Intelligent MoS₂ Nanotheranostic for Targeted and Enzyme-/pH-/NIR-Responsive Drug Delivery To Overcome Cancer Chemotherapy Resistance Guided by PET Imaging

Abstract

Chemotherapy resistance remains a major hurdle for cancer therapy in clinic because of the poor cellular uptake and insufficient intracellular release of drugs. Herein, an intelligent, multifunctional MoS₂ nanotheranostic (MoS₂-PEI-HA) ingeniously decorated with biodegradable hyaluronic acid (HA) assisted by polyethyleneimine (PEI) is reported to combat drug-resistant breast cancer (MCF-7-ADR) after loading with the chemotherapy drug doxorubicin (DOX). HA can not only target CD44-overexpressing MCF-7-ADR but also be degraded by hyaluronidase (HAase) that is concentrated in the tumor microenvironment, thus accelerating DOX release. Furthermore, MoS₂ with strong near-infrared (NIR) photothermal conversion ability can also promote the release of DOX in the acidic tumor environment at a mild 808 nm laser irradiation, achieving a superior antitumor activity based on the programmed response to HAase and NIR laser actuator. Most importantly, HA targeting combined with mild NIR laser stimuli, rather than using hyperthermia, can potently downregulate the expression of drug-resistance-related P-glycoprotein (P-gp), resulting in greatly enhanced intracellular drug accumulation, thus achieving drug resistance reversal. After labeled with ⁶⁴Cu by a simple chelation strategy, MoS₂ was employed for real-time positron emission tomography (PET) imaging of MCF-7-ADR tumor in vivo. This multifunctional nanoplatform paves a new avenue for PET imaging-guided spatial-temporal-controlled accurate therapy of drug-resistant cancer.