Doxorubicin-conjugated biodegradable polymeric micelles having acid-cleavable linkages.
Doxorubicin was chemically conjugated to the terminal end of a di-block copolymer composed of poly(L-lactic acid) (PLLA) and methoxy-poly(ethylene glycol) (mPEG) via two acid-cleavable linkages. A hydrazone bond and a cis-acotinyl bond were formed between doxorubicin and the terminal group of PLLA segment in the block copolymer. Doxorubicin-conjugated PLLA-mPEG di-block copolymers self-assembled to form micelles in aqueous solution. The doxorubicin-conjugated micelles were about 89.1 nm in diameter and their critical micelle concentration was 1.3 microg/ml. These values were comparable with those of unconjugated micelles. In an acidic condition, the conjugated doxorubicin in the hydrazone linkage was readily cleaved, releasing doxorubicin in an intact structure. Doxorubicin-conjugated PLLA-mPEG micelles were more potent in cell cytotoxicity than free doxorubicin, suggesting that they were more easily taken up within cells with concomitant rapid release of cleaved doxorubicin into the cytoplasm from acidic endosomes.
Yoo
Hyuk Sang
HS
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea.
Lee
Eun Ah
EA
Park
Tae Gwan
TG
D001672:Biocompatible Materials / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems; D006801:Humans; D008823:Micelles; D011091:Polyesters / Q000737:chemistry* / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry; D014407:Tumor Cells, Cultured
D001672:Biocompatible Materials; D008823:Micelles; D011091:Polyesters; D011108:Polymers; C466990:doxorubicin-conjugated poly-(L-lactic acid)-di-block-methoxypoly(ethylene glycol); D004317:Doxorubicin