title: Targeted transferrin-modified polymeric micelles: enhanced efficacy in vitro and in vivo in ovarian carcinoma.
abstract: In this study, transferrin (Tf)-modified poly(ethylene glycol)-phosphatidylethanolamine (mPEG-PE) micelles loaded with the poorly water-soluble drug, R547 (a potent and selective ATP-competitive cyclin-dependent kinase (CDK) inhibitor), were prepared and evaluated for their targeting efficiency and cytotoxicity in vitro and in vivo to A2780 ovarian carcinoma cells, which overexpress transferrin receptors (TfR). At 10 mM lipid concentration, both Tf-modified and plain micelles solubilized 800 μg of R547. Tf-modified micelles showed enhanced interaction with A2780 ovarian carcinoma cells in vitro. The involvement of TfR in endocytosis of Tf-modified micelles was confirmed by colocalization studies of micelle-treated cells with the endosomal marker Tf-Alexa488. We confirmed endocytosis of micelles in an intact form with micelles loaded with a fluorescent dye and additionally labeled with fluorescent lipid. The in vitro cytotoxicity and in vivo tumor growth inhibition studies in A2780-tumor bearing mice confirmed the enhanced efficacy of Tf-modified R547-loaded micelles compared to free drug solution and to nonmodified micelles. The results of this study demonstrate the potential application of Tf-conjugated polymeric micelles in the treatment of tumors overexpressing TfR.
authors: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston, Massachusetts 02115, United States.
authors: Rupa R
authors: RR
authors: Sawant
authors: Aditi M
authors: AM
authors: Jhaveri
authors: Alexander
authors: A
authors: Koshkaryev
authors: Lin
authors: L
authors: Zhu
authors: Farooq
authors: F
authors: Qureshi
authors: Vladimir P
authors: VP
authors: Torchilin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008823:Micelles; D018613:Microscopy, Confocal; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D014168:Transferrin / Q000378:metabolism*; D014867:Water / Q000737:chemistry
chemical_list: C515235:(4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl)(2,3-difluoro-6-methoxyphenyl)methanone; D000970:Antineoplastic Agents; D008823:Micelles; D011743:Pyrimidines; D014168:Transferrin; D014867:Water