Soluplus®-based solid dispersion enhances oral bioavailability of A10: a cGAS-STING and ICD activator for bladder...

Bladder cancer (BCa) is one of the most prevalent malignancies worldwide, and the clinical treatment effect is limited due to the resistance and the associated low survival rates in patients. A10, as a novel camptothecin (CPT) derivative, possesses potent anti-tumor activity by targeting Topo Ⅰ/DDX5 (p68). However, the poor aqueous solubility and low bioavailability of A10 restrict its further application. We developed a Soluplus® - based solid dispersion (A10-SD) to enhance solubility by 389-fold and oral bioavailability by 14.38-fold. This research provided evidence of the immune activation induced by A10 against BCa T24 cells, and A10 could activate the cGAS-STING pathway, promote DAMPs release, and induce Immunogenic Cell Death (ICD) for anti-tumor activity against BCa cells in vitro. A10-SD meanwhile demonstrated remarkable tumor-suppressive efficacy in vivo with TGI of 99.84%, and its immune activation was preliminarily confirmed in vivo. A10-SD also showed good safety. This strategy provides an effective approach for the development of orally administered poorly soluble compounds, helping to unlock their therapeutic potential and promote their application.