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Synthesis and characterization of biodegradable and biocompatible amphiphilic chitosan derivatives and their application as antitumor drug carriers

【摘要】:A new series of amphiphilically modified chitosan molecules with long alkyl chains as hydrophobic moieties and glycol groups as hydrophilic moieties (N-octyl-O-glycol chitosan, OGC) were synthesized for the use as drug carriers. The chemical structure was characterized by FT-IR, 1H-NMR and elemental analysis. OGC could easily self-assemble to form nano-micelles in an aqueous environment and exhibited a low critical micellar concentration (CMC) at 5.3-32.5 mg/L. The biocompatibility and low toxicity of OGC as excipient for the dosage forms aimed at i.v. administration was confirmed by the results of hemolysis, acute toxicity and histopathological studies. Furthermore, the possibility of solubilizing paclitaxel (PTX), a water-insoluble antitumor drug, with OGC micelle was also explored. PTX was successfully loaded into OGC micelles using a simple dialysis process. The drug loading capacity of OGC, stability of drug-loaded micelles and in vitro release rate of PTX were significantly affected by the degree of substation (DS) of alkyl chains. Moreover, a series of safety studies including hemolysis, hypersensitivity, maximum tolerated dose, acute toxicity, and organ toxicity revealed that the PTX-loaded OGC micelles had advantages over the commercially available injectable preparation of PTX (Taxol), in terms of low toxicity levels and increased dose. Additionally, cytotoxicity studies showed that the PTX-loaded OGC micelles were comparable to the commercial formulation, but the blank micelles were far less toxic than the Cremophor EL vehicle. These results suggest that OGC is a promising carrier for injectable PTX micelles.

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