pH-Ultrasensitive Membranolytic Polyesters with Alternating Sequence of Ionizable and Hydrophobic Groups for Selective Oncolytic Therapy

Oncolytic therapy, inducing cell death via cell membrane lysis, holds considerable promise in cancer treatment. However, achieving precise control over the structure and function of oncolytic materials for highly selective oncolytic therapy is a key challenge in the context of the subtle differences between tumor and normal tissues/cells. Herein, we report the development of pH-ultrasensitive oncolytic polyesters (pOPs) with an alternating sequence of ionizable and hydrophobic groups. This design enables a refined "OFF" to "ON" switch within 0.2 pH units, ensuring high selectivity in membranolytic activity and cytotoxicity of pOPs between the pH levels of normal tissues and tumor acidity. The top-performing pOP, P(P-AC7), demonstrated a maximum tolerated dose of >100 mg kg^-1 after intravenous administration and potent cytotoxicity at pH 6.8. Notably, the molecular weight of P(P-AC7) had a minimal effect on its pH-dependent cytotoxicity once the degree of polymerization was ≥49, ensuring consistency in properties across batches. P(P-AC7) exerts membranolytic activity by interacting with phosphatidylserine at pH 6.8 and shows high antitumor efficacy in various tumor models. Overall, we developed a strategy to develop oncolytic polymers with a precise structure for selective oncolytic therapy.