PolyMPC–Doxorubicin Prodrugs

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...

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Bibliographic Details
Published in:Bioconjugate chemistry 2012-09, Vol.23 (9), p.1753-1763
Main Authors: Chen, Xiangji, Parelkar, Sangram S, Henchey, Elizabeth, Schneider, Sallie, Emrick, Todd
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Cell culture
Cell Line, Tumor
Chemical compounds
Doxorubicin - chemistry
Doxorubicin - pharmacokinetics
Drug dosages
Half-Life
Humans
Magnetic Resonance Spectroscopy
Methacrylates - chemistry
Microscopy, Fluorescence
Molecular weight
Pharmaceuticals
Phosphorylcholine - analogs & derivatives
Phosphorylcholine - chemistry
Polymerization
Prodrugs - chemistry
Rodents
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Summary: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 (IC50) 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.
ISSN:1043-1802
1520-4812
DOI:10.1021/bc200667s