Journal
ACS APPLIED POLYMER MATERIALS
Volume 2, Issue 6, Pages 2126-2133Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsapm.0c00083
Keywords
DHBC; thermo-sensitivity; reduction-sensitivity; pH sensitivity; polymeric prodrug; RAFT; ATRP
Funding
- National Natural Science Foundation of China [51473072, 21504035]
- Thousand Young Talent Program
- Outstanding Youth Fund of Natural Science Foundation of Hunan Province [2017JJ1024]
- National Key R&D Program of China [2018YFB1900201]
- Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
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Reduction- and acidic-pH-dual-sensitive micelles have been frequently highlighted to present a synergistic effect on the promotion of intracellular drug release for enhanced therapeutic efficiency compared to the delivery systems based on a single biorelevant trigger. However, the preparation of dual-responsive block copolymers with well-defined structures, especially for those with a reducible backbone, are highly desirable for polymer degradation but still suffer from less control, tedious purification, and low efficiency, likely due to the adopted synthetic strategies including various coupling reactions between two polymers. To further develop a versatile route toward well-defined block copolymers with reducible block junctions based on the previously reported RAFT-ATRP double-head agent, 4-cyanopentanoic acid dithio-benzoate-SS-2-hydroxyethyl-2'-(bromoisobutyryl)ethyl disulfide (CPADB-SS-iBuBr), that was only applicable to the glycidyl methacrylate (GMA) monomer, we reported in this study the preparation of a thermo-sensitive double hydrophilic block copolymer (DHBC)-based polymeric prodrug with both a reduction-responsive disulfide link in the backbone and acid-sensitive hydrazone links in the side chain via a combination of reversible addition-fragmentation chain transfer (RAFT) polymerization, removal of RAFT group, subsequent atom transfer radical polymerization (ATRP), and final drug conjugation. The resulting alkyne-poly(N-(2-hydroxypropyl) methacrylamide-st-(ethyl glycinate methacrylamide-doxorubicin))-SS-poly(N-isopropylacrylamide) (alkyne-P(HPMA-st-(EGMA-DOX))-SS-P(NIPPAm)) can self-assemble into core-shell micelles with an average diameter of 180 nm in water at the physical temperature of 37 degrees C above the lower critical solution temperature (LCST) of PNIPAAm block. The intracellular simultaneous cleavage of the disulfide links and hydrazone bonds led to significantly promoted degradation of the micelle prodrugs toward accelerated drug release and greater cytotoxicity against cancer cells. Together with the facile decoration of the outer corona of the micelle prodrugs with highly efficient click chemistry, this strategy provides a robust means toward various types of multi-responsive block copolymers for controlled release applications.
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