A sequentially responsive cascade nanoplatform for increasing chemo-chemodynamic therapy

Abstract

Poly(lactide-co-glycolide) (PLGA) is promising carrier material for drugs delivery in cancer therapy. However, the slow degradation and lack of targeting have greatly limited the clinical effectiveness of PLGA-based nanomedicines. Herein, we fabricated a hybrid nanosystem (3 P @ He/Pt-NPs) comprising of acid-sensitive polymer (mPOE-PLGA), active-targeting polymer (PBA-PLGA) and therapeutic agents (hemin+cisplatin) to combat these problems. In neutral environment, PEGylation can effectively improve the blood stability and circulation time of hybrid nanosystem. After reaching tumor regions, this nanosystem efficiently increased cellular uptake by dePEGylation and PBA-mediated active-targeting. Furthermore, encapsulated hemin could catalyze the oxygen bubbles generation, which remarkably increasing the drugs release rate. Subsequently, hybrid particles produced a higher cell-killing effect to lung cancer cells (A549) by the combination therapy (chemotherapy and chemodynamic therapy (CDT)). Importantly, cisplatin further amplified CDT effect by inducing H₂O₂ regeneration owing to the cascade enzymatic reactions, while hemin decreased intracellular glutathione (GSH) level, resulting in a low detoxification effect to cisplatin. Thus, hybrid particles could efficiently inhibit drug-resistant tumor growth and the inhibition rate reached 83.2%. Overall, this hybrid polymer nanosystem improve the drawbacks of PLGA-based nanocarriers, and can realize a cascading enhanced tumor treatment.

Keywords: Active-targeting; DePEGylation; Fenton reaction; GSH depletion; Gas-triggered drugs release.