Antitumor Activity of Death Receptor 5-Targeted Camptothecin-Loaded Nanoparticles in Murine Syngeneic Models

Death receptor 5 (DR5) is a key mediator of the extrinsic apoptotic pathway that is often upregulated in tumors, rendering it an attractive target for cancer therapy. Activation of DR5 requires oligomerization, which can be achieved through multivalent presentation of DR5 ligands on nanoparticles. DR5-targeted nanoparticles can efficiently agonize DR5 to inhibit the growth of human xenografts, although it remains unclear whether these effects would translate to a syngeneic tumor model with an immunocompetent microenvironment. Here, we develop camptothecin-loaded polymeric nanoparticles coated with the murine DR5 antibody MD5-1 and demonstrate their pro-apoptotic effects in murine cell lines in vitro. Moreover, we show that these nanoparticles inhibit the growth of MC38 colorectal allografts in vivo by >90% relative to control nanoparticles. Collectively, our work confirms that the antitumor efficacy of DR5-targeted nanoparticles extends to syngeneic models, paving the way for future studies to explore their impact on tumor immunity and the surrounding microenvironment.