Synthesis and characterization of low-toxic amphiphilic chitosan derivatives and their application as micelle carrier for antitumor drug.
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) was synthesized for use as drug carriers. The chemical structure was characterized by Fourier transform infrared, (1)H nuclear magnetic resonance, and elemental analysis. OGC could easily self-assemble to form nanomicelles in an aqueous environment and exhibited a low critical micellar concentration of 5.3-32.5mg/L. The biocompatibility and low toxicity of OGC as excipient for the dosage forms aimed at i.v. administration were confirmed by hemolysis, acute toxicity and histopathological studies. Furthermore, the possibility of solubilizing paclitaxel (PTX), a water-insoluble antitumor drug, with OGC micelles was also explored. PTX was successfully loaded into OGC micelles by using a simple dialysis process. The drug-loading capacity of OGC and stability of drug-loaded micelles were significantly affected by the degree of substitution 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((R))), in terms of low toxicity levels and increased tolerated 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.
Huo
Meirong
M
Department of Pharmaceutics, China Pharmaceutical University, No. 24, Tongjiaxiang, 210009, Nanjing, China.
Zhang
Yong
Y
Zhou
Jianping
J
Zou
Aifeng
A
Yu
Di
D
Wu
Yiping
Y
Li
Jing
J
Li
Hong
H
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000633:toxicity; D048271:Chitosan / Q000737:chemistry*; D003956:Dialysis; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004355:Drug Stability; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000633:toxicity; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D023382:Toxicity Tests, Acute
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; C000515:cremophor EL; D048271:Chitosan; D017239:Paclitaxel; D005990:Glycerol