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Well‐Defined Polymer–Paclitaxel Prodrugs by a Grafting‐from‐Drug Approach
Author(s) -
Louage Benoit,
Nuhn Lutz,
Risseeuw Martijn D. P.,
Vanparijs Nane,
De Coen Ruben,
Karalic Izet,
Van Calenbergh Serge,
De Geest Bruno G.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201605892
Subject(s) - raft , paclitaxel , prodrug , chain transfer , chemistry , conjugate , combinatorial chemistry , polymerization , reversible addition−fragmentation chain transfer polymerization , polymer , cytotoxicity , monomer , solubility , drug , surface modification , organic chemistry , in vitro , radical polymerization , pharmacology , biochemistry , chemotherapy , medicine , mathematical analysis , surgery , mathematics
We report on the design of a polymeric prodrug of the anticancer agent paclitaxel (PTX) by a grafting‐from‐drug approach. A chain transfer agent for reversible addition fragmentation chain transfer (RAFT) polymerization was efficiently and regioselectively linked to the C2′ position of paclitaxel, which is crucial for its bioactivity. Subsequent RAFT polymerization of a hydrophilic monomer yielded well‐defined paclitaxel–polymer conjugates with high drug loading, water solubility, and stability. The versatility of this approach was further demonstrated by ω‐end post‐functionalization with a fluorescent tracer. In vitro experiments showed that these conjugates are readily taken up into endosomes where native PTX is efficiently cleaved off and then reaches its subcellular target. This was confirmed by the cytotoxicity profile of the conjugate, which matches those of commercial PTX formulations based on mere physical encapsulation.