pH-Ultrasensitive Membranolytic\nPolyesters with Alternating\nSequence of Ionizable and Hydrophobic Groups for Selective Oncolytic\nTherapy

Oncolytic therapy, inducing cell\ndeath via cell membrane\nlysis,\nholds considerable promise in cancer treatment. However, achieving\nprecise control over the structure and function of oncolytic materials\nfor highly selective oncolytic therapy is a key challenge in the context\nof the subtle differences between tumor and normal tissues/cells.\nHerein, we report the development of pH-ultrasensitive oncolytic polyesters\n(pOPs) with an alternating sequence of ionizable and hydrophobic groups.\nThis design enables a refined “OFF” to “ON”\nswitch within 0.2 pH units, ensuring high selectivity in membranolytic\nactivity and cytotoxicity of pOPs between the pH levels of normal\ntissues and tumor acidity. The top-performing pOP, P(P-AC7), demonstrated\na maximum tolerated dose of >100 mg kg<sup>–1</sup> after\nintravenous\nadministration and potent cytotoxicity at pH 6.8. Notably, the molecular\nweight of P(P-AC7) had a minimal effect on its pH-dependent cytotoxicity\nonce the degree of polymerization was ≥49, ensuring consistency\nin properties across batches. P(P-AC7) exerts membranolytic activity\nby interacting with phosphatidylserine at pH 6.8 and shows high antitumor\nefficacy in various tumor models. Overall, we developed a strategy\nto develop oncolytic polymers with a precise structure for selective\noncolytic therapy.