title: Combination cytotoxicity of backbone degradable HPMA copolymer gemcitabine and platinum conjugates toward human ovarian carcinoma cells.
abstract: Multiblock, backbone degradable HPMA copolymer-drug conjugates containing gemcitabine and DACH platinum (mP-GEM and mP-DACH Pt), respectively were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and subsequent chain extension by click chemistry. Using combination index analysis, the cytotoxicities of the two multiblock conjugates, as single agent and in combination, were evaluated in vitro in A2780 human ovarian cancer cells, with free drugs as controls. The greatest synergistic cytotoxic effect was observed when A2780 cells were sequentially exposed to mP-GEM for 24h and mP-DACH Pt for 48h. In addition, mechanistic studies support the rationale of the synergy between mP-GEM and mP-DACH Pt: mP-GEM pretreatment was able to enhance the platinum-DNA adduct accumulation and inhibit cell proliferation to a higher extent than single mP-DACH Pt treatment. These observations are useful for the development of combination macromolecular therapeutics for ovarian cancer based on the second-generation backbone degradable HPMA copolymers.
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; School of Medical Sciences, University of Phayao, Phayao, Thailand.
authors: Acharaporn
authors: A
authors: Duangjai
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
authors: Kui
authors: K
authors: Luo
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
authors: Yan
authors: Y
authors: Zhou
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
authors: Jiyuan
authors: J
authors: Yang
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT, USA. Electronic address: jindrich.kopecek@utah.edu.
authors: Jindřich
authors: J
authors: Kopeček
mesh_terms: D001672:Biocompatible Materials / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004357:Drug Synergism; D006801:Humans; D008689:Methacrylates / Q000737:chemistry*; D015394:Molecular Structure; D008970:Molecular Weight; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000093542:Gemcitabine
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D008689:Methacrylates; D009944:Organoplatinum Compounds; D003841:Deoxycytidine; C032802:hydroxypropyl methacrylate; D000093542:Gemcitabine
keywords: Biodegradable polymers; Combination therapy; DACH Pt; Gemcitabine; HPMA copolymers; Ovarian cancer