Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused immune stimulation.
Sachin H BhagchandaniFarrukh VohidovLauren E MillingEvelyn Yuzhou TongChristopher M BrownMichelle L RamseierBin LiuTimothy B FessendenHung V-T NguyenGavin R KielLori WonRobert S LangerStefani SprangerAlex K ShalekDarrell J IrvineJeremiah A JohnsonPublished in: Science advances (2023)
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.
Keyphrases
- toll like receptor
- immune response
- inflammatory response
- nuclear factor
- papillary thyroid
- squamous cell
- induced apoptosis
- drug induced
- dendritic cells
- high dose
- aqueous solution
- liver failure
- childhood cancer
- bone marrow
- oxidative stress
- lymph node metastasis
- cell cycle arrest
- high throughput
- acute respiratory distress syndrome
- cell death
- climate change
- extracorporeal membrane oxygenation
- risk assessment