title: Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment.
abstract: The synthesis, characterization, and in vitro evaluation of a combination delivery of multiblock poly(N-2-hydroxypropyl)methacrylamide (HPMA), gemcitabine (GEM) and paclitaxel (PTX) conjugates is described in this study. Multiblock copolymer conjugates of a large molecular weight (Mw>200 kDa) were studied and compared to traditional, small molecular weight (Mw<45 kDa) conjugates. Stability of the conjugates in different pH was assessed, and their cytotoxicity in combination toward A2780 human ovarian cancer cells was evaluated by combination index analysis. Treatment duration (4 and 72 h) and sequence of addition were explored. In addition, an HPMA copolymer conjugate with both GEM and PTX in the side chains was evaluated in a similar manner and compared to a physical mixture of individual conjugates. Conjugates with narrow molecular weight distribution (Mw/Mn<1.1) were obtained via RAFT polymerization, and drug loadings of between 5.5 and 9.2 wt% were achieved. Conjugates demonstrated moderate stability with less than 65% release over 24h at pH 7.4, and near complete drug release in the presence of the lysosomal enzyme cathepsin B in 3h. In combination, the cytotoxic effects of a mixture of the conjugates were primarily additive. Synergistic effects were observed when A2780 human ovarian cancer cells were treated simultaneously for 4h with multiblock conjugates (CI<0.7). When both GEM and PTX were conjugated to the same copolymer backbone, moderate antagonism (CI 1.3-1.6) was observed. These results demonstrate that multiblock HPMA copolymer-GEM and -PTX conjugates, when delivered as a mixture of individual agents, are promising for the treatment of ovarian cancer.
authors.affiliation: TheraTarget, Inc., Salt Lake City, UT 84108, USA.
authors.forename: Nate
authors.initials: N
authors.lastname: Larson
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Yang
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
authors.forename: Darwin L
authors.initials: DL
authors.lastname: Cheney
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
authors.forename: Jindřich
authors.initials: J
authors.lastname: Kopeček
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002401:Cathepsin B / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers; D004355:Drug Stability; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D008970:Molecular Weight; D010051:Ovarian Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization; D011109:Polymethacrylic Acids / Q000737:chemistry*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D000093542:Gemcitabine
chemical_list: D004337:Drug Carriers; D011109:Polymethacrylic Acids; D003841:Deoxycytidine; C011533:Duxon; D002401:Cathepsin B; D017239:Paclitaxel; D000093542:Gemcitabine
keywords: Biodegradable polymers; Combination therapy; Gemcitabine; HPMA copolymers; Ovarian cancer; Paclitaxel