Abstract 1993: Sulfobutylether-β-cyclodextrin hydrogel microspheres delivering TLR 7/8 agonist for transarterial immunoembolization
Authors: Updyke Joel , Bhatnagar Shubhmita , Bhaskar Nitu , Parise Rachel , Nagar Swati , Schultz John , Ferguson David , Kucaba Tamara , Griffith Thomas , Siegel Ronald , Panyam Jayanth 
Published: April 2023

Drug-eluting bead transcatheter arterial chemoembolization (DEB-TACE) is a treatment procedure for liver cancer that involves the selective catheterization and subsequent embolization of tumor-feeding arteries with drug-eluting beads (DEBs). DEB-TACE elicits ischemic cell death in the embolized tumor while simultaneously delivering a local, sustained release of chemotherapy. We hypothesize that the application of DEBs loaded with an immunostimulatory adjuvant in the DEB-TACE procedure will promote local antigen presenting cells to utilize the antigens released by dying tumor cells to generate a systemic, adaptive anti-tumor immune response. This approach represents a novel form of transarterial immunoembolization (TIE). 558 is a highly potent, small molecule Toll-like receptor 7/8 agonist that activates both innate and adaptive immune responses to eliminate tumor cells in various preclinical tumor models. Hydrogel microspheres composed of cross-linked sulfobutylether-β-cyclodextrin (SBE-βCD) were investigated as DEBs for 558 in the current study. SBE-βCD hydrogel microspheres (SBE-βCDMS) of 10 - 300 μm diameter were synthesized via suspension polymerization of SBE-βCD and ethylene glycol diglycidyl ether followed by wet sieving. 558 loading was achieved by incubating blank SBE-βCDMS in aqueous solutions of 558. Under non-saturating conditions, SBE-βCDMS absorbed almost the entirety of 558 from loading solutions in 4 h. The dose of 558 loaded in SBE-βCDMS was tuned by altering the initial amount of 558 in solution, up to a maximum loading of 0.28 mg 558/mg dry SBE-βCDMS determined under saturating conditions. The time to 50% release of 558 from loaded SBE-βCDMS was less than 30 min when phosphate buffered saline was used as release media. However, the release of 558 was negligible when deionized water was used as release media. The released drug was as effective as free 558 in stimulating cytokine response from human peripheral blood mononuclear cells in vitro. As a surrogate for TIE, we evaluated plasma and tumor pharmacokinetics upon intratumoral injection of 558-loaded SBE-βCDMS (50 - 100 μm diameter) or free 558 at a dose of 100 μg in C57BL/6 mice bearing B16F10-OVA flank tumors. The gradual release of 558 from loaded SBE-βCDMS prevented an initial spike in plasma concentration that was observed for mice administered with free 558, and maintained constant tumor concentrations for at least 4 h post-injection. High-resolution MALDI mass spectrometry imaging of 15 μm-thick tumor cryosections indicated that 558 was initially concentrated within SBE-βCDMS after intratumoral injection, and extensively released into the surrounding tumor tissue 24 h post-injection. Taken together, these results suggest that 558-loaded SBE-βCDMS are a promising platform for local drug delivery and immune cell stimulation via TIE.

Citation Format: Joel Updyke, Shubhmita Bhatnagar, Nitu Bhaskar, Rachel Parise, Swati Nagar, John Schultz, David Ferguson, Tamara Kucaba, Thomas Griffith, Ronald Siegel, Jayanth Panyam. Sulfobutylether-β-cyclodextrin hydrogel microspheres delivering TLR 7/8 agonist for transarterial immunoembolization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1993.