Targeted dual-responsive nanocapsules for synergistic cisplatin and paclitaxel prodrug delivery in the treatment of lung cancer.

Abstract

Background: The clinical application of traditional chemotherapy for treating patients with lung cancer is restricted by its poor targeting efficacy and severe systemic toxicity. In this study, we developed an acid-sensitive lipid-polymer nanocapsule (PTX/Pt@RGD) for the co-delivery of a redox-sensitive paclitaxel (PTX) prodrug and cisplatin (Pt), which can facilitate both tumor microenvironment-responsive drug release and active targeting.

Methods: The physicochemical properties of the nanocapsules were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The drug-loading efficiency and release profile were analyzed via high-performance liquid chromatography (HPLC). In vitro antitumor activity was evaluated with Cell Counting Kit-8 assay, Annexin V/propidium iodide (PI) double staining, and Transwell assay. The underlying mechanisms were explored via reactive oxygen species (ROS) detection to assess oxidative stress levels, JC-1 mitochondrial membrane potential assay to evaluate mitochondrial dysfunction, γ-H2AX immunofluorescence to quantify DNA double-strand breaks, and Western blot analysis to determine the expression of apoptosis-related proteins. Tumor-bearing mouse models were established to assess the in vivo targeting efficacy, therapeutic effect, and biosafety of PTX/Pt@RGD.

Results: PTX/Pt@RGD exhibited a regular spherical morphology with a particle size of 99.4 nm, a drug-loading efficiency of 2.60%, an encapsulation efficiency (EE) of 44.68%, and the ability for pH/redox dual-responsive drug release. In vitro, PTX/Pt@RGD induced apoptosis by promoting ROS generation, reducing mitochondrial membrane potential, causing DNA damage, and activating apoptotic proteins, resulting in a total apoptosis rate of 84.2% in the group treated with PTX/Pt@RGD. In vivo, arginine-glycine-aspartic acid (RGD) modification enhanced tumor-specific accumulation, effectively suppressing tumor growth and angiogenesis, and demonstrated a favorable safety profile.

Conclusions: PTX/Pt@RGD integrates active targeting with pH/redox dual-responsive release, achieving a high tumor-to-background ratio and efficacy comparable to that of the free PTX/cisplatin combination, together with reduced systemic toxicity and a favorable in vivo safety profile. Although the in vivo therapeutic benefit of RGD-mediated targeting warrants further investigation, our findings support the proactive evaluation of this combinatorial nanoplatform for lung cancer combination chemotherapy.