title: Biodegradable hybrid polymer micelles for combination drug therapy in ovarian cancer.
abstract: The co-delivery of drug combination at a controlled ratio via the same vehicle to the cancer cells is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and increased therapeutic potency. In an attempt to develop such multidrug vehicle this work focuses on functional biodegradable and biocompatible polypeptide-based polymeric micelles. Triblock copolymers containing the blocks of ethylene glycol, glutamic acid and phenylalanine (PEG-PGlu-PPhe) were successfully synthesized via NCA-based ring-opening copolymerization and their composition was confirmed by (1)H NMR. Self-assembly behavior of PEG-PGlu90-PPhe25 was utilized for the synthesis of hybrid micelles with PPhe hydrophobic core, cross-linked ionic PGlu intermediate shell layer, and PEG corona. Cross-linked (cl) micelles were about 90nm in diameter (ξ-potential=-20mV), uniform (narrow size distribution), and exhibited nanogels-like behavior. Degradation of cl-micelles was observed in the presence of proteolytic enzymes (cathepsin B). The resulting cl-micelles can incorporate the combination of drugs with very different physical properties such as cisplatin (15 w/w% loading) and paclitaxel (9 w/w% loading). Binary drug combination in cl-micelles exhibited synergistic cytotoxicity against human ovarian A2780 cancer cells and exerted a superior antitumor activity by comparison to individual drug-loaded micelles or free cisplatin in cancer xenograft model in vivo. Tunable composition and stability of these hybrid biodegradable micelles provide platform for drug combination delivery in a broad range of cancers.
authors.affiliation: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha 68198-5830, USA.
authors.forename: Swapnil S
authors.initials: SS
authors.lastname: Desale
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.forename: Tatiana K
authors.initials: TK
authors.lastname: Bronich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000627:therapeutic use; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005260:Female; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D010649:Phenylalanine / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D008823:Micelles; D018698:Glutamic Acid; D011092:Polyethylene Glycols; D010649:Phenylalanine; D017239:Paclitaxel; D002945:Cisplatin
keywords: Cisplatin; Combination drug delivery; Controlled release; Cross-linked polymer micelles; Ovarian cancer; Paclitaxel