title: PolyMPC-doxorubicin prodrugs.
abstract: We demonstrate the conjugation of the cancer drug doxorubicin (DOX) to poly(methacryloyloxyethyl phosphorylcholine) (polyMPC), linked by hydrazone groups, using (1) a one-pot ATRP/click sequence, and (2) a post-polymerization conjugation strategy. While the one-pot method gave polyMPC-DOX conjugates in a facile single step, post-polymerization conjugation gave higher-molecular-weight polymers with very high DOX loadings. DOX release from the polyMPC backbone was pH-dependent (faster at pH 5.0 than at pH 7.4) owing to the hydrazone linkage. Half-life values of DOX release ranged from 2 to 40 h at pH 5.0. Cell culture experiments showed that highly loaded polyMPC-DOX conjugates exhibited higher intracellular drug accumulation and lower half-maximal inhibitory concentration (IC(50)) values, while a polymer with 30 wt % drug loading showed a maximum tolerated dose in the range of 30-50 mg/kg DOX equivalent weight in healthy mice.
authors.affiliation: Polymer Science & Engineering Department, 120 Governors Drive, University of Massachusetts, Amherst, Massachusetts 01003, USA.
authors.forename: Xiangji
authors.initials: X
authors.lastname: Chen
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Parelkar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Henchey
authors.forename: Sallie
authors.initials: S
authors.lastname: Schneider
authors.forename: Todd
authors.initials: T
authors.lastname: Emrick
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D008689:Methacrylates; D011355:Prodrugs; D010767:Phosphorylcholine; C070638:2-methacryloyloxyethyl phosphorylcholine; D004317:Doxorubicin