Chenhong Wang

Multifunctional superparamagnetic nanocarriers with folate-mediated and pH-responsive targeting properties for anticancer drug delivery.

Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe(3)O(4) nanoparticle cores with a mixture of the triblock copolymer methoxy poly(ethylene glycol)-b-poly(methacrylic acid-co-n-butyl methacrylate)-b-poly(glycerol monomethacrylate) and the folate-conjugated block copolymer folate-poly(ethylene glycol)-b-poly(glycerol monomethacrylate). The model anticancer agent adriamycin (ADR), containing an amine group and a hydrophobic moiety, was loaded into the nanocarrier at pH 7.4 by ionic bonding and hydrophobic interactions. The release rate of the loaded drug molecules was slow at pH 7.4 (i.e. mimicking the blood environment) but increased significantly at acidic pH (i.e. mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the polycarboxylate protonation of poly(methacrylic acid), which broke the ionic bond between the carrier and ADR. Cellular uptake by folate receptor-overexpressing HeLa cells of the folate-conjugated ADR-loaded nanoparticles was higher than that of non-folated-conjugated nanoparticles. Thus, folate conjugation significantly increased nanoparticle cytotoxicity. These findings show the potential viability of a folate-targeting, pH-responsive nanocarrier for amine-containing anticancer drugs.

Superparamagnetic iron oxide nanoparticles coated with a folate-conjugated polymer

Folate-functionalized magnetic fluids were prepared by direct chemisorption of a folate-tetra(ethylene glycol)-poly(glycerol monoacrylate) (FA-TEG-PGA) conjugate on Fe3O4nanoparticles. In the magnetic fluids, the PGA block of FA-TEG-PGA was chemisorbed onto the Fe3O4nanoparticle surface through its 1,2-diol groups, while the TEG chain conjugated with FA extended into the water matrix. Characterization by transmission electron microscopy, X-ray diffraction and a vibrating sample magnetometer indicated that the pure Fe3O4 superparamagnetic nanoparticles were formed and the coating process did not significantly affect the size and structure of Fe3O4nanoparticles. Fourier transform infrared spectroscopy, UV-vis spectroscopy, thermogravimetric analysis and X-ray photoelectron spectroscopy confirmed the successful coating of FA-TEG-PGA on the Fe3O4nanoparticles, suggested a coating mechanism for the FA-TEG-PGA, and revealed the maximum weight ratio of FA-TEG-PGA to Fe3O4. The dispersion of FA-TEG-PGA-coated Fe3O4nanoparticles possessed excellent stability over a wide range of pH and salt concentrations. Such folate-functionalized magnetic fluids are expected to be targeting contrast agents for magnetic resonance imaging (MRI) applications. This approach represents a new strategy to synthesize functionalized magnetic nanoparticles that form stable dispersions in water and facilitates potential biomedical applications of these magnetic nanoparticles.

Enhanced cell uptake of superparamagnetic iron oxide nanoparticles through direct chemisorption of FITC-Tat-PEG600-b-poly(glycerol monoacrylate)

Magnetic nanoparticles (MNPs) functionalized with specific ligands are emerging as a highly integrated platform for cancer targeting, drug delivery, and magnetic resonance imaging applications. In this study, we describe a multifunctional magnetic nanoparticle system (FITC-Tat MNPs) consisting of a fluorescently labeled cell penetrating peptide (FITC-Tat peptide), a biocompatible block copolymer PEG(600)-b-poly(glycerol monoacrylate) (PEG(600)-b-PGA), and a superparamagnetic iron oxide (SPIO) nanoparticle core. The particles were prepared by direct chemisorption of PEG(600)-b-PGA conjugated with FITC-Tat peptide on the SPIO nanoparticles. FITC-MNPs without Tat were prepared for comparison. Flow cytometry assays revealed significantly higher uptake of FITC-Tat MNPs compared to FITC-MNPs in Caco-2 cells. These results were confirmed using confocal laser scanning microscopy (LSCM), which further demonstrated that the FITC-Tat MNPs accumulated in the cytoplasm and nucleus while the FITC-MNPs were localized in the cell membrane compartments. The FITC-Tat MNPs did not exhibit observable cytotoxicity in MTS assays.

Cisplatin-loaded polymer/magnetite composite nanoparticles as multifunctional therapeutic nanomedicine

Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe3O4 nanoparticles with diblock copolymer folate-poly(ethylene glycol)-b-poly(glycerol monomethacrylate) (FA-PEG-b-PGMA), and triblock copolymer methoxy poly(ethylene glycol)-b-poly(2-(dimethylamino) ethyl methacrylate)-b-poly(glycerol monomethacrylate) (MPEG-b-PDMA-b-PGMA). The PGMA segment was attached to the surfaces of Fe3O4 nanoparticles, and the outer PEG shell imparted biocompatibility. In addition, folate was conjugated onto the surfaces of the nanocarriers. Cisplatin was then loaded into the nanocarrier by coordination between the Pt atom in cisplatin and the amine groups in the inner shell of the multilayer architecture. The loaded cisplatin showed pH-responsive release: slower release at pH 7.4 (i.e. mimicking the blood environment) and faster release at more acidic pH (i.e. mimicking endosome/lysosome conditions). All of the cisplatin-loaded nanoparticles showed concentration-dependent cytotoxicity in HeLa cells. However, the folate-conjugated cisplatin-loaded carriers exhibited higher cytotoxicity in HeLa cells than non-folate conjugated cisplatin-loaded carriers.

Morpholino-decorated long circulating polymeric micelles with the function of surface charge transition triggered by pH changes

Micelles with surface morpholino groups were stealthy at blood and normal tissue pH (7.4) due to the unprotonated hydrophilic morpholino groups on the surfaces. At tumor pH (<7), the micelle surfaces were positively charged because of the protonation of the morpholino groups, which promoted the cellular uptake of the micelles.

Polymeric micelles with α-glutamyl-terminated PEG shells show low non-specific protein adsorption and a prolonged in vivo circulation time.

Although PEG remains the gold standard for stealth functionalization in drug delivery field up to date, complete inhibition of protein corona formation on PEG-coated nanoparticles remains a challenge. To improve the stealth property of PEG, herein an α-glutamyl group was conjugated to the end of PEG and polymeric micelles with α-glutamyl-terminated PEG shells were prepared. After incubation with bovine serum albumin or in fetal calf serum, the size of the micelles changed slightly, while the size of the micelles of similar diblock copolymer but without α-glutamyl group increased markedly. These results indicated that the micelles with α-glutamyl-terminated PEG shells showed low non-specific protein adsorption. In vivo blood clearance kinetics assay showed that the micelles with α-glutamyl-terminated PEG shells exhibited a longer in vivo blood circulation time compared with similar micelles but without α-glutamyl groups. The better stealth property of the micelles with α-glutamyl-terminated PEG shells was presumably attributed to the zwitterionic property of the α-glutamyl groups.

Co-administration of a charge-conversional dendrimer enhances antitumor efficacy of conventional chemotherapy

Graphical abstract Figure. No caption available. &NA; Despite extensive investigations, the clinical translation of nanocarrier‐based drug delivery systems (NDDS) for cancer therapy is hindered by inefficient delivery and poor tumor penetration. Conventional chemotherapy by administration of free small molecule anticancer drugs remains the standard of care for many cancers. Herein, other than for carrying and releasing drugs, small nanoparticles were used as a potentiator of conventional chemotherapy by co‐administration with free chemotherapeutic agents. This strategy avoided the problems associated with drug loading and controlled release encountered in NDDS, and was also much simpler than NDDS. Negatively charged poly(amido amine)‐2,3‐dimethylmaleic monoamide (PAMAM‐DMA) dendrimers were prepared, which possessed low toxicity and can be converted to positively charged PAMAM dendrimers responsive to tumor acidic pH. The in situ formed PAMAM in tumor tissue promoted cellular uptake of co‐administered doxorubicin by increasing the cell membrane permeability, and subsequently enhanced the cytotoxicity of doxorubicin. The small size of the dendrimers was favorable for deep penetration in tumor. Co‐injection of PAMAM‐DMA with doxorubicin into nude mice bearing human tumors almost completely inhibited tumor growth, with a mean tumor weight reducing by 55.9% after the treatment compared with the treatment with doxorubicin alone.