In vivo evaluation of doxorubicin-loaded polymeric micelles targeting folate receptors and early endosomal pH in drug-resistant ovarian cancer.
The second generation of pH-sensitive micelles composed of poly(l-histidine-co-l-phenlyalanine(16 mol %))(MW:5K)-b-PEG(MW:2K) and poly(l-lactic acid)(MW:3K)-b-PEG(MW:2K)-folate (80/20 wt/wt %) was previously optimized by physicochemical and in vitro tests for both folate receptor and early endosomal pH targeting (pH approximately 6.0). In this study, the therapeutic efficacy of the doxorubicin (DOX)-loaded micelles (DOX loading content: 20 wt %) was evaluated using in vivo tests. Multidrug-resistant (MDR) ovarian tumor-xenografted mouse models were employed. The skin-fold dorsal window chamber model was applied for visualization of extravasation and drug retention for the initial one hour after iv injection. Noninvasive imaging followed, providing evidence of drug accumulation in the tumor after the first hour. The biodistribution study further supported the long circulation of the drug carrier, tumor-selective accumulation and intracellular drug delivery. Comprehensive tumor growth inhibition experiments examined the collective efficacy of the pH-sensitive micelles. The micelle formulation effectively suppressed the growth of existing MDR tumors in mice for at least 50 days by three iv injections at a 3-day interval at a dose of 10 mg of DOX/kg. The body weight of the animals treated with the test micelle formulation gradually increased over the experimental time period, rather than decreasing. The micelle formulation was superior to its first generation, which targeted pH 6.8 and folate receptor.
Kim
Dongin
D
Department of Pharmaceutics, University of Utah, 421 Wakara Way, Suite 318, Salt Lake City, Utah 84108, USA.
Gao
Zhong Gao
ZG
Lee
Eun Seong
ES
Bae
You Han
YH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D004337:Drug Carriers; D058973:Folate Receptors, GPI-Anchored; D008823:Micelles; D011091:Polyesters; D011108:Polymers; D011506:Proteins; D011956:Receptors, Cell Surface; C507888:poly(histidine-co-phenylalanine)-block-poly(ethylene glycol); C534468:poly(lactic acid)-block-polyethylene glycol-folate; D011092:Polyethylene Glycols; D004317:Doxorubicin