Journal
BIOCONJUGATE CHEMISTRY
Volume 23, Issue 9, Pages 1753-1763Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bc200667s
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Funding
- National Science Foundation Materials Research Science & Engineering Center (MRSEC) on Polymers [DMR-0820506]
- NSF [DMI-0531171]
- SciDose, Inc
- Department of Energy [DE-SC0005166]
- Rays of Hope Foundation
- Center for Excellence in Apoptosis Research (CEAR) of the Pioneer Valley Life Sciences Institute (PVLSI)
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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.
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