The delivery of doxorubicin to 3-D multicellular spheroids and tumors in a murine xenograft model using tumor-penetrating triblock polymeric micelles.
Doxorubicin (DOX) is an effective chemotherapeutic against a wide range of solid tumors. However, its clinical use is limited by severe side effects such as cardiotoxicity as well as inherent and acquired drug resistance of tumors. DOX encapsulation within self-assembled polymeric micelles has the potential to decrease the systemic distribution of free drug and enhance the drug accumulation in the tumor via the enhanced permeability and retention (EPR). In this study, DOX was encapsulated in micelles composed of poly (ethylene oxide)-poly [(R)-3-hydroxybutyrate]-poly (ethylene oxide) (PEO-PHB-PEO) triblock copolymers. Micelle size, DOX loading and DOX release were characterized. To evaluate DOX activity, micelles were tested in both monolayer cell cultures and three-dimensional (3-D) multicellular spheroids (MCS) that mimic solid tumors. Antitumor activity in vivo was further studied with tumor-bearing mice. The micelles improved the efficiency of Dox penetration in 3-D MCS compared with free DOX. Efficient cell killing by Dox-micelles in both monolayer cells and 3-D MCS was also demonstrated. Finally, DOX-loaded micelles mediate efficient tumor delivery from tail vein injections to tumor-bearing mice with much less toxicity compared with free DOX.
Kim
Tae-Hee
TH
Department of Bioengineering, University of Washington, Seattle, WA 98195-5061, USA.
Mount
Christopher W
CW
Gombotz
Wayne R
WR
Pun
Suzie H
SH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004339:Drug Compounding; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D008422:Materials Testing; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism; D000091402:Prohibitins; D018874:Spheroids, Cellular / Q000187:drug effects*; D014183:Transplantation, Heterologous; D000094122:Polyhydroxybutyrates
D000903:Antibiotics, Antineoplastic; D001672:Biocompatible Materials; D004317:Doxorubicin; D008823:Micelles; D011092:Polyethylene Glycols; D011108:Polymers; D000091402:Prohibitins; C000717328:PHB protein, human; C512724:poly(ethylene oxide)-poly(3-hydroxybutyrate)-poly(ethylene oxide); D000094122:Polyhydroxybutyrates