focused on improving the mucoadhesive nature of P(MAA-g-EG) by functionalizing these hydrogel carriers with wheat germ agglutinin (WGA) to create a specific mucosal interaction and then evaluating the potential of these carriers as oral insulin delivery systems by in vitro methods. From these studies, it is concluded that the addition of the WGA on the microparticles produces a specific adhesion to carbohydrate-containing surfaces and that P(MAA-g-EG) WGA shows great promise as an oral insulin delivery system.
Co-reporter:Donald E. Owens III;Jackson K. Eby;Yicun Jian
Journal of Biomedical Materials Research Part A 2007 Volume 83A(Issue 3) pp:692-695
Publication Date(Web):25 MAY 2007
DOI:10.1002/jbm.a.31284
The objective of this study was to synthesize and characterize a thermally responsive polymer-metal nanocomposite system comprised of a solid gold nanoparticle core and thermally responsive interpenetrating polymer network (IPN) shell, which was surface functionalized or PEGylated with a covalently bound linear poly(ethylene glycol) chain layer. Gold nanoparticles (50 nm diameter) were prepared using standard gold chloride and citrate reduction method. These particles were then encapsulated inside of a polyacrylamide (PAAm)/poly(acrylic acid) (PAA) IPN shell via an in situ inverse emulsion polymerization. The surface of the nanocomposite system was then PEGylated via covalent grafting of a linear methoxy-PEG-N-hydroxysuccinimide (M.W. 3400) to the primary amine groups of the PAAm network. Scanning and transmission electron microscopy were used to confirm the successful synthesis and encapsulation of gold nanoparticles within the IPN shell. Dynamic light scattering was used to examine the temperature swelling response of the IPN particles. Zeta-potential analysis was used to confirm the successful PEGylation of the final nanocomposite system. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res 2007
Co-reporter:J. Z. Hilt;N. A. Peppas;A. Khademhosseini;R. Langer
Advanced Materials 2006 Volume 18(Issue 11) pp:1345-1360
Publication Date(Web):29 MAY 2006
DOI:10.1002/adma.200501612
Hydrophilic polymers are the center of research emphasis in nanotechnology because of their perceived “intelligence”. They can be used as thin films, scaffolds, or nanoparticles in a wide range of biomedical and biological applications. Here we highlight recent developments in engineering uncrosslinked and crosslinked hydrophilic polymers for these applications. Natural, biohybrid, and synthetic hydrophilic polymers and hydrogels are analyzed and their thermodynamic responses are discussed. In addition, examples of the use of hydrogels for various therapeutic applications are given. We show how such systems' intelligent behavior can be used in sensors, microarrays, and imaging. Finally, we outline challenges for the future in integrating hydrogels into biomedical applications.
Co-reporter:Ebru Oral
Journal of Biomedical Materials Research Part A 2006 Volume 78A(Issue 1) pp:205-210
Publication Date(Web):6 APR 2006
DOI:10.1002/jbm.a.30725
Highly cross-linked 2-hydroxyethyl methacrylate (HEMA) and poly(ethylene glycol) dimethacrylate with poly(ethylene glycol) of molecular weight 600 (PEG600DMA) were molecularly imprinted with hydrophilic templates glucose and proxyphylline using water as a solvent. Glucose-imprinted polymers showed increased recognitive capacity compared to nonimprinted polymers as well as increased glucose uptake compared to structurally similar galactose and methylglucopyranoside. Increasing glucose concentration in the imprinting mixture resulted in higher capacity and selective binding. Similar results were obtained for proxyphylline-imprinted P(HEMA-co-PEG600DMA) polymers, where the proxyphylline uptake was higher than structurally similar theophylline. Glucose-imprinted networks also showed diffusion coefficients on the order of 10−6 cm2/s, conducive to applications in drug delivery and tissue engineering. This work showed that using pairs of hydrogen-bonding monomers and templates, selective, high-affinity sites could be created despite nonspecific binding. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006
Co-reporter:Nikhil J. Kavimandan, Elena Losi, Nicholas A. Peppas
Biomaterials 2006 Volume 27(Issue 20) pp:3846-3854
Publication Date(Web):July 2006
DOI:10.1016/j.biomaterials.2006.02.026
A variety of approaches have been investigated to address the problems associated with oral insulin delivery, but the bioavailability of oral insulin is still low. Insulin is rapidly degraded by the enzymes in the GI tract and is not transported across the epithelial barrier easily. The oral insulin formulation developed in this work makes use of complexation hydrogels for oral delivery of insulin bioconjugates. The insulin bioconjugates synthesized in this work consist of insulin bound to transferrin molecule which can be uptaken by the epithelial cells. The conjugates can increase the permeability of insulin across the epithelial barrier by receptor-mediated transcytosis. The transferrin in the conjugate is also shown to stabilize insulin in the presence of intestinal enzymes. Use of complexation hydrogels for delivery of insulin–transferrin conjugate may greatly increase the bioavailability of oral insulin. This is because, the complexation hydrogels are known to exhibit characteristics that make them ideal candidates for oral protein delivery. They can also inhibit the degradation of insulin in the GI tract. Thus, combination of these two approaches may provide an innovative platform for oral insulin delivery.
Co-reporter:Laura Serra, Joseph Doménech, Nicholas A. Peppas
Biomaterials 2006 Volume 27(Issue 31) pp:5440-5451
Publication Date(Web):November 2006
DOI:10.1016/j.biomaterials.2006.06.011
Controlled drug release devices of pH-sensitive, complexing poly(acrylic acid-g-ethylene glycol) (P(AA-g-EG)) hydrogels were prepared by free radical solution UV polymerization. The effects of hydrogel composition, polymerization conditions and surrounding environment on theophylline release kinetics and drug transport mechanisms were evaluated in these P(AA-g-EG) polymer networks. Release studies indicated a dependence of the theophylline release kinetics and diffusion coefficients on the hydrogel structure, polymerization conditions and pH of the environment. The theophylline transport mechanism was studied by fitting experimental data to five different model equations and calculating the corresponding parameters. The Akaike information criterion was also considered to elucidate the best-fit equation. Results indicated that in most release cases, the drug release mechanism was anomalous (non-Fickian). This indicates that such systems may, under certain conditions, provide release characteristics approaching zero-order release. The pH of the dissolution medium appeared to have a strong effect on the drug transport mechanism. At more basic pH values, Case II transport was observed, indicating a drug release mechanism highly influenced by macromolecular chain relaxation. The results obtained in this research work lead us to the conclusion that P(AA-g-EG) hydrogels can be successfully used as drug delivery systems. Their versatility to be designed with specifically tuned release properties renders these biomaterials promising pharmaceutical carriers for therapeutic agents.
Co-reporter:James Blanchette
Journal of Biomedical Materials Research Part A 2005 Volume 72A(Issue 4) pp:381-388
Publication Date(Web):21 JAN 2005
DOI:10.1002/jbm.a.30243
Hydrogel nanospheres composed of methacrylic acid and poly(ethylene glycol) were loaded with bleomycin and tested as a potential oral delivery system for chemotherapeutic agents. The gastrointestinal epithelium was modeled through the use of Caco-2 monolayers for studies of permeation enhancement by the carriers as well as bleomycin transport. Bleomycin efficacy following release from the carrier was evaluated with a DLD-1 tumor cell model. The nanospheres release bleomycin in response to a pH increase similar to that seen when passing from the stomach into the upper small intestine. These carriers can also increase the permeability of a model of the epithelial barrier, which would hopefully improve drug transport into the bloodstream. Efficacy studies using a tumor cell model showed retention of activity for bleomycin following loading and release from the nanospheres. The carriers described performed well during in vitro evaluation and can hopefully expand the spectrum of chemotherapeutic agents capable of being administered orally. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res 72A: 381–388, 2005
Co-reporter:Nicholas A. Peppas;Ebru Oral
Journal of Biomedical Materials Research Part A 2004 Volume 68A(Issue 3) pp:439-447
Publication Date(Web):9 JAN 2004
DOI:10.1002/jbm.a.20076
Polymeric networks that have inherent capabilities to recognize different molecules and chemical changes in their environment are the next generation of materials that will aid in the diagnosis and treatment of diseases. We have prepared new networks based on star polymers that were designed to be responsive and recognitive. Using molecular imprinting with D-glucose and crosslinking with poly(ethylene glycol) dimethacrylate with an ethylene glycol chain of nominal molecular weight 600, we prepared star polymer networks, which exhibited over 300% more uptake for D-glucose compared to D-fructose. Using copolymerization with methacrylic acid, we prepared star polymer networks with pH-sensitivity, which showed a sharp transition in swelling around a pH of 4.5. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 439–447, 2004
Co-reporter:Hideki Ichikawa
Journal of Biomedical Materials Research Part A 2003 Volume 67A(Issue 2) pp:609-617
Publication Date(Web):6 OCT 2003
DOI:10.1002/jbm.a.10128
Poly[methacrylic acid-grafted-poly(ethylene glycol)] [P(MAA-g-EG)] is a complexation hydrogel molecularly designed for oral peptide delivery. In this work, the cytotoxicity and insulin-transport enhancing effect of P(MAA-g-EG) microparticles on intestinal epithelial cells were evaluated using Caco-2 cell monolayers. A series of P(MAA-g-EG) microparticles with different polymer compositions were prepared by a photo-initiated free radical solution polymerization and subsequent pulverization. The hydrogel microparticles were preswollen in either Ca2+-containing (CM+) or Ca2+-free medium (CM−; pH 7.4) and applied to the apical side of the Caco-2 monolayers. No significant cytotoxic effects, as determined by a calorimetric assay with P(MAA-g-EG) microparticles preswollen in the CM+, were observed at doses ranging from 3 to 31 mg/cm2 of cell monolayer. Transepithelial electrical resistance (TEER) measurements showed that the P(MAA-g-EG) microparticles induced a Ca2+ concentration-dependent lowering in TEER values. The reduction effect in CM− media was greater than that in CM+ media (17 ± 2% reduction in CM+ and 45 ± 3% reduction in CM−, respectively). Insulin transport in the presence of the preswollen P(MAA-g-EG) microparticles was also strongly depended on the Ca2+ concentration in the medium. The respective estimated permeability for insulin alone and the insulin with hydrogels in CM+ were 0.77 and 1.16 × 10−8 cm/s, whereas those in CM− were 1.18 and 24.78 × 10−8 cm/s. The results demonstrate that the P(MAA-g-EG) hydrogel microparticles could be used as a cytocompatible carrier possessing the transport-enhancing effect of insulin on the intestinal epithelial cells. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 67A: 609–617, 2003
Co-reporter:Bumsang Kim;Kristen La Flamme
Journal of Applied Polymer Science 2003 Volume 89(Issue 6) pp:1606-1613
Publication Date(Web):23 MAY 2003
DOI:10.1002/app.12337
There have been many attempts to use anionic hydrogels as oral protein delivery carriers because of their pH-responsive swelling behavior. The dynamic swelling behavior of poly(methacrylic acid-co-methacryloxyethyl glucoside) and poly(methacrylic acid-g-ethylene glycol) hydrogels was investigated to determine the mechanism of water transport through these anionic hydrogels. The exponential relation Mt/M∞ = ktn (where Mt is the mass of water absorbed at time t and M∞ is the mass of water absorbed at equilibrium) was used to calculate the exponent (n) describing the Fickian or non-Fickian behavior of swelling polymer networks. The mechanism of water transport through these gels was significantly affected by the pH of the swelling medium. The mechanism of water transport became more relaxation-controlled in a swelling medium of pH 7.0, which was higher than pKa of the gels. The experimental results of the time-dependent swelling behaviors of the gels were analyzed with several mathematical models. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1606–1613, 2003
Co-reporter:William Leobung;Hideki Ichikawa;Yoshinobu Fukumori
Journal of Applied Polymer Science 2003 Volume 87(Issue 10) pp:1678-1684
Publication Date(Web):30 DEC 2002
DOI:10.1002/app.11612
Poly(ethylene glycol)-based nanoparticles have received significant attention in the field of biomedicine. When they are copolymerized with pH- or temperature-sensitive comonomers, their small size allows them to respond very quickly to changes in the environment, including changes in the pH, ionic strength, and temperature. In addition, the high surface-to-volume ratio makes them highly functionalized. In this work, nanoparticles composed of temperature-sensitive poly(N-isopropylacrylamide), poly(ethylene glycol) 400 dimethacrylate, and poly(ethylene glycol) 1000 methacrylate were prepared by a thermally initiated, free-radical dispersion polymerization method. The temperature-responsive behavior of the hydrogel nanoparticles was characterized by the study of their particle size with photon correlation spectroscopy. The size of the nanoparticles varied from 200 to 1100 nm and was a strong function of the temperature of the system, from 5 to 40°C. The thermal, structural, and morphological characteristics were also investigated. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1678–1684, 2003
Co-reporter:Jennifer H. Ward;Kimberly Furman
Journal of Applied Polymer Science 2003 Volume 89(Issue 13) pp:3506-3519
Publication Date(Web):15 JUL 2003
DOI:10.1002/app.12519
The design of novel biomaterials for applications in biological recognition, drug delivery, or diagnostics requires a judicious choice of preparation conditions and methods for the production of well-characterized 3-dimensional structures, preferably by benign processes. In this work, the polymerization of poly(ethylene glycol) (PEG) methacrylates was examined by kinetic gelation modeling and kinetic analysis in order to ascertain the factors affecting the resulting structure. The kinetics of the polymerization and structure of the final polymer network are strongly affected by the length of the PEG graft chain. The propagation of the polymer chains becomes increasingly diffusion limited with the incorporation of longer PEG grafts. In addition, a more heterogeneous network consisting of numerous microgel regions is produced as the length of the PEG graft is increased. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 3506–3519, 2003
Co-reporter:Ebru Oral;Mark E. Byrne;J. Zachary Hilt
Polymers for Advanced Technologies 2002 Volume 13(Issue 10‐12) pp:798-816
Publication Date(Web):6 JAN 2003
DOI:10.1002/pat.272
Engineering the molecular design of biomaterials by controlling recognition and specificity is the first step in coordinating and duplicating complex biological and physiological processes. Studies of protein binding domains reveal molecular architectures with specific chemical moieties that provide a framework for selective recognition of target biomolecules in aqueous environment. By matching functionality and positioning of chemical residues, we have been successful in designing biomimetic polymer networks that specifically bind biomolecules in aqueous environments. Our work addresses the preparation, behavior, and dynamics of the three-dimensional structure of biomimetic polymers for selective recognition via non-covalent complexation. In particular, the synthesis and characterization of recognitive gels for the macromolecular recognition of D-glucose is highlighted. Novel copolymer networks containing poly(ethylene glycol) (PEG) and functional monomers such as acrylic acid, 2-hydroxyethyl methacrylate, and acrylamide were synthesized in dimethyl sulfoxide (polar, aprotic solvent) and water (polar, protic solvent) via UV-free radical polymerization. Polymers were characterized by single and competitive equilibrium and kinetic binding studies, single and competitive fluorescent and confocal microscopy studies, dynamic network swelling studies, and ATR-FTIR. Results qualitatively and quantitatively demonstrate effective glucose-binding polymers in aqueous solvent. Owing to the presence of template, the imprinting process resulted in a more macroporous structure as exhibited by dynamic swelling experiments and confocal microscopy. Polymerization kinetic studies suggest that the template molecule has more than a dilution effect on the polymerization, and the effect of the template is related strongly to the rate of propagation. In addition, PEG containing networks were micropatterned to fabricate microstructures, which would be the basis for micro-diagnostic and tissue engineering devices. Utilizing photolithography techniques, polymer micropatterns of a variety of shapes and dimensions have been created on polymer and silicon substrates using UV free-radical polymerizations with strict spatial control. Micropatterns were characterized using optical microscopy, SEM, and profilometry. The processes and analytical techniques presented are applicable to other stimuli-sensitive and recognitive networks for biomolecules, in which hydrogen bonding, hydrophobic, or ionic contributions will direct recognition. Further developments are expected to have direct impact on applications such as analyte controlled and modulated drug and protein delivery, drug and biological elimination, drug targeting, tissue engineering, and micro- or nano-devices. This work is supported by NSF Grant DGE-99-72770. Copyright © 2003 John Wiley & Sons, Ltd.
Co-reporter:Amey S. Puranik, Ludovic P. Pao, Vanessa M. White, Nicholas A. Peppas
European Journal of Pharmaceutics and Biopharmaceutics (November 2016) Volume 108() pp:196-213
Publication Date(Web):1 November 2016
DOI:10.1016/j.ejpb.2016.09.007
pH-responsive, polyanionic nanoscale hydrogels were developed for the oral delivery of hydrophobic therapeutics, such as common chemotherapeutic agents. Nanoscale hydrogels were designed to overcome physicochemical and biological barriers associated with oral delivery of hydrophobic therapeutics such as low solubility and poor permeability due to P-glycoprotein related drug efflux. Synthesis of these nanoscale materials was achieved by a robust photoemulsion polymerization method. By varying hydrophobic monomer components, four formulations were synthesized and screened for optimal physicochemical properties and in vitro biocompatibility. All of the responsive nanoscale hydrogels were capable of undergoing a pH-dependent transition in size. Depending on the selection of the hydrophobic monomer, the sizes of the nanoparticles vary widely from 120 nm to about 500 nm at pH 7.4. Polymer composition was verified using Fourier transform infrared spectroscopy and 1H-nuclear magnetic resonance spectroscopy. Polymer biocompatibility was assessed in vitro with an intestinal epithelial cell model. All formulations were found to have no appreciable cytotoxicity, defined as greater than 80% viability after polymer incubation. We demonstrate that these nanoscale hydrogels possess desirable physicochemical properties and exhibit agreeable in vitro biocompatibility for oral delivery applications.Download high-res image (119KB)Download full-size image
Co-reporter:Heidi R Culver, Adam M Daily, Ali Khademhosseini, Nicholas A Peppas
Current Opinion in Chemical Engineering (May 2014) Volume 4() pp:105-113
Publication Date(Web):1 May 2014
DOI:10.1016/j.coche.2014.02.001
•Combining nanomaterials and responsive polymers is beneficial for medicine.•Responsive materials are useful for controlled release, imaging, and sensing.•Scalable, low-cost fabrication techniques will promote clinical translation.There is a bright future in the development and utilization of nanoscale systems based on intelligent materials that can respond to external input providing a beneficial function. Specific functional groups can be incorporated into polymers to make them responsive to environmental stimuli such as pH, temperature, or varying concentrations of biomolecules. The fusion of such ‘intelligent’ biomaterials with nanotechnology has led to the development of powerful therapeutic and diagnostic platforms. For example, targeted release of proteins and chemotherapeutic drugs has been achieved using pH-responsive nanocarriers while biosensors with ultra-trace detection limits are being made using nanoscale, molecularly imprinted polymers. The efficacy of therapeutics and the sensitivity of diagnostic platforms will continue to progress as unique combinations of responsive polymers and nanomaterials emerge.
Co-reporter:Nicole M. Bergmann, Nicholas A. Peppas
Progress in Polymer Science (March 2008) Volume 33(Issue 3) pp:271-288
Publication Date(Web):1 March 2008
DOI:10.1016/j.progpolymsci.2007.09.004
The hierarchical system of recognition in nature is based on interaction between the smallest elements in a matrix such as molecules and the cumulative interactions of larger parts such as the helices and sheets of proteins. The active sites of enzymes are composed of several amino acids, which bind the ligand molecules in a very specific way. However, the activity of the site is dependent on the stabilization of the three-dimensional structure by the interactions of hundreds of other residues. Likewise, a biomimetic polymeric network can be prepared by designing interactions between the building blocks of a biocompatible network and the desired specific analyte and stabilizing these interactions by a three-dimensional structure. This structure is at the same time flexible enough to allow for diffusion of solvent and analytes into and out of the network. This paper reviews advances in molecular recognition systems, and outlines methods of making molecularly imprinted polymer systems that can recognize large molecular weight analytes.
Co-reporter:Nicholas A. Peppas
Advanced Drug Delivery Reviews (January 2013) Volume 65(Issue 1) pp:5-9
Publication Date(Web):1 January 2013
DOI:10.1016/j.addr.2012.09.040
We review the early developments in drug delivery from 1960 to 1990 with emphasis on the fundamental aspects of the field and how they shaped the collaboration of pharmaceutical scientists, chemists, biologists, engineers and medical scientists towards the development of advanced drug delivery systems. Emphasis is given on the advances of biomaterials as drug delivery agents and on the use of design equations and mathematical modeling to achieve a wide range of successful systems.
Co-reporter:David S Spencer, Amey S Puranik, Nicholas A Peppas
Current Opinion in Chemical Engineering (February 2015) Volume 7() pp:84-92
Publication Date(Web):1 February 2015
DOI:10.1016/j.coche.2014.12.003
•Size, charge and surface properties are design considerations for nanoparticles.•Delivery of nanoparticles to primary, metastatic, and multidrug resistant cancers reviewed.•Nanoparticle design must be tailored for diverse cancer physiologies.Treatment of cancer using nanoparticle-based approaches relies on the rational design of carriers with respect to size, charge, and surface properties. Polymer-based nanomaterials, inorganic materials such as gold, iron oxide, and silica as well as carbon based materials such as carbon nanotubes and graphene are being explored extensively for cancer therapy. The challenges associated with the delivery of these nanoparticles depend greatly on the type of cancer and stage of development. This review highlights design considerations to develop nanoparticle-based approaches for overcoming physiological hurdles in cancer treatment, as well as emerging research in engineering advanced delivery systems for the treatment of primary, metastatic, and multidrug resistant cancers. A growing understanding of cancer biology will continue to foster development of intelligent nanoparticle-based therapeutics that take into account diverse physiological contexts of changing disease states to improve treatment outcomes.
Co-reporter:Nicholas A. Peppas
Advanced Drug Delivery Reviews (December 2012) Volume 64(Supplement) pp:1-3
Publication Date(Web):1 December 2012
DOI:10.1016/j.addr.2012.10.006
Co-reporter:Michael H. Smolensky, Nicholas A. Peppas
Advanced Drug Delivery Reviews (31 August 2007) Volume 59(Issues 9–10) pp:823-824
Publication Date(Web):31 August 2007
DOI:10.1016/j.addr.2007.08.004
Co-reporter:E.H. Lauten, N.A. Peppas
Journal of Drug Delivery Science and Technology (2009) Volume 19(Issue 6) pp:391-399
Publication Date(Web):1 January 2009
DOI:10.1016/S1773-2247(09)50082-2
Molecularly imprinted polymer carriers have a large potential for use as drug delivery systems using the recognitive mechanism as the trigger for the release of a therapeutic compound in response to external stimuli or even as the sensing element to give feedback as part of a biological sensor. We discuss the principles of this process using a type of molecular imprinting termed "configurational biomimesis" which produces polymeric surfaces or polymeric recognitive networks that have three dimensional, stereospecific binding micro- and nanocavities based on a given template molecule. The new synthetic recognitive biomaterials are designed to mimic biological recognition, which is ultimately an improvement over using expensive and unstable naturally occurring biological macromolecules and ligands. We show an application to the recognition of angiotensin II, a biomarker of high blood pressure.
Co-reporter:N.A. Peppas, N. Kavimandan
Journal of Drug Delivery Science and Technology (2009) Volume 19(Issue 5) pp:365-368
Publication Date(Web):1 January 2009
DOI:10.1016/S1773-2247(09)50075-5
Developing oral insulin formulations for the treatment of diabetes can greatly improve the quality of life of patients. Many different approaches have been investigated to address the problems associated with oral insulin delivery, but the bioavailability of oral insulin is still low, even in some of the most successful formulations. Insulin is rapidly degraded by the enzymes in the gastrointestinal (GI) tract and is not transported across the epithelial barrier easily. The oral insulin formulation developed in this work makes use of complexation hydrogels for oral delivery of insulin. Use of complexation hydrogels for delivery of insulin may greatly increase the bioavailability of oral insulin.
Co-reporter:T.G. Farmer, T.F. Edgar, N.A. Peppas
Journal of Drug Delivery Science and Technology (2008) Volume 18(Issue 6) pp:387-391
Publication Date(Web):1 January 2008
DOI:10.1016/S1773-2247(08)50076-1
A pharmacokinetic model is proposed to describe the glucoregulatory process. The model describes the dynamics of glucose, amino acids, and fatty acids, as well as both the hormonal actions and dynamics of insulin, glucagon, epinephrine, and glucagon-like peptide-one. The model was developed assuming that the dynamics of each species occurs in only one compartment. Several forms of the metabolic absorption and elimination rates, along with possibilities for increasing the complexity of each compartimentai model are discussed. Once properly identified and validated, the novel model has the potential to be more descriptive than other models describing glucose dynamics in the body.
Co-reporter:O.Z. Fisher, N.A. Peppas
Journal of Drug Delivery Science and Technology (2008) Volume 18(Issue 1) pp:47-50
Publication Date(Web):1 January 2008
DOI:10.1016/S1773-2247(08)50006-2
Facilitation of protein transport across biomimetic polymers and carriers used in drug delivery is a subject of major importance in the field of oral delivery. Quantitative immunofluorescence of epithelial tight junctions can be a valuable tool in the evaluation of paracellular permeation enhancement and macromolecular drug absorption. The tight junction space is composed of transmembrane protein networks that provide both mechanical support and a transport barrier. Both of these may be affected by drug delivery agents that enhance paracytosis. Imaging is the only tool that can tease apart these processes. A confocal microscopy imaging method was developed to determine the effect of microparticulate poly(methacrylic acid) grafted poly(ethylene glycol) (P(MAA-g-EG)) hydrogel drug carriers on the integrity of claudin-1 and E-cadherin networks in Caco-2 monolayers. Z-stack projection images showed the lateral disruption of tight junctions in the presence of drug carriers. Tight junction image fraction measurements showed more significant differences between membranes exposed to microparticles and a control group. Mechanical disruption was much more pronounced in the presence of P(MAA-g-EG) microparticles as compared to the effect of EDTA.
Co-reporter:Mary Caldorera-Moore, Nicholas A. Peppas
Advanced Drug Delivery Reviews (17 December 2009) Volume 61(Issue 15) pp:1391-1401
Publication Date(Web):17 December 2009
DOI:10.1016/j.addr.2009.09.002
Advances in medical treatments of a wide variety of pathophysiological conditions require the development of better therapeutic agents, as well as a combination of the required therapeutic agents with device-integrated biomaterials that can serve as sensors and carriers. Combination of micro- and nano-fabricated systems with intelligent biomaterials that have the ability to sense and respond is a promising avenue for the development of better diagnostic and therapeutic medical systems. Micro- and nano-electromechanical systems (MEMs and NEMs) are now becoming a family of potentially powerful new technologies for drug delivery, diagnostic tools, and tissue engineering. Improvements in micro- and nano-fabrication technologies have enhanced the ability to create better performing therapeutic systems for numerous pathophysiological applications. More importantly, MEMS- and NEMS-based tissue regeneration scaffolds, biosensors, and drug delivery devices provide new opportunities to mimic the natural intelligence and response of biological systems.
Co-reporter:Stephanie D. Steichen, Mary Caldorera-Moore, Nicholas A. Peppas
European Journal of Pharmaceutical Sciences (14 February 2013) Volume 48(Issue 3) pp:416-427
Publication Date(Web):14 February 2013
DOI:10.1016/j.ejps.2012.12.006
The tumor microenvironment provides unique challenges for the delivery of chemotherapeutic agents in doses that are effective while ensuring minimal systemic toxicity. The primary limitation of current therapeutics is a lack of specificity in delivery, as they target healthy and cancerous cells alike. The development of nanoscale carriers capable of delivering cancer therapies has the potential to overcome both systemic and tumor barriers and provide specific, targeted delivery. This review seeks to provide an overview of available nanoscale drug carriers by exploring the wide variety of developed nanostructures and the most commonly used moieties for targeted delivery. Additionally, the use of nanoscale carriers will be motivated by examining tumor physiology and the specific barriers present within both the tumor microenvironment and systemic delivery.Download high-res image (65KB)Download full-size image
Co-reporter:Shilpa Sant, Sarah L. Tao, Omar Z. Fisher, Qiaobing Xu, ... Ali Khademhosseini
Advanced Drug Delivery Reviews (1 May 2012) Volume 64(Issue 6) pp:496-507
Publication Date(Web):1 May 2012
DOI:10.1016/j.addr.2011.11.013
Micro-/nanoscale technologies such as lithographic techniques and microfluidics offer promising avenues to revolutionalize the fields of tissue engineering, drug discovery, diagnostics and personalized medicine. Microfabrication techniques are being explored for drug delivery applications due to their ability to combine several features such as precise shape and size into a single drug delivery vehicle. They also offer to create unique asymmetrical features incorporated into single or multiple reservoir systems maximizing contact area with the intestinal lining. Combined with intelligent materials, such microfabricated platforms can be designed to be bioadhesive and stimuli-responsive. Apart from drug delivery devices, microfabrication technologies offer exciting opportunities to create biomimetic gastrointestinal tract models incorporating physiological cell types, flow patterns and brush-border like structures. Here we review the recent developments in this field with a focus on the applications of microfabrication in the development of oral drug delivery devices and biomimetic gastrointestinal tract models that can be used to evaluate the drug delivery efficacy.Download high-res image (364KB)Download full-size image
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