Oncolytic polymer-mediated combretastatin A4 phosphate delivery for enhancing vascular disrupting therapy

Although vascular disrupting agents (VDAs) can induce shutdown of blood flow and necrosis in the tumor core, eradicating tumor rim cells remains a significant challenge. Recently, researchers have developed various combination treatment strategies to improve the efficacy of VDAs. However, the aggravated hypoxic tumor microenvironment following vascular disruption limits the effectiveness of conventional therapeutic approaches. Here, we developed an ε-polylysine-derived oncolytic polymer (named OPAA) with membrane lytic activity. Its cytotoxic effect on tumor cells is largely unaffected by hypoxic conditions, as evidenced by the ratio of its IC50 value for 4 T1 cells under normoxic conditions to that under hypoxic conditions, which is 0.98. Subsequently, a pH-responsive combretastatin A4 phosphate disodium salt (CA4P)-loaded nanoparticle (OPAA@CA4P NPs) has been designed to efficiently deliver OPAA and CA4P to solid tumors. OPAA@CA4P NPs exhibited a prolonged serum half-life (t_1/2 = 3.15 h) compared to CA4P (t_1/2 = 0.31 h) and an enhanced tumor accumulation. In addition, CA4P can be responsively released within the tumor microenvironment, leading to necrosis in the tumor center. Concurrently, OPAA released from the nanoparticles eradicated the surviving cancer cells at the tumor periphery, thereby improving the overall therapeutic effect. Notably, compared to the CA4P + doxorubicin group (tumor suppression rates, TSR = 36.17 %), the OPAA@CA4P NPs group demonstrated superior therapeutic outcomes (TSR = 60.30 %). Overall, the introduction of oncolytic polymers provides new insights into the potential future applications of VDAs.