pH-Triggered Cell Surface Anti-Hapten Antibody Recruitment by Amphiphilic Block Copolymers Containing Ionizable Amines and Haptens in the Hydrophobic Block.

Abstract

Cancer progression often results from immune evasion mechanisms within the tumor microenvironment (TME). Therapeutic interventions leveraging the immune system's molecular tools, such as monoclonal antibodies (mAbs), have revolutionized oncological treatments by enhancing immune responses against cancer cells. However, the efficacy of mAbs is limited by the specificity of tumor antigens. Here, we introduce a novel class of pH-sensitive antibody-recruiting molecules based on amphiphilic block copolymers. These copolymers, containing pH-responsive azepanyl motifs, undergo micelle-to-unimer transitions under mildly acidic conditions characteristic of solid tumors. Functionalized with dinitrophenol (DNP) hapten motifs, these polymers facilitate electrostatic interactions with cell surfaces in the acidic TME, enabling targeted recruitment of anti-DNP antibodies. Our findings demonstrate pH-dependent nanoparticle formation, enhanced cellular association at acidic pH, and selective antibody recruitment, warranting further investigations for tumor-targeted immunotherapy independent of specific tumor antigens.