ABC triblock bottlebrush copolymer-based injectable hydrogels: design, synthesis, and application to expanding the therapeutic index of cancer immunochemotherapy
Name
d0sc02611e.pdf
Description
Published version
Size
1.53 MB
Format
Adobe PDF
Checksum (MD5)
30cbcbc8cafe1eb6c812237b8e7f69ac
Author(s)
Vohidov, Farrukh
Milling, Lauren Elizabeth
Chen, Qixian
Zhang, Wenxu
Bhagchandani, Sachin Haresh
Nguyen, Hung V.-T.
Irvine, Darrell J
Johnson, Jeremiah A.
Date Issued
June 2020
Journal
Chemical Science
Publisher
Royal Society of Chemistry (RSC)
Citation
Vohidov, Farrukh et al. "ABC triblock bottlebrush copolymer-based injectable hydrogels: design, synthesis, and application to expanding the therapeutic index of cancer immunochemotherapy." Chemical Science 11, 23 (June 2020): 5974-5986 © 2020 The Royal Society of Chemistry
Version
Final published version
Abstract
Bottlebrush copolymers are a versatile class of macromolecular architectures with broad applications in the fields of drug delivery, self-assembly, and polymer networks. Here, the modular nature of graft-through ring-opening metathesis polymerization (ROMP) is exploited to synthesize "ABC"triblock bottlebrush copolymers (TBCs) from polylactic acid (PLA), polyethylene glycol (PEG), and poly(N-isopropylacrylamide) (PNIPAM) macromonomers. Due to the hydrophobicity of their PLA domains, these TBCs self-assemble in aqueous media at room temperature to yield uniform ∼100 nm micelles that can encapsulate a wide range of therapeutic agents. Heating these micellar solutions above the lower critical solution temperature (LCST) of PNIPAM (∼32 °C) induces the rapid formation of multi-compartment hydrogels with PLA and PNIPAM domains acting as physical crosslinks. Following the synthesis and characterization of these materials in vitro, TBC micelles loaded with various biologically active small molecules were investigated as injectable hydrogels for sustained drug release in vivo. Specifically, intratumoral administration of TBCs containing paclitaxel and resiquimod-the latter a potent Toll-like receptor (TLR) 7/8 agonist-into mice bearing subcutaneous CT26 tumors resulted in a significantly enhanced therapeutic index compared to the administration of these two drugs alone. This effect is attributed to the TBC hydrogel maintaining a high local drug concentration, thus reducing systemic immune activation and local inflammation. Collectively, this work represents, to our knowledge, the first example of thermally-responsive TBCs designed for multi-compartment hydrogel formation, establishing these materials as versatile scaffolds for self-assembly and drug delivery.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution 3.0 unported license
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DOI of Published Version
https://doi.org/10.1039/d0sc02611e
