Co-reporter:Jonathan J. Faig, Alysha Moretti, Laurie B. Joseph, Yingyue Zhang, Mary Joy Nova, Kervin Smith, and Kathryn E. Uhrich
Biomacromolecules 2017 Volume 18(Issue 2) pp:
Publication Date(Web):December 27, 2016
DOI:10.1021/acs.biomac.6b01353
Kojic acid (KA) is a naturally occurring fungal metabolite that is utilized as a skin-lightener and antibrowning agent owing to its potent tyrosinase inhibition activity. While efficacious, KA’s inclination to undergo pH-mediated, thermal-, and photodegradation reduces its efficacy, necessitating stabilizing vehicles. To minimize degradation, poly(carbonate-esters) and polyesters comprised of KA and natural diacids were prepared via solution polymerization methods. In vitro hydrolytic degradation analyses revealed KA release was drastically influenced by polymer backbone composition (e.g., poly(carbonate-ester) vs polyester), linker molecule (aliphatic vs heteroatom-containing), and release conditions (physiological vs skin). Tyrosinase inhibition assays demonstrated that aliphatic KA dienols, the major degradation product under skin conditions, were more potent then KA itself. All dienols were found to be less toxic than KA at all tested concentrations. Additionally, the most lipophilic dienols were statistically more effective than KA at inhibiting melanin biosynthesis in cells. These KA-based polymer systems deliver KA analogues with improved efficacy and cytocompatible profiles, making them ideal candidates for sustained topical treatments in both medical and personal care products.
Co-reporter:Bahar Demirdirek, Kathryn E. Uhrich
International Journal of Pharmaceutics 2017 Volume 528, Issues 1–2(Issue 1) pp:
Publication Date(Web):7 August 2017
DOI:10.1016/j.ijpharm.2017.05.047
In this work, salicylic acid (SA), a non-steroidal anti-inflammatory, was chemically incorporated into hydrogel systems to achieve sustained SA release profiles. With its anti-inflammatory properties, sustained release of SA would be relevant for treating diseases such as diabetes and cancer. In this work, SA was chemically incorporated into hydrogel systems via covalent attachment to an itaconate moiety followed by UV-initiated crosslinking using acrylic acid and poly(ethylene glycol) diacrylate. The chemical composition of the hydrogel system was confirmed using FT-IR spectroscopy. The SA-based hydrogels were designed as pH-responsive hydrogels, collapsing at acidic pH (1.2) values and swelling at higher pH (7.4) values for gastrointestinal-specific delivery. The hydrogel systems exhibited a pH-dependent SA release profile: SA release was much slower at pH 1.2 compared to pH 7.4. Under acidic pH conditions, 30 wt% SA was released after 24 h, whereas 100 wt% SA was released in a sustained manner within 24 h in pH 7.4 PBS buffer. The pore structure of the gel networks were studied using SEM and exhibit appropriate pore sizes (15–60 μm) for physically encapsulating drugs. In addition, rheological studies of the hydrogels proved that these systems are mechanically strong and robust. Mucoadhesive behaviors were confirmed using a Texture Analyzer, the work of adhesion for the hydrogels was around 290 g·mm and the maximum detachment force was around 135 g. The SA-based hydrogels demonstrate great potential for oral delivery of bioactives in combination with SA to treat serious diseases such as cancer and diabetes.Download high-res image (79KB)Download full-size image
Co-reporter:Almudena Prudencio;Jonathan J. Faig;MinJung Song
Macromolecular Bioscience 2016 Volume 16( Issue 2) pp:214-222
Publication Date(Web):
DOI:10.1002/mabi.201500244
Poly(anhydride-esters) comprised of naturally occurring, non-toxic phenolic acids, namely syringic and vanillic acid, with antioxidant properties were prepared via solution polymerization methods. Polymer and polymer precursor physiochemical properties were characterized, including polymer molecular weight and thermal properties. In vitro release studies illustrated that polymer hydrolytic degradation was influenced by relative hydrophobicity and degree of methoxy substitution of the phenolic acids. Further, the released phenolic acids were found to maintain antioxidant potency relative to free phenolic acid controls as determined by a 2,2-diphenyl-1-picrylhydrazyl assay. Polymer cytotoxicity was assessed with L929 fibroblasts in polymer-containing media; appropriate cell morphology and high fibroblast proliferation were obtained for the polymers at the lower concentrations. These polymers deliver non-cytotoxic levels of naturally occurring antioxidants, which could be efficacious in topical delivery of antioxidant therapies.
Co-reporter:Yingyue Zhang, Evan Mintzer, Kathryn E. Uhrich
Journal of Colloid and Interface Science 2016 Volume 482() pp:19-26
Publication Date(Web):15 November 2016
DOI:10.1016/j.jcis.2016.07.013
Long-circulating liposomes are typically prepared with poly(ethylene glycol)- (PEG-) modified lipids, where the lipid portion is inserted in the lipid bilayers as an anchor and the hydrophilic PEG coats the surface to prevent liposome aggregation and rapid clearance in vivo. However, these steric protection effects are compromised upon systemic administration due to low retention of PEGylated lipids within liposome membranes upon dilution. Hence, a series of PEGylated bolaamphiphiles (PEG-bolas) were for the first time developed to increase retention in the lipid bilayer, presumably leading to enhanced integrity of the PEG protective layer upon dilution. We hypothesized that PEG-bolas with a sufficiently long hydrophobic domain and rigid central group could predominantly adopt a membrane-spanning configuration, taking full advantage of steric protection offered by PEG and enhanced retention in liposomes enabled by the bola geometry. In this paper, liposomes stabilized by PEG-bolas comprised of a biphenyl core and twelve-carbon alkyl chain not only exhibited similar storage and biological stability compared to conventional PEGylated lipid stabilized liposomes, but also significantly improved retention upon dilution. Our findings facilitate new designs of liposome-stabilizing agents and can be applied to improve the delivery efficiency of liposomal delivery vehicles in vivo.
Co-reporter:Stephan Bien-Aime;Weiling Yu
Macromolecular Bioscience 2016 Volume 16( Issue 7) pp:978-983
Publication Date(Web):
DOI:10.1002/mabi.201500454
Co-reporter:Jonathan J. Faig;Kervin Smith;Alysha Moretti;Weiling Yu
Macromolecular Chemistry and Physics 2016 Volume 217( Issue 16) pp:1842-1850
Publication Date(Web):
DOI:10.1002/macp.201600115
Co-reporter:Jonathan J. Faig;Sarah Klein;Michelle A. Ouimet;Weiling Yu
Macromolecular Chemistry and Physics 2016 Volume 217( Issue 1) pp:108-114
Publication Date(Web):
DOI:10.1002/macp.201500411
Co-reporter:David E. Orban;Alysha Moretti
Magnetic Resonance in Chemistry 2016 Volume 54( Issue 7) pp:575-583
Publication Date(Web):
DOI:10.1002/mrc.4401
Abstract
A combination of nuclear magnetic resonance (NMR) techniques including, proton NMR, relaxation analysis, two-dimensional nuclear Overhauser effect spectroscopy, and diffusion-ordered spectroscopy, has been used to demonstrate the spatial location of indomethacin within a unimolecular micelle. Understanding the location of drugs within carrier molecules using such NMR techniques can facilitate rational carrier design. In addition, this information provides insight to encapsulation efficiency of different drugs to determine the most efficient system for a particular bioactive. This study demonstrates that drugs loaded by the unimolecular amphiphile under investigation are not necessarily encapsulated but reside or localize to the periphery or interfacial region of the carrier molecule. The results have further implications as to the features of the unimolecular carrier that contribute to drug loading. In addition, evidence of drug retention associated with the unimolecular surfactant is possible in organic media, as well as in an aqueous environment. Such findings have implications for rational carrier design to correlate the carrier features to the drug of interest and indicate the strong retention capabilities of the unimolecular micelle for delivery applications. Copyright © 2016 John Wiley & Sons, Ltd.
Co-reporter:Jennifer W. Chan, Amy Huang, and Kathryn E. Uhrich
Langmuir 2016 Volume 32(Issue 20) pp:5038-5047
Publication Date(Web):May 11, 2016
DOI:10.1021/acs.langmuir.6b00524
Although drug-eluting stent technologies have significantly improved clinical outcomes over the past decade, substantial issues with postimplantation vessel reocclusion still remain. To combat these issues, bioactive amphiphilic macromolecules (AMs), comprised of a functional end group, a branched hydrophobic domain, and a hydrophilic poly(ethylene glycol) tail, were investigated as a therapeutic coating to reduce smooth muscle cell (SMC) proliferation and platelet adhesion. In this study, grafting-from and grafting-to approaches for AM surface functionalization were compared to determine the effects of fabrication method on bioactive delivery characteristics, including the AM loading, release, and biological activity. Grafted-from coatings were formed by stepwise synthesis of phosphonate AMs, 1pM, on the substrate, first by alkyl phosphonate coordination to stainless steel and subsequent carbodiimide coupling to conjugate the hydrophobic and hydrophilic domains. In contrast, grafted-to monolayers were assembled utilizing presynthesized 1pM in a tethering by aggregation and growth technique. Coatings formed using the grafting-from approach yielded high AM grafting density and a highly ordered layer, which corresponded to a slower release rate and sustained bioactivity over 28 days. In contrast, the grafted-to coatings yielded less dense, heterogeneous layers, which released faster and were therefore less efficacious in suppressing prolonged SMC proliferation. Both coatings significantly reduced platelet adhesion compared to an uncoated control, but similar platelet adhesion results between grafted-from and grafted-to coatings suggest that both surfaces maintained a molecular density favorable for antiplatelet activity. Overall, the grafting-from method produced uniform coatings with improved loading, release, and bioactive properties compared to the grafting-to approach, highlighting the potential of AM controlled release coatings for therapeutic delivery.
Co-reporter:Yingyue Zhang, Jennifer W. Chan, Alysha Moretti, Kathryn E. Uhrich
Journal of Controlled Release 2015 Volume 219() pp:355-368
Publication Date(Web):10 December 2015
DOI:10.1016/j.jconrel.2015.09.053
Sugar-based polymers have been extensively explored as a means to increase drug delivery systems' biocompatibility and biodegradation. Here, we review the use of sugar-based polymers for drug delivery applications, with a particular focus on the utility of the sugar component(s) to provide benefits for drug targeting and stimuli-responsive systems. Specifically, numerous synthetic methods have been developed to reliably modify naturally-occurring polysaccharides, conjugate sugar moieties to synthetic polymer scaffolds to generate glycopolymers, and utilize sugars as a multifunctional building block to develop sugar-linked polymers. The design of sugar-based polymer systems has tremendous implications on both the physiological and biological properties imparted by the saccharide units and are unique from synthetic polymers. These features include the ability of glycopolymers to preferentially target various cell types and tissues through receptor interactions, exhibit bioadhesion for prolonged residence time, and be rapidly recognized and internalized by cancer cells. Also discussed are the distinct stimuli-sensitive properties of saccharide-modified polymers to mediate drug release under desired conditions. Saccharide-based systems with inherent pH- and temperature-sensitive properties, as well as enzyme-cleavable polysaccharides for targeted bioactive delivery, are covered. Overall, this work emphasizes inherent benefits of sugar-containing polymer systems for bioactive delivery.
Co-reporter:Jennifer W. Chan, Yingyue Zhang, and Kathryn E. Uhrich
Bioconjugate Chemistry 2015 Volume 26(Issue 7) pp:1359
Publication Date(Web):June 4, 2015
DOI:10.1021/acs.bioconjchem.5b00208
A significant limitation of cardiovascular stents is restenosis, where excessive smooth muscle cell (SMC) proliferation following stent implantation causes blood vessel reocclusion. While drug-eluting stents minimize SMC proliferation through releasing cytotoxic or immunosuppressive drugs from polymer carriers, significant issues remain with delayed healing, inflammation, and hypersensitivity reactions associated with drug and polymer coatings. Amphiphilic macromolecules (AMs) comprising a sugar-based hydrophobic domain and a hydrophilic poly(ethylene glycol) tail are noncytotoxic and recently demonstrated a concentration-dependent ability to suppress SMC proliferation. In this study, we designed a series of AMs and studied their coating properties (chemical composition, thickness, grafting density, and coating uniformity) to determine the effect of headgroup chemistry on bioactive AM grafting and release properties from stainless steel substrates. One carboxyl-terminated AM (1cM) and two phosphonate- (Me-1pM and Pr-1pM) terminated AMs, with varying linker lengths preceding the hydrophobic domain, were grafted to stainless steel substrates using the tethering by aggregation and growth (T-BAG) approach. The AMs formed headgroup-dependent, yet uniform, biocompatible adlayers. Pr-1pM and 1cM demonstrated higher grafting density and an extended release from the substrate over 21 days compared to Me-1pM, which exhibited lower grafting density and complete release within 7 days. Coinciding with their release profiles, Me-1pM and 1cM coatings initially suppressed SMC proliferation in vitro, but their efficacy decreased within 7 and 14 days, respectively, while Pr-1pM coatings suppressed SMC proliferation over 21 days. Thus, AMs with phosphonate headgroups and propyl linkers are capable of sustained release from the substrate and have the ability to suppress SMC proliferation during the restenosis that occurs in the 3–4 weeks after stent implantation, demonstrating the potential for AM coatings to provide sustained delivery via desorption from coated coronary stents and other metal-based implants.
Co-reporter:Michelle A. Ouimet;Renata Fogaça;Sabrina S. Snyder;Sameer Sathaye;Luiz H. Catalani;Darrin J. Pochan
Macromolecular Bioscience 2015 Volume 15( Issue 3) pp:342-350
Publication Date(Web):
DOI:10.1002/mabi.201400238
Polymers such as poly(N-vinyl-2-pyrrolidone) (PVP) have been used to prepare hydrogels for wound dressing applications but are not inherently bioactive. For enhanced healing, PVP was blended with salicylic acid-based poly(anhydride-esters) (SAPAE) and shown to exhibit hydrogel properties upon swelling. In vitro release studies demonstrated that the chemically incorporated drug (SA) was released from the polymer blends over 3–4 d in contrast to 3 h, and that blends of higher PVP content displayed greater swelling values and faster SA release. The polymer blends significantly the inflammatory cytokine, TNF-α, in vitro without negative effects.
Co-reporter:Nicholas D. Stebbins;Weiling Yu
Macromolecular Bioscience 2015 Volume 15( Issue 8) pp:1115-1124
Publication Date(Web):
DOI:10.1002/mabi.201500030
Novel ibuprofen-containing monomers comprising naturally occurring and biocompatible compounds were synthesized and subsequently polymerized via enzymatic methods. Through the use of a malic acid sugar backbone, ibuprofen was attached as a pendant group, and then subsequently polymerized with a linear aliphatic diol (1,3-propanediol, 1,5-pentanediol, or 1,8-octanediol) as comonomer using lipase B from Candida antarctica, a greener alternative to traditional metal catalysts. Polymer structures were elucidated by nuclear magnetic resonance and infrared spectroscopies, and thermal properties and molecular weights were determined. All polymers exhibited sustained ibuprofen release, with the longer chain, more hydrophobic diols exhibiting the slowest release over the 30 d study. Polymers were deemed cytocompatible using mouse fibroblasts, when evaluated at relevant therapeutic concentrations. Additionally, ibuprofen retained its chemical integrity throughout the polymerization and in vitro hydrolytic degradation processes. This methodology of enzymatic polymerization of a drug presents a more environmentally friendly synthesis and a novel approach to bioactive polymer conjugates.
Co-reporter:N. D. Stebbins, J. J. Faig, W. Yu, R. Guliyev and K. E. Uhrich
Biomaterials Science 2015 vol. 3(Issue 8) pp:1171-1187
Publication Date(Web):02 Jun 2015
DOI:10.1039/C5BM00051C
Significant and promising advances have been made in the polymer field for controlled and sustained bioactive delivery. Traditionally, small molecule bioactives have been physically incorporated into biodegradable polymers; however, chemical incorporation allows for higher drug loading, more controlled release, and enhanced processability. Moreover, the advent of bioactive-containing monomer polymerization and hydrolytic biodegradability allows for tunable bioactive loading without yielding a polymer residue. In this review, we highlight the chemical incorporation of different bioactive classes into novel biodegradable and biocompatible polymers. The polymer design, synthesis, and formulation are summarized in addition to the evaluation of bioactivity retention upon release via in vitro and in vivo studies.
Co-reporter:Sabrina S. Snyder, Theodore J. Anastasiou, Kathryn E. Uhrich
Polymer Degradation and Stability 2015 Volume 115() pp:70-76
Publication Date(Web):May 2015
DOI:10.1016/j.polymdegradstab.2015.02.002
Polyanhydrides have been studied as a drug delivery vehicles due to their surface-eroding behavior which results in zero-order release. However, many polyanhyrides have thermal and solubility properties that make them difficult to formulate for these applications. Poly[α,α′-bis(ortho-carboxyphenoxy)-para-xylene] (oCPX) is an aromatic polyanhydride that has thermal and solubility properties enabling facile processing. The polymer's in vitro degradation profile exhibited an induction period up to 10 days in which degradation product concentration in the media was minimal, followed by a period of stable release of the biocompatible degradation product. Scanning electron microscope images and molecular weight changes of the polymer matrices confirm that this polymer is primarily surface-eroding. The combination of thermal properties, solubility, polymer degradation time, and erosion mechanism indicate that poly(oCPX) is be a suitable matrix candidate for extended, controlled drug delivery.
Co-reporter:Leonid Garber;Neel Jingar;Roselin Rosario-Meléndez
Journal of Polymer Science Part B: Polymer Physics 2015 Volume 53( Issue 10) pp:685-689
Publication Date(Web):
DOI:10.1002/polb.23690
ABSTRACT
This work describes how physicochemical properties of salicylate-based poly(anhydride-esters) (PAEs) can be tuned for drug delivery and optimized by comparing copolymerization with polymer blending. These alterations reduced the lag time of drug release, while still maintaining a long-term drug release profile. The chemical composition of the copolymers and polymer blends was determined by proton nuclear magnetic resonance and additional properties such as molecular weight, glass transition temperature and contact angle measurements were obtained. In vitro salicylic acid release from the copolymers and blends is studied in an environment mimicking physiological conditions. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 685–689
Co-reporter:Allison Faig, Timothy D. Arthur, Patrick O. Fitzgerald, Michael Chikindas, Evan Mintzer, and Kathryn E. Uhrich
Langmuir 2015 Volume 31(Issue 43) pp:11875-11885
Publication Date(Web):October 21, 2015
DOI:10.1021/acs.langmuir.5b03347
Cationic amphiphiles have received increasing attention as antimicrobials given their unique ability to disrupt bacteria cell membranes. While extensive research has demonstrated that amphiphiles’ hydrophobic-to-charge ratio significantly modulates antibacterial activity, less work has focused on elucidating the specific impact of charge location on amphiphile bioactivity. In this study, two series of cationic amphiphiles, termed bola-like and gemini-like, were synthesized with analogous hydrophobic-to-charge ratios yet differing charge location, and their resulting antibacterial activity was assessed. Bola-like amphiphiles exhibited preferential activity against two Gram-positive bacteria, with activity increasing with increasing hydrophobicity, whereas gemini-like amphiphiles were active against both Gram-positive and Gram-negative bacteria, with activity decreasing with increasing hydrophobicity. After identifying lead compounds from each amphiphile series (bola- and gemini-like), biophysical experiments indicated that both amphiphiles were membrane-active; notably, the lead gemini-like amphiphile exhibited a strong dependence on electrostatic interactions for membrane interaction. In contrast, the lead bola-like amphiphile exhibited a reliance on both hydrophobic and electrostatic contributions. These results demonstrate that charge location significantly impacts cationic amphiphiles’ antibacterial and membrane activity.
Co-reporter:Michelle A. Ouimet, Jonathan J. Faig, Weiling Yu, and Kathryn E. Uhrich
Biomacromolecules 2015 Volume 16(Issue 9) pp:
Publication Date(Web):August 10, 2015
DOI:10.1021/acs.biomac.5b00824
Ferulic acid-based polymers with aliphatic linkages have been previously synthesized via solution polymerization methods, yet they feature relatively slow ferulic acid release rates (∼11 months to 100% completion). To achieve a more rapid release rate as required in skin care formulations, ferulic acid-based polymers with ethylene glycol linkers were prepared to increase hydrophilicity and, in turn, increase ferulic acid release rates. The polymers were characterized using nuclear magnetic resonance and Fourier transform infrared spectroscopies to confirm chemical composition. The molecular weights, thermal properties (e.g., glass transition temperature), and contact angles were also obtained and the polymers compared. Polymer glass transition temperature was observed to decrease with increasing linker molecule length, whereas increasing oxygen content decreased polymer contact angle. The polymers’ chemical structures and physical properties were shown to influence ferulic acid release rates and antioxidant activity. In all polymers, ferulic acid release was achieved with no bioactive decomposition. These polymers demonstrate the ability to strategically release ferulic acid at rates and concentrations relevant for topical applications such as skin care products.
Co-reporter:Nicholas D. Stebbins, Weiling Yu, and Kathryn E. Uhrich
Biomacromolecules 2015 Volume 16(Issue 11) pp:
Publication Date(Web):October 9, 2015
DOI:10.1021/acs.biomac.5b01088
Sugar alcohols, such as mannitol and xylitol, are biocompatible polyols that have been used to make highly cross-linked polyester elastomers and dendrimers for tissue engineering and drug delivery. However, research that utilizes the secondary hydroxyl groups as sites for pendant bioactive attachment and subsequent polymerization is limited. This work is the first report of a linear, completely biodegradable polymer with a sugar alcohol backbone and chemically incorporated pendant bioactives that exhibits sustained bioactive release and high bioactive loading (∼70%). With four pendant esters per repeat unit, this poly(anhydride-ester) has high loading and biodegrades into three biocompatible products: bioactive, sugar alcohol, and alkyl-based diacid. Ibuprofen serves as a representative bioactive, whereas mannitol is a representative polyol. Polymerization was achieved through reaction with (trimethylsilyl)ethoxyacetylene. Drug release via polymer degradation was quantified by high performance liquid chromatography. Additionally, a cytocompatibility study with fibroblast cells was performed to elucidate the polymer’s suitability for in vivo use and a cyclooxygenase-2 (COX-2) assay was performed on the degradation media to ensure that released ibuprofen retained its anti-inflammatory activity. This work enables the future development of novel, biodegradable polymers exhibiting two key features: (i) polymer backbones with easily modified pendant groups, such as targeting moieties, and (ii) high drug loading using a multitude of bioactive classes.
Co-reporter:Li Gu, Leora M. Nusblat, Nasim Tishbi, Sarah C. Noble, Chaya M. Pinson, Evan Mintzer, Charles M. Roth, Kathryn E. Uhrich
Journal of Controlled Release 2014 Volume 184() pp:28-35
Publication Date(Web):28 June 2014
DOI:10.1016/j.jconrel.2014.04.005
The accumulated evidence has shown that lipids and polymers each have distinct advantages as carriers for siRNA delivery. Composite materials comprising both lipids and polymers may present improved properties that combine the advantage of each. Cationic amphiphilic macromolecules (CAMs) containing a hydrophobic alkylated mucic acid segment and a hydrophilic poly(ethylene glycol) (PEG) tail were non-covalently complexed with two lipids, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), to serve as a siRNA delivery vehicle. By varying the weight ratio of CAM to lipid, cationic complexes with varying compositions were obtained in aqueous media and their properties evaluated. CAM–lipid complex sizes were relatively independent of composition, ranging from 100 to 200 nm, and zeta potentials varied from 10 to 30 mV. Transmission electron microscopy confirmed the spherical morphology of the complexes. The optimal N/P ratio was 50 as determined by electrophoretic mobility shift assay. The ability to achieve gene silencing was evaluated by anti-luciferase siRNA delivery to a U87-luciferase cell line. Several weight ratios of CAM–lipid complexes were found to have similar delivery efficiency compared to the gold standard, Lipofectamine. Isothermal titration calorimetry revealed that siRNA binds more tightly at pH = 7.4 than pH = 5 to CAM–lipid (1:10 w/w). Further intracellular trafficking studies monitored the siRNA escape from the endosomes at 24 h following transfection of cells. The findings in the paper indicate that CAM–lipid complexes can serve as a novel and efficient siRNA delivery vehicle.
Co-reporter:Dalia Abdelhamid, Hulya Arslan, Yingyue Zhang and Kathryn E. Uhrich
Polymer Chemistry 2014 vol. 5(Issue 4) pp:1457-1462
Publication Date(Web):05 Dec 2013
DOI:10.1039/C3PY01072D
A novel series of amphiphilic macromolecules (AMs) composed of a sugar backbone, aliphatic chains, and branched, hydrophilic poly(oligoethylene glycol) methyl ether methacrylate (POEGMA) were developed for drug delivery applications. The branched, hydrophilic domains (POEGMA homopolymers with one hydroxyl group) were prepared via atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) monomers using 2-hydroxyethyl-2-bromoisobutyrate (HEBiB) as an initiator and copper bromide/bipyridine (CuBr/Bpy) as the catalyst system. To form the amphiphilic structures, the branched POEGMAs were coupled to hydrophobic domains that were formed via acylation of a sugar backbone. The impact of branching in the hydrophilic domain was investigated by comparing the AMs' solution and thermal properties with those of the linear counterparts. Although these highly branched AMs showed similar critical micelle concentration (CMC) values as compared to linear analogues, they possessed quite low glass transition (Tg) temperatures. Consequently, these novel AMs with branched hydrophilic domain combine the desirable thermal properties of POEGMA with favorable solution properties of amphiphilic architectures, which make them suitable for injectable drug delivery systems.
Co-reporter:Li Tao, Allison Faig, Kathryn E. Uhrich
Journal of Colloid and Interface Science 2014 Volume 431() pp:112-116
Publication Date(Web):1 October 2014
DOI:10.1016/j.jcis.2014.06.004
•The amphiphilic macromolecule (AM) prevents DPPC-based liposomes from aggregating.•AM reduces leakage from DPPC-based liposomes in a concentration-dependent manner.•AM reduces in vitro uptake of DPPC-based liposomes by macrophages.Liposomes are an important class of colloidal drug delivery systems, yet the clinical applications of conventional liposomes can be hampered by poor colloidal and biological stabilities. In this work, a sugar-based, PEGylated amphiphilic macromolecule (AM) was evaluated for its ability to stabilize dipalmitoyl phosphatidylcholine (DPPC)-based liposomes. Compared to unmodified liposomes, AM-stabilized liposomes exhibited enhanced colloidal stability, maintaining relatively constant particle sizes for 5 weeks without aggregation. AM-stabilized liposomes also showed significantly decreased membrane permeability, even in the presence of serum. Finally, AM-stabilized liposomes displayed improved biological stability, significantly inhibiting phagocytosis by macrophages. Overall, the effectiveness of AM to stabilize liposomes was comparable to a conventional stabilizing agent, PEG-modified phosphatidylethanolamine. Based upon these results, AM is a promising stabilizing agent for colloidal drug delivery applications and currently being optimized.
Co-reporter:Ashley L. Carbone-Howell, Nicholas D. Stebbins, and Kathryn E. Uhrich
Biomacromolecules 2014 Volume 15(Issue 5) pp:
Publication Date(Web):April 7, 2014
DOI:10.1021/bm500303a
Carvacrol, thymol, and eugenol are naturally occurring phenolic compounds known to possess antimicrobial activity against a range of bacteria, as well as antioxidant activity. Biodegradable poly(anhydride-esters) composed of an ethylenediaminetetraacetic acid (EDTA) backbone and antimicrobial pendant groups (i.e., carvacrol, thymol, or eugenol) were synthesized via solution polymerization. The resulting polymers were characterized to confirm their chemical composition and understand their thermal properties and molecular weight. In vitro release studies demonstrated that polymer hydrolytic degradation was complete after 16 days, resulting in the release of free antimicrobials and EDTA. Antioxidant and antibacterial assays determined that polymer release media exhibited bioactivity similar to that of free compound, demonstrating that polymer incorporation and subsequent release had no effect on activity. These polymers completely degrade into components that are biologically relevant and have the capability to promote preservation of consumer products in the food and personal care industries via antimicrobial and antioxidant pathways.
Co-reporter:Allison Faig, Latrisha K. Petersen, Prabhas V. Moghe, and Kathryn E. Uhrich
Biomacromolecules 2014 Volume 15(Issue 9) pp:
Publication Date(Web):July 28, 2014
DOI:10.1021/bm500809f
Amphiphilic macromolecules (AMs) composed of sugar backbones modified with branched aliphatic chains and a poly(ethylene glycol) (PEG) tail can inhibit macrophage uptake of oxidized low-density lipoproteins (oxLDL), a major event underlying atherosclerosis development. Previous studies indicate that AM hydrophobic domains influence this bioactivity through interacting with macrophage scavenger receptors, which can contain basic and/or hydrophobic residues within their binding pockets. In this study, we compare two classes of AMs to investigate their ability to promote athero-protective potency via hydrogen-bonding or hydrophobic interactions with scavenger receptors. A series of ether-AMs, containing methoxy-terminated aliphatic arms capable of hydrogen-bonding, was synthesized. Compared to analogous AMs containing no ether moieties (alkyl-AMs), ether-AMs showed improved cytotoxicity profiles. Increasing AM hydrophobicity via incorporation of longer and/or alkyl-terminated hydrophobic chains yielded macromolecules with enhanced oxLDL uptake inhibition. These findings indicate that hydrophobic interactions and the length of AM aliphatic arms more significantly influence AM bioactivity than hydrogen-bonding.
Co-reporter:Michelle A. Ouimet;Nicholas D. Stebbins
Macromolecular Rapid Communications 2013 Volume 34( Issue 15) pp:1231-1236
Publication Date(Web):
DOI:10.1002/marc.201300323
Co-reporter:Roselin Rosario-Meléndez, Weiling Yu, and Kathryn E. Uhrich
Biomacromolecules 2013 Volume 14(Issue 10) pp:
Publication Date(Web):August 19, 2013
DOI:10.1021/bm400889a
Controlled release of nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen could be beneficial for the treatment of inflammatory diseases while reducing the side effects resulting from their continuous use. Novel biodegradable polyesters solely comprised of biocompatible components (e.g., tartaric acid, 1,8-octanediol, and ibuprofen or naproxen as pendant groups) have been synthesized using tin(II) 2-ethylhexanoate as catalyst at 130 °C and subsequently characterized to determine their structures and physicochemical properties. The polymers release the free drug (ibuprofen or naproxen) in vitro in a controlled manner without burst release, unlike the release rates achieved when the drugs are encapsulated in other polymers. These new biomaterials are not cytotoxic toward mouse fibroblasts up to 0.10 mg/mL. The drugs retain their chemical structure following hydrolytic degradation of the polymer, suggesting that bioactivity is preserved.
Co-reporter:Dawanne E. Poree, Kyle Zablocki, Allison Faig, Prabhas V. Moghe, and Kathryn E. Uhrich
Biomacromolecules 2013 Volume 14(Issue 8) pp:
Publication Date(Web):June 24, 2013
DOI:10.1021/bm400537w
Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) and counteract foam cell formation, a key characteristic of early atherogenesis. To investigate the influence of lipophilicity and stereochemistry on the AMs’ physicochemical and biological properties, mucic acid-based AMs bearing four aliphatic chains (2a) and tartaric acid-based AMs bearing two (2b and 2l) and four aliphatic chains (2g and 2k) were synthesized and evaluated. Solution aggregation studies suggested that both the number of hydrophobic arms and the length of the hydrophobic domain impact AM micelle sizes, whereas stereochemistry impacts micelle stability. 2l, the meso analogue of 2b, elicited the highest reported oxLDL uptake inhibition values (89%), highlighting the crucial effect of stereochemistry on biological properties. This study suggests that stereochemistry plays a critical role in modulating oxLDL uptake and must be considered when designing biomaterials for potential cardiovascular therapies.
Co-reporter:Michelle A. Ouimet, Jeremy Griffin, Ashley L. Carbone-Howell, Wen-Hsuan Wu, Nicholas D. Stebbins, Rong Di, and Kathryn E. Uhrich
Biomacromolecules 2013 Volume 14(Issue 3) pp:
Publication Date(Web):January 17, 2013
DOI:10.1021/bm3018998
Ferulic acid (FA) is an antioxidant and photoprotective agent used in biomedical and cosmetic formulations to prevent skin cancer and senescence. Although FA exhibits numerous health benefits, physicochemical instability leading to decomposition hinders its efficacy. To minimize inherent decomposition, a FA-containing biodegradable polymer was prepared via solution polymerization to chemically incorporate FA into a poly(anhydride-ester). The polymer was characterized using nuclear magnetic resonance and infrared spectroscopies. The molecular weight and thermal properties were also determined. In vitro studies demonstrated that the polymer was hydrolytically degradable, thus providing controlled release of the chemically incorporated bioactive with no detectable decomposition. The polymer degradation products were found to exhibit antioxidant and antibacterial activity comparable to that of free FA, and in vitro cell viability studies demonstrated that the polymer is noncytotoxic toward fibroblasts. This renders the polymer a potential candidate for use as a controlled release system for skin care formulations.
Co-reporter:Roselin Rosario-Meléndez, Carolyn L. Harris, Roberto Delgado-Rivera, Lei Yu, Kathryn E. Uhrich
Journal of Controlled Release 2012 Volume 162(Issue 3) pp:538-544
Publication Date(Web):28 September 2012
DOI:10.1016/j.jconrel.2012.07.033
Morphine, a potent narcotic analgesic used for the treatment of acute and chronic pain, was chemically incorporated into a poly(anhydride-ester) backbone. The polymer termed “PolyMorphine”, was designed to degrade hydrolytically releasing morphine in a controlled manner to ultimately provide analgesia for an extended time period. PolyMorphine was synthesized via melt-condensation polymerization and its structure was characterized using proton and carbon nuclear magnetic resonance spectroscopies, and infrared spectroscopy. The weight-average molecular weight and the thermal properties were determined. The hydrolytic degradation pathway of the polymer was determined by in vitro studies, showing that free morphine is released. In vitro cytocompatibility studies demonstrated that PolyMorphine is non-cytotoxic towards fibroblasts. In vivo studies using mice showed that PolyMorphine provides analgesia for 3 days, 20 times the analgesic window of free morphine. The animals retained full responsiveness to morphine after being subjected to an acute morphine challenge.
Co-reporter:Sarah Hehir, Nicole M. Plourde, Li Gu, Dawanne E. Poree, William J. Welsh, Prabhas V. Moghe, Kathryn E. Uhrich
Acta Biomaterialia 2012 Volume 8(Issue 11) pp:3956-3962
Publication Date(Web):November 2012
DOI:10.1016/j.actbio.2012.07.022
Abstract
Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) mediated by scavenger receptor A (SR-A) and counteract foam cell formation, the characteristic “atherosclerotic” phenotype. A series of AMs was prepared by altering the carbohydrate chemistry to evaluate the influence of backbone architecture on the physicochemical and biological properties. Upon evaluating the degree of polymer-based inhibition of oxLDL uptake in human embryonic kidney cells expressing SR-A, two AMs (2a and 2c) were found to have the most efficacy. Molecular modeling and docking studies show that these same AMs have the most favorable binding energies and most close interactions with the molecular model of the SR-A collagen-like domain. Thus, minor changes in the AMs’ architecture can significantly affect the physicochemical properties and inhibition of oxLDL uptake. These insights can be critical for designing optimal AM-based therapeutics for the management of cardiovascular disease.
Co-reporter:Li Gu, Kyle Zablocki, Linda Lavelle, Stanko Bodnar, Frederick Halperin, Ike Harper, Prabhas V. Moghe, Kathryn E. Uhrich
Polymer Degradation and Stability 2012 Volume 97(Issue 9) pp:1686-1689
Publication Date(Web):September 2012
DOI:10.1016/j.polymdegradstab.2012.06.017
An amphiphilic macromolecule (AM) was exposed to ionizing radiation (both electron beam and gamma) at doses of 25 kGy and 50 kGy to study the impact of these sterilization methods on the physicochemical properties and bioactivity of the AM. Proton nuclear magnetic resonance and gel permeation chromatography were used to determine the chemical structure and molecular weight, respectively. Size and zeta potential of the micelles formed from AMs in aqueous media were evaluated by dynamic light scattering. Bioactivity of irradiated AMs was evaluated by measuring inhibition of oxidized low-density lipoprotein uptake in macrophages. From these studies, no significant changes in the physicochemical properties or bioactivity were observed after the irradiation, demonstrating that the AMs can withstand typical radiation doses used to sterilize materials.
Co-reporter:Sarah M. Sparks;Carolyn L. Waite;Alexer M. Harmon;Leora M. Nusblat;Charles M. Roth
Macromolecular Bioscience 2011 Volume 11( Issue 9) pp:1192-1200
Publication Date(Web):
DOI:10.1002/mabi.201100064
Co-reporter:Roselin Rosario-Meléndez, Linda Lavelle, Stanko Bodnar, Frederick Halperin, Ike Harper, Jeremy Griffin, Kathryn E. Uhrich
Polymer Degradation and Stability 2011 Volume 96(Issue 9) pp:1625-1630
Publication Date(Web):September 2011
DOI:10.1016/j.polymdegradstab.2011.06.005
The effect of electron beam and gamma radiation on the physicochemical properties of a salicylate-based poly(anhydride-ester) was studied by exposing polymers to 0 (control), 25 and 50 kGy. After radiation exposure, salicylic acid release in vitro was monitored to assess any changes in drug release profiles. Molecular weight, glass transition temperature and decomposition temperature were evaluated for polymer chain scission and/or crosslinking as well as changes in thermal properties. Proton nuclear magnetic resonance and infrared spectroscopies were also used to determine polymer degradation and/or chain scission. In vitro cell studies were performed to identify cytocompatibility following radiation exposure. These studies demonstrate that the physicochemical properties of the polymer are not substantially affected by exposure to electron beam and gamma radiation.
Co-reporter:Roberto Delgado-Rivera, Jeremy Griffin, Christopher L. Ricupero, Martin Grumet, Sally Meiners, Kathryn E. Uhrich
Colloids and Surfaces B: Biointerfaces 2011 Volume 84(Issue 2) pp:591-596
Publication Date(Web):1 June 2011
DOI:10.1016/j.colsurfb.2011.01.014
Microscale plasma-initiated patterning (μPIP) is a novel micropatterning technique used to create biomolecular micropatterns on polymer surfaces. The patterning method uses a polydimethylsiloxane (PDMS) stamp to selectively protect regions of an underlying substrate from oxygen plasma treatment resulting in hydrophobic and hydrophilic regions. Preferential adsorption of the biomolecules onto either the plasma-exposed (hydrophilic) or plasma-protected (hydrophobic) regions leads to the biomolecular micropatterns. In the current work, laminin-1 was applied to an electrospun polyamide nanofibrillar matrix following plasma treatment. Radial glial clones (neural precursors) selectively adhered to these patterned matrices following the contours of proteins on the surface. This work demonstrates that textured surfaces, such as nanofibrillar scaffolds, can be micropatterned to provide external chemical cues for cellular organization.Graphical abstractRepresentative SEM image of electrospun polyamide nanofibers; laminin-1 applied to the polyamide nanofibrillar matrix following microscale plasma-initiated patterning (μPIP).Research highlights► Polymer matrix micropatterned with microscale plasma-initiated patterning (μPIP). ► μPIP promotes cell orientation at the surface of polymer scaffolds. ► Cell alignment was obtained for radial glial cultures with laminin-1 micropatterns. ► Textured surfaces can be micropatterned to provide external chemical cues.
Co-reporter:Alexander M. Harmon, Melissa H. Lash, Nasim Tishbi, Danielle Lent, Evan A. Mintzer, and Kathryn E. Uhrich
Langmuir 2011 Volume 27(Issue 15) pp:9131-9138
Publication Date(Web):July 6, 2011
DOI:10.1021/la200038a
Surfactant amphiphilic macromolecules (AMs) were complexed with a 1:1 ratio of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), either by a coevaporation (CE) or postaddition (PA) method, to form AM–lipid complexes with enhanced drug delivery applications. By characterizing the surfactant–lipid interactions, these heterogeneous drug delivery systems can be better controlled and engineered for optimal therapeutic outcomes. In this study, the physical interactions between DOPE:DOTAP liposomes and AM surfactants were investigated. Langmuir film balance and isothermal calorimetry studies showed cooperative intermolecular interactions between pure lipids and AM in monolayers and high thermostability of structure formed by the addition of AM micelles to DOTAP:DOPE vesicles in buffer solution respectively. Increasing the AM weight ratio in the complexes via the CE method led to complete vesicle solubilization—from lamellar aggregates, to a mixture of coexisting vesicles and micelles, to mixed micelles. Isothermal calorimetry evaluation of AM-lipid complexes shows that, at higher AM weight ratios, PA-produced complexes exhibit greater stability than complexes at lower AM weight ratios. Similar studies show that AM-lipid complexes produced by the CE methods display stronger interactions between AM-lipid components than complexes produced by the PA method. The results suggest that the PA method produces vesicles with AM molecules associated with its outer leaflet only (i.e., an AM-coated vesicle), while the CE method produces complexes ranging from mixed vesicles to mixed micelle in which the AM-lipid components are more intimately associated. These results will be helpful in the design of AM-lipid complexes as structurally defined, stable, and effective drug delivery systems.
Co-reporter:Leilani S. del Rosario;Bahar Demirdirek;Alexer Harmon;David Orban
Macromolecular Bioscience 2010 Volume 10( Issue 4) pp:415-423
Publication Date(Web):
DOI:10.1002/mabi.200900335
Co-reporter:Brittany M. deRonde, Ashley L. Carbone, Kathryn Uhrich
Polymer Degradation and Stability 2010 Volume 95(Issue 9) pp:1778-1782
Publication Date(Web):September 2010
DOI:10.1016/j.polymdegradstab.2010.05.008
Storage stability was evaluated on a biodegradable salicylate-based poly(anhydride-ester) to elucidate the effects of storage conditions over time. The hydrolytically labile polymer samples were stored in powdered form at five relevant storage temperatures (−12 °C, 4 °C, 27 °C, 37 °C, 50 °C) and monitored over four weeks for changes in color, glass transition temperature, molecular weight, and extent of hydrolysis. Samples stored at lower temperatures remained relatively constant with respect to bond hydrolysis and molecular weight. Whereas, samples stored at higher temperatures displayed significant hydrolysis. For hydrolytically degradable polymers, such as these poly(anhydride-esters), samples are best stored at low temperatures under an inert atmosphere.
Co-reporter:Youngmi Kim
Journal of Polymer Science Part A: Polymer Chemistry 2010 Volume 48( Issue 24) pp:6003-6008
Publication Date(Web):
DOI:10.1002/pola.24381
Co-reporter:Jinzhong Wang, Leilani S. del Rosario, Bahar Demirdirek, Angela Bae, Kathryn E. Uhrich
Acta Biomaterialia 2009 Volume 5(Issue 3) pp:883-892
Publication Date(Web):March 2009
DOI:10.1016/j.actbio.2008.10.019
Abstract
Two classes of amphiphilic macromolecules were evaluated for drug delivery applications: those that exist as unimolecular micelles and those that self-assemble in aqueous solution to form micelles. This study compares the poly(ethylene glycol) (PEG) chain length and density that constitute the corona of both classes. In particular, the effect of PEG branching on micellar size, water-solubility, resolubilization rate, drug loading efficiency and drug release rate were analyzed. Pluronic P85 and Cremophor EL, commonly used in pharmaceutical applications, were used as controls. Indomethacin (IMC) was used as the drug for encapsulation, release and resolubilization experiments. Results indicated that smaller micellar sizes, higher water solubilities and faster resolubilization rates were achieved from higher PEG densities compared to linear PEG analog of similar mass. Further, micellar sizes of both higher density PEG and linear PEG macromolecules were constant over a wide temperature range (2–70 °C). In contrast, Cremophor EL formed aggregates at 15 °C and Pluronic P85 underwent a size transition at 45 °C. IMC loading efficiencies for all amphiphilic macromolecules were comparable to controls. However, faster resolubilization and slower drug release were observed for higher density PEG macromolecules compared to linear PEG analogs and controls.
Co-reporter:Almudena Prudencio;Ashley L. Carbone;Jeremy Griffin
Macromolecular Rapid Communications 2009 Volume 30( Issue 13) pp:1101-1108
Publication Date(Web):
DOI:10.1002/marc.200900059
Co-reporter:Ashley L. Carbone
Macromolecular Rapid Communications 2009 Volume 30( Issue 12) pp:1021-1026
Publication Date(Web):
DOI:10.1002/marc.200900029
Co-reporter:Michelle L. Johnson
Journal of Biomedical Materials Research Part A 2009 Volume 91A( Issue 3) pp:671-678
Publication Date(Web):
DOI:10.1002/jbm.a.32288
Abstract
A polymer blend consisting of antimicrobials (chlorhexidine, clindamycin, and minocycline) physically admixed at 10% by weight into a salicylic acid-based poly (anhydride-ester) (SA-based PAE) was developed as an adjunct treatment for periodontal disease. The SA-based PAE/antimicrobial blends were characterized by multiple methods, including contact angle measurements and differential scanning calorimetry. Static contact angle measurements showed no significant differences in hydrophobicity between the polymer and antimicrobial matrix surfaces. Notable decreases in the polymer glass transition temperature (Tg) and the antimicrobials' melting points (Tm) were observed indicating that the antimicrobials act as plasticizers within the polymer matrix. In vitro drug release of salicylic acid from the polymer matrix and for each physically admixed antimicrobial was concurrently monitored by high pressure liquid chromatography during the course of polymer degradation and erosion. Although the polymer/antimicrobial blends were immiscible, the initial 24 h of drug release correlated to the erosion profiles. The SA-based PAE/antimicrobial blends are being investigated as an improvement on current localized drug therapies used to treat periodontal disease. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009
Co-reporter:Ashley L. Carbone, MinJung Song and Kathryn E. Uhrich
Biomacromolecules 2008 Volume 9(Issue 6) pp:
Publication Date(Web):May 16, 2008
DOI:10.1021/bm8000759
Poly(anhydride-esters) based on iodinated versions of salicylic acid were synthesized via both melt-condensation and solution polymerization techniques to generate radiopaque biomaterials. The poly(anhydride-esters) from iodinated salicylates were highly X-ray opaque compared to poly(anhydride-esters) from salicylic acid. Molecular weight and Young’s modulus of polymers prepared by melt-condensation were typically two-to-three times higher than polymers prepared by solution methods. The glass transition temperatures of the polymers were dependent on the iodine concentration; polymers containing more iodine had higher glass transition temperatures. Cytotoxicity studies using mouse fibroblasts indicated that iodinated salicylate-based poly(anhydride-esters) prepared by both polymerization methods are biocompatible with cells at low polymer concentrations (0.01 mg/mL).
Co-reporter:MinJung Song
Annals of Biomedical Engineering 2007 Volume 35( Issue 10) pp:1812-1820
Publication Date(Web):2007 October
DOI:10.1007/s10439-007-9348-0
Micropattern dimensions can significantly influence neurite outgrowth orientation, rate, and length. Laminin micropatterns of various widths from 10 to 50 μm at 10 μm intervals separated by 40 μm spaces were generated on poly(methyl methacrylate) surfaces using microscale plasma-initiated patterning (μPIP). Dissociated dorsal root ganglion (DRG) neurons were seeded on the micropatterned surfaces and cultured for 24 h in serum-free media. Neurite outgrowth numbers, lengths, rates, and orientations were measured on all micropatterned substrates. The results indicated that the dimension of the laminin pattern influenced the neurite outgrowth length, rate, and orientation, but not the numbers of neurite outgrowth. Neurons on more than 30 μm wide laminin pattern showed faster neurite outgrowth compared to other dimensions, and relatively low orientation at 50 μm pattern dimensions. Neurites at 40 μm laminin pattern widths demonstrated the fastest outgrowth rates and were highly oriented. The 40 μm laminin dimension is wide enough to provide sufficient laminin amounts for neuron growth and narrow enough to efficiently guide neurites. Based on these results, adhesive protein micropatterns of 40 μm dimensions are recommended when investigating DRG neurons.
Co-reporter:Yingyue Zhang, Ammar Algburi, Ning Wang, Vladyslav Kholodovych, Drym O. Oh, Michael Chikindas, Kathryn E. Uhrich
Nanomedicine: Nanotechnology, Biology and Medicine (February 2017) Volume 13(Issue 2) pp:
Publication Date(Web):February 2017
DOI:10.1016/j.nano.2016.07.018
Inspired by high promise using naturally occurring antimicrobial peptides (AMPs) to treat infections caused by antimicrobial-resistant bacteria, cationic amphiphiles (CAms) were strategically designed as synthetic mimics to overcome associated limitations, including high manufacture cost and low metabolic stability. CAms with facially amphiphilic conformation were expected to demonstrate membrane-lytic properties and thus reduce tendency of resistance development. By systematically tuning the hydrophobicity, CAms with optimized compositions exhibited potent broad-spectrum antimicrobial activity (with minimum inhibitory concentrations in low μg/mL range) as well as negligible hemolytic activity. Electron microscope images revealed the morphological and ultrastructure changes of bacterial membranes induced by CAm treatment and validated their membrane-disrupting mechanism. Additionally, an all-atom molecular dynamics simulation was employed to understand the CAm-membrane interaction on molecular level. This study shows that these CAms can serve as viable scaffolds for designing next generation of AMP mimics as antimicrobial alternatives to combat drug-resistant pathogens.Taking a biomimetic approach, we strategically synthesized two series of cationic camphiphiles (CAms) as synthetic mimics of antimicrobial peptides. Notably, one identified lead compound has one of the best antimicrobial properties reported in the literature to date, with minimum inhibitory concentrations in low μg/mL range, as well as negligible toxicity. We validated that CAms possess antimicrobial activity with membrane-disrupting mechanism, which can reduce tendency of resistance development in bacteria. This study demonstrates that these CAms can serve as viable scaffolds for rationally designing the next generation of effective antimicrobial agents to combat drug-resistant pathogens.
Co-reporter:Jennifer W. Chan, Daniel R. Lewis, Latrisha K. Petersen, Prabhas V. Moghe, Kathryn E. Uhrich
Biomaterials (April 2016) Volume 84() pp:
Publication Date(Web):April 2016
DOI:10.1016/j.biomaterials.2015.12.033
While the development of second- and third-generation drug-eluting stents (DES) have significantly improved patient outcomes by reducing smooth muscle cell (SMC) proliferation, DES have also been associated with an increased risk of late-stent thrombosis due to delayed re-endothelialization and hypersensitivity reactions from the drug-polymer coating. Furthermore, DES anti-proliferative agents do not counteract the upstream oxidative stress that triggers the SMC proliferation cascade. In this study, we investigate biocompatible amphiphilic macromolecules (AMs) that address high oxidative lipoprotein microenvironments by competitively binding oxidized lipid receptors and suppressing SMC proliferation with minimal cytotoxicity. To determine the influence of nanoscale assembly on proliferation, micelles and nanoparticles were fabricated from AM unimers containing a phosphonate or carboxylate end-group, a sugar-based hydrophobic domain, and a hydrophilic poly(ethylene glycol) domain. The results indicate that when SMCs are exposed to high levels of oxidized lipid stimuli, nanotherapeutics inhibit lipid uptake, downregulate scavenger receptor expression, and attenuate scavenger receptor gene transcription in SMCs, and thus significantly suppress proliferation. Although both functional end-groups were similarly efficacious, nanoparticles suppressed oxidized lipid uptake and scavenger receptor expression more effectively compared to micelles, indicating the relative importance of formulation characteristics (e.g., higher localized AM concentrations and nanotherapeutic stability) in scavenger receptor binding as compared to AM end-group functionality. Furthermore, AM coatings significantly prevented platelet adhesion to metal, demonstrating its potential as an anti-platelet therapy to treat thrombosis. Thus, AM micelles and NPs can effectively repress early stage SMC proliferation and thrombosis through non-cytotoxic mechanisms, highlighting the promise of nanomedicine for next-generation cardiovascular therapeutics.
Co-reporter:Jennifer W. Chan, Daniel R. Lewis, Latrisha K. Petersen, Prabhas V. Moghe, Kathryn E. Uhrich
Biomaterials (April 2016) Volume 84() pp:219-229
Publication Date(Web):April 2016
DOI:10.1016/j.biomaterials.2015.12.033
While the development of second- and third-generation drug-eluting stents (DES) have significantly improved patient outcomes by reducing smooth muscle cell (SMC) proliferation, DES have also been associated with an increased risk of late-stent thrombosis due to delayed re-endothelialization and hypersensitivity reactions from the drug-polymer coating. Furthermore, DES anti-proliferative agents do not counteract the upstream oxidative stress that triggers the SMC proliferation cascade. In this study, we investigate biocompatible amphiphilic macromolecules (AMs) that address high oxidative lipoprotein microenvironments by competitively binding oxidized lipid receptors and suppressing SMC proliferation with minimal cytotoxicity. To determine the influence of nanoscale assembly on proliferation, micelles and nanoparticles were fabricated from AM unimers containing a phosphonate or carboxylate end-group, a sugar-based hydrophobic domain, and a hydrophilic poly(ethylene glycol) domain. The results indicate that when SMCs are exposed to high levels of oxidized lipid stimuli, nanotherapeutics inhibit lipid uptake, downregulate scavenger receptor expression, and attenuate scavenger receptor gene transcription in SMCs, and thus significantly suppress proliferation. Although both functional end-groups were similarly efficacious, nanoparticles suppressed oxidized lipid uptake and scavenger receptor expression more effectively compared to micelles, indicating the relative importance of formulation characteristics (e.g., higher localized AM concentrations and nanotherapeutic stability) in scavenger receptor binding as compared to AM end-group functionality. Furthermore, AM coatings significantly prevented platelet adhesion to metal, demonstrating its potential as an anti-platelet therapy to treat thrombosis. Thus, AM micelles and NPs can effectively repress early stage SMC proliferation and thrombosis through non-cytotoxic mechanisms, highlighting the promise of nanomedicine for next-generation cardiovascular therapeutics.
Co-reporter:N. D. Stebbins, J. J. Faig, W. Yu, R. Guliyev and K. E. Uhrich
Biomaterials Science (2013-Present) 2015 - vol. 3(Issue 8) pp:NaN1187-1187
Publication Date(Web):2015/06/02
DOI:10.1039/C5BM00051C
Significant and promising advances have been made in the polymer field for controlled and sustained bioactive delivery. Traditionally, small molecule bioactives have been physically incorporated into biodegradable polymers; however, chemical incorporation allows for higher drug loading, more controlled release, and enhanced processability. Moreover, the advent of bioactive-containing monomer polymerization and hydrolytic biodegradability allows for tunable bioactive loading without yielding a polymer residue. In this review, we highlight the chemical incorporation of different bioactive classes into novel biodegradable and biocompatible polymers. The polymer design, synthesis, and formulation are summarized in addition to the evaluation of bioactivity retention upon release via in vitro and in vivo studies.
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