Cisplatin resistance reversal in lung cancer by tumor acidity-activable vesicular nanoreactors via tumor oxidative stress amplification

Abstract

Drug resistance of cisplatin significantly limits its therapeutic efficacy in clinical applications against different cancers. Herein, we develop a novel strategy to overcome cisplatin drug resistance through sensitizing cisplatin-resistant human lung cancer cells (A549R) under amplified oxidative stress using a vesicular nanoreactor for simultaneous cisplatin delivery and H₂O₂ generation. We engineer the nanoreactor by the self-assembly of the amphiphilic diblock copolymers to co-deliver glucose oxidase (GOD) and cisplatin (Cis) (Cis/GOD@Bz-V). Cis/GOD@Bz-V was rationally designed to stay impermeable during blood circulation while mild acidity (pH 6.5–6.8) can activate its molecular-weight selective membrane permeability and release cisplatin locally. Diffusion of small molecules such as oxygen and glucose across the membranes can induce the in situ generation of superfluous H₂O₂ to promote cellular oxidative stress and sensitize A549R cells via activation of pro-apoptotic pathways. Cis/GOD@Bz-V nanoreactors could effectively kill A549R at pH 6.8 in the presence of glucose by the combination of H₂O₂ generation and cisplatin release. Growth of A549R xenograft tumors can be inhibited efficiently without the obvious toxic side effects via the systemic administration of Cis/GOD@Bz-V. Accordingly, the tumor acidity-activable cisplatin-loaded nanoreactors show great potential to enhance the therapeutic efficacy against cisplatin-resistant cancers.