Novel CD44-Targeting and pH/redox Dual-Stimuli Responsive Core-Shell Nanoparticles Loading Triptolide to Combat Breast Cancer Growth and Lung Metastasis

Abstract BackgroundThe toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited its clinical application. Therefore, we fabricated a CD44-targeting and tumor-microenvironment pH/redox sensitive nanosystem, composed by hyaluronic acid-Vitamin E succinate (HA-VE) and Poly (β-Amino Esters) (PBAEss) polymers, to enhance the suppression of breast cancer proliferation and lung metastasis of TPL. ResultsThe generated TPL/NPs had the high drug loading efficiency (94.93 ± 2.1%) and a desirable average size (191 nm). Mediated by PBAEss core, TPL/NPs displayed a pH/redox dual stimuli drug release profile in vitro. Based on HA coating, TPL/NPs exhibited selective tumor-cellular uptake and high tumor-tissue accumulation capacity via targeting CD44. As a consequence, TPL/NPs showed higher cell proliferation suppression, pro-apoptosis and cell cycle arrest activities, and stronger inhibitory effects on cell migration and invasion than free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and block lung metastasis in a 4T1 breast cancer mice model at equivalent or lower TPL dosage compared to free TPL, with the decreased systemic toxicity. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis, suppressed expression of matrix metalloproteinases, which all these contributed to inhibit tumor growth and pulmonary metastasis. ConclusionCollectively, our results demonstrate that TPL/NPs, which integrates tumor active-targeting and pH/redox responsive drug release, pro-apoptosis, and anti-mobility, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity.