Abstract
Doxorubicin (DOX) is one of the most common chemotherapeutic agents for the treatment of various cancers, but its clinical usage is limited by dose-dependent cardiotoxicity. We have recently synthesized a series of Chondroitin sulfate/poly (d,l-lactideco-glycolide) block copolymers (Chs-b-PLGA) with different length of hydrophobic block by an end-to-end coupling strategy. The structure of the amphiphilic block copolymers with low critical micelle concentration (∼28mg/L) were confirmed by 1H NMR. The copolymers could self-assemble into stable micelles in aqueous environment with homogeneous size distribution and negative zeta potential. The hemolytic study indicated their excellent blood compatibility and potential application for intravenous administration. DOX can be efficiently encapsulated by the Chs-b-PLGA micelles. The DOX-loaded micelles showed a sustained and pH dependent drug release behavior. The cytotoxicity assay showed no associated toxicity with blank micelles while concentration-related cell inhibition with DOX-loaded micelles. Moreover, fast cellular uptake of DOX-loaded micelles was observed by fluorescent microscope. In vivo pharmacokinetics study showed that the Chs-b-PLGA micelles could significantly prolong the blood circulation time of DOX. The maximum tolerated dose (MTD) of DOX-loaded micelles in Kunming mice was about 2-fold higher of the MTD of free DOX, indicating a high tolerance of the DOX-loaded micelles. In conclusion, the Chs-b-PLGA micelles would be a potentially useful drug delivery system for cancer therapy.
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