Nanogels (NGs) as soft nanosized materials have gained a variety of interests in biomedical fields. The versatile NG scaffolds with 3-dimensional spherical shape, high loading efficiency, tunable surface functionalization, and excellent biocompatibility afford their uses as carrier to load mono- or multi-mode molecular imaging contrast agents (CAs). This review summarizes the synthesis routes and applications of NGs as CAs for molecular imaging applications including magnetic resonance (MR), computed tomography (CT), radionuclide, optical, and dual/multi-modality imaging.

Capturing circulating tumor cells (CTCs) with sufficient sensitivity and specificity in vitro is of paramount importance for early cancer diagnosis. Here a facile approach to immobilizing hyaluronic acid (HA) onto electrospun polyvinyl alcohol/polyethyleneimine (PVA/PEI) nanofibers for capturing cancer cells overexpressing CD44 receptors is reported. In this study, electrospun PVA/PEI nanofibers were crosslinked using glutaraldehyde vapor, covalently conjugated with HA via N-(3-dimethy-laminopropyl)-N′-ethylcarbodiimide/N-hydroxysuccinimide coupling reaction, followed by neutralization of the remaining fiber surface PEI amines via acetylation. The formed nanofibers were characterized using different techniques. It is shown that the HA-modified PVA/PEI nanofibers with a mean diameter of 459.7 nm possess a smooth and uniform fibrous morphology, similar to the PVA/PEI nanofibers without HA modification. The HA-modified PVA/PEI nanofibers display good cytocompatibility and hemocompatibility as confirmed by cell viability, hemolysis, and anticoagulant assays. Importantly, with the modified HA, the nanofibers exhibit superior capability to capture CD44 receptor-overexpressing cancer cells. The developed HA-modified PVA/PEI nanofibers may hold a great promise to be applied for capturing CTCs for cancer diagnosis applications.

We report here a general approach to using poly(amidoamine) (PAMAM) dendrimers modified with polyethylene glycol (PEG) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for in vitro cancer therapy applications. In this approach, PEGylated PAMAM dendrimers were synthesized by conjugating monomethoxypolyethylene glycol with carboxylic acid end group (mPEG-COOH) onto the surface of generation 5 amine-terminated PAMAM dendrimer (G5.NH₂), followed by acetylation of the remaining dendrimer terminal amines. By varying the molar ratios of mPEG-COOH/G5.NH₂, G5.NHAc-mPEG_n (n = 5, 10, 20, and 40, respectively) with different PEGylation degrees were obtained. We show that the PEGylated dendrimers are able to encapsulate DOX with approximately similar loading capacity regardless of the PEGylation degree. The formed dendrimer/DOX complexes are water soluble and stable. In vitro release studies show that DOX complexed with the PEGylated dendrimers can be released in a sustained manner. Further cell viability assay in conjunction with cell morphology observation demonstrates that the G5.NHAc-mPEG_n/DOX complexes display effective antitumor activity, and the DOX molecules encapsulated within complexes can be internalized into the cell nucleus, similar to the free DOX drug. Findings from this study suggest that PEGylated dendrimers may be used as a general drug carrier to encapsulate various hydrophobic drugs for different therapeutic applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40358.

We report the use of multifunctional dendrimer-modified multi-walled carbon nanotubes (MWCNTs) for targeted and pH-responsive delivery of doxorubicin (DOX) into cancer cells. In this study, amine-terminated generation 5 poly(amidoamine) (PAMAM) dendrimers modified with fluorescein isothiocyanate (FI) and folic acid (FA) were covalently linked to acid-treated MWCNTs, followed by acetylation of the remaining dendrimer terminal amines to neutralize the positive surface potential. The formed multifunctional MWCNTs (MWCNT/G5.NHAc-FI-FA) were characterized via different techniques. Then, the MWCNT/G5.NHAc-FI-FA was used to load DOX for targeted and pH-responsive delivery to cancer cells overexpressing high-affinity folic acid receptors (FAR). We showed that the MWCNT/G5.NHAc-FI-FA enabled a high drug payload and encapsulation efficiency both up to 97.8% and the formed DOX/MWCNT/G5.NHAc-FI-FA complexes displayed a pH-responsive release property with fast DOX release under acidic environment and slow release at physiological pH conditions. Importantly, the DOX/MWCNT/G5.NHAc-FI-FA complexes displayed effective therapeutic efficacy, similar to that of free DOX, and were able to target to cancer cells overexpressing high-affinity FAR and effectively inhibit the growth of the cancer cells. The synthesized multifunctional dendrimer-modified MWCNTs may be used as a targeted and pH-responsive delivery system for targeting therapy of different types of cancer cells.

In this article, we report the surface modification of branched polyethyleneimine (PEI) for improved biocompatibility. PEIs with different surface functionalities were synthesized via covalent modification of the PEI amines, including neutralized PEI modified with acetic anhydride, negatively charged PEI modified with succinic anhydride, hydroxylated PEI modified with glycidol, and PEI–poly(ethylene glycol) (PEG) conjugates modified with both PEG and acetic anhydride. The modified PEI derivatives were characterized with ¹H-NMR, Fourier transform infrared spectroscopy, and ζ-potential measurements. An in vitro cytotoxicity assay of mouse fibroblasts revealed that the biocompatibility of PEI was significantly improved after these modifications. The neutral and negatively charged PEIs were nontoxic at concentrations up to 200 μg/mL, whereas the pristine PEI was toxic to cells at concentrations as low as 10 μg/mL. The successfully modified PEIs with different surface charges and functionalities may provide a range of opportunities for various biomedical applications. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

One of the major problems of nanofiber scaffold or other devices like cardiovascular or blood-contacting medical devices is their weak mechanical properties and the lack of hemocompatibility of their surfaces. In this study, halloysite nanotubes (HNTs) and carbon nanotubes (CNTs) were incorporated within poly(lactic-co-glycolic acid) (PLGA) nanofibers and the mechanical property and hemocompatibility of both types of composite nanofibers with different doping levels were thoroughly investigated. The morphology and internal distribution of the doped nanotubes within the nanofibers were characterized using scanning electron microscopy and transmission electron microscopy. Mechanical properties of the electrospun nanofibers were tested using a material testing machine. The hemocompatibility of the composite nanofibers was examined through hemolytic and anticoagulant assay, respectively. We show that the doped HNTs or CNTs are distributed in the nanofibers with a coaxial manner and the incorporation of HNTs or CNTs does not significantly change the morphology of the PLGA nanofibers. Importantly, the incorporation of HNTs or CNTs within PLGA nanofibers significantly improves the mechanical property of PLGA nanofibers, and PLGA nanofibers with or without doping of the HNTs and CNTs display good anticoagulant property and negligible hemolytic effect to human red blood cells. With the enhanced mechanical property, great hemocompatibility, and previously demonstrated biocompatibility of both HNTs- and CNTs-doped composite PLGA nanofibers, these composite nanofibers may be used as therapeutic artificial tissue/organ substitutes for tissue engineering applications. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

We report a facile approach to fabricating low-generation poly(amidoamine) (PAMAM) dendrimer-stabilized gold nanoparticles (Au DSNPs) functionalized with folic acid (FA) for in vitro and in vivo targeted computed tomography (CT) imaging of cancer cells. In this study, amine-terminated generation 2 PAMAM dendrimers were employed as stabilizers to form Au DSNPs without additional reducing agents. The formed Au DSNPs with an Au core size of 5.5 nm were covalently modified with the targeting ligand FA, followed by acetylation of the remaining dendrimer terminal amines to endow the particles with targeting specificity and improved biocompatibility. Our characterization data show that the formed FA-modified Au DSNPs are stable at different pH values (5—8) and temperatures (4–50 °C), as well as in different aqueous media. MTT assay data along with cell morphology observations reveal that the FA-modified Au DSNPs are noncytotoxic in the particle concentration range of 0–3000 nM. X-ray attenuation coefficient measurements show that the CT value of FA-modified Au DSNPs is much higher than that of Omnipaque (a clinically used CT contrast agent) at the same concentration of the radiodense elements (Au or iodine). Importantly, the FA-modified Au DSNPs are able to specifically target a model cancer cell line (KB cells, a human epithelial carcinoma cell line) over-expressing FA receptors and they enable targeted CT imaging of the cancer cells in vitro and the xenografted tumor model in vivo after intravenous administration of the particles. With the simple synthesis approach, easy modification, good cytocompatibility, and high X-ray attenuation coefficient, the FA-modified low-generation Au DSNPs could be used as promising contrast agents for targeted CT imaging of different tumors over-expressing FA receptors.

Monodisperse silica-coated manganese oxide nanoparticles (NPs) with a diameter of ∼35 nm are synthesized and are aminated through silanization. The amine-functionalized core–shell NPs enable the covalent conjugation of a fluorescent dye, Rhodamine B isothiocyanate (RBITC), and folate (FA) onto their surface. The formed Mn₃O₄@SiO₂(RBITC)–FA core–shell nanocomposites are water-dispersible, stable, and biocompatible when the Mn concentration is below 50 µg mL⁻¹ as confirmed by a cytotoxicity assay. Relaxivity measurements show that the core–shell NPs have a T₁ relaxivity (r₁) of 0.50 mM⁻¹ s⁻¹ on the 0.5 T scanner and 0.47 mM⁻¹ s⁻¹ on the 3.0 T scanner, suggesting the possibility of using the particles as a T₁ contrast agent. Combined flow cytometry, confocal microscopy, and magnetic resonance imaging studies show that the Mn₃O₄@SiO₂(RBITC)–FA nanocomposites can specifically target cancer cells overexpressing FA receptors (FARs). Findings from this study suggest that the silica-coated Mn₃O₄ core–shell NPs could be used as a platform for bimodal imaging (both magnetic resonance and fluorescence) in various biological systems.

Polyacrylic acid (PAA) is an important polymer material for metal ion complexation and for nanocomposite materials syntheses. Generating ultrafine, uniform, and stable PAA nanofibers is of great scientific and technological interest for various applications. In this study, we systematically investigated the influence of processing parameters on the morphology and stability of the electrospun ultrafine PAA nanofibers. We show that a higher concentration (up to 25 wt %) favored the formation of uniform PAA nanofibers, whereas at the concentration of 10 wt %, only bead structures were produced. Increasing the applied voltage (up to 22.5 kV) resulted in more uniform PAA nanofibers. In addition, longer collection distance (20 cm) was beneficial for the evaporation of solvent and for decreasing the adhesion between nanofibers, thus leading to the nanofibrous mats with high porosity. Finally, the PAA nanofibers could be rendered water insoluble by heating the electrospun composite PAA/polyvinyl alcohol (PVA) nanofibers at 145°C for 30 min. The resulting nanofibrous mats exhibited excellent performance to remove Cu(II) ions in aqueous solution. The formed nanofibers may find various applications in ultrafiltration, separation, and environmental sciences. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Dendrimer-based nanotechnology significantly advances the area of targeted cancer imaging and therapy. Herein, we compared the difference of surface acetylated fluorescein isocyanate (FI) and folic acid (FA) modified generation 5 (G5) poly(amidoamine) dendrimers (G5.NHAc-FI-FA), and dendrimer-entrapped gold nanoparticles with similar modifications ([(Au⁰)_51.2-G5.NHAc-FI-FA]) in terms of their specific internalization to FA receptor (FAR)-overexpressing cancer cells. Confocal microscopic studies show that both G5.NHAc-FI-FA and [(Au⁰)_51.2-G5.NHAc-FI-FA] exhibit similar internalization kinetics regardless of the existence of Au nanoparticles (NPs). Molecular dynamics simulation of the two different nanostructures reveals that the surface area and the FA moiety distribution from the center of the geometry are slightly different. This slight difference may not be recognized by the FARs on the cell membrane, consequently leading to similar internalization kinetics. This study underlines the fact that metal or inorganic NPs entrapped within dendrimers interact with cells in a similar way to that of dendrimers lacking host NPs. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 936–942, 2009.

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