Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused immune stimulation
Name
sciadv.adg2239.pdf
Description
Published version
Size
1.95 MB
Format
Adobe PDF
Checksum (MD5)
03ae506453dcecfff6f123a0d6733419
Author(s)
Bhagchandani, Sachin H
Vohidov, Farrukh
Milling, Lauren E
Tong, Evelyn Yuzhou
Brown, Christopher M
Ramseier, Michelle L
Liu, Bin
Fessenden, Timothy B
Nguyen, Hung V-T
Kiel, Gavin R
Date Issued
April 19, 2023
Journal
Science Advances
Publisher
American Association for the Advancement of Science
Citation
Sachin H. Bhagchandani et al. ,Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused immune stimulation.Sci. Adv. 9, eadg2239 (2023).
Version
Final published version
Abstract
Imidazoquinolines (IMDs), such as resiquimod (R848), are of great interest as potential cancer immunotherapies because of their ability to activate Toll-like receptor 7 (TLR7) and/or TLR8 on innate immune cells. Nevertheless, intravenous administration of IMDs causes severe immune-related toxicities, and attempts to improve their tissue-selective exposure while minimizing acute systemic inflammation have proven difficult. Here, using a library of R848 “bottlebrush prodrugs” (BPDs) that differ only by their R848 release kinetics, we explore how the timing of R848 exposure affects immune stimulation in vitro and in vivo. These studies led to the discovery of R848-BPDs that exhibit optimal activation kinetics to achieve potent stimulation of myeloid cells in tumors and substantial reductions in tumor growth following systemic administration in mouse syngeneic tumor models without any observable systemic toxicity. These results suggest that release kinetics can be tuned at the molecular level to provide safe yet effective systemically administered immunostimulant prodrugs for next-generation cancer immunotherapies.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
Ragon Institute of MGH, MIT and Harvard
Massachusetts Institute of Technology. Department of Biological Engineering
Institute for Medical Engineering and Science
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution
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DOI of Published Version
https://doi.org/10.1126/sciadv.adg2239
