pH-Sensitive Nanoparticles Codelivering Docetaxel and Dihydroartemisinin Effectively Treat Breast Cancer by Enhancing Reactive Oxidative Species-Mediated Mitochondrial Apoptosis.

Tumor growth and metastasis are the major causes of high mortality in breast cancer. We previously constructed pH-sensitive nanoparticles (D/D NPs) for the codelivery of docetaxel (DTX) and dihydroartemisinin (DHA) and demonstrated that D/D NPs showed anticancer activity in breast cancer cells in vitro. The present study further investigated the therapeutic effect of D/D NPs on orthotopic breast cancer in vivo and examined the antitumor mechanism of D/D NPs. D/D NPs significantly increased the apoptosis of 4T1 cells with a synergistic effect of DTX and DHA. D/D NPs increased reactive oxygen species, reduced mitochondrial membrane potential, increased the expression of p53, and induced cytochrome c release into the cytoplasm to activate caspase-3. In an orthotopic metastatic breast cancer mouse model derived from 4T1 cells, D/D NPs inhibited tumor growth and prevented lung metastasis due to the synergistic effect of DTX and DHA. No distinct changes were observed in the histology of major organs. These results indicate that pH-sensitive D/D NP-based combination therapy may be a promising strategy for the treatment of metastatic breast cancers via the ROS-mediated mitochondrial apoptosis pathway.

Injectable Chitosan-Based Thermosensitive Hydrogel/Nanoparticle-Loaded System for Local Delivery of Vancomycin in the Treatment of Osteomyelitis.

PURPOSE: Osteomyelitis, particularly chronic osteomyelitis, remains a major challenge for orthopedic surgeons. The traditional treatment for osteomyelitis, which involves antibiotics and debridement, does not provide a complete solution for infection and bone repair. Antibiotics such as vancomycin (VCM) are commonly used to treat osteomyelitis in clinical settings. VCM use is limited by a lack of effective delivery methods that provide sustained, high doses to entirely fill irregular bone tissue to treat infections. METHODS: We engineered a chitosan (CS)-based thermosensitive hydrogel to produce a VCM-nanoparticle (NPs)/Gel local drug delivery system. The VCM-NPs were formed with quaternary ammonium chitosan and carboxylated chitosan nanoparticles (VCM-NPs) by positive and negative charge adsorption to enhance the encapsulation efficiency and drug loading of VCM, with the aim of simultaneously preventing infection and repairing broken bones. This hydrogel was evaluated in a rabbit osteomyelitis model. RESULTS: The VCM-NPs had high encapsulation efficiency and drug loading, with values of 60.1±2.1% and 24.1±0.84%, respectively. When embedded in CS-Gel, the VCM-NPs maintained their particle size and morphology, and the injectability and thermosensitivity of the hydrogel, which were evaluated by injectability test and rheological measurement, were retained. The VCM-NPs/Gel exhibited sustained release of VCM over 26 days. In vitro tests revealed that the VCM-NPs/Gel promoted osteoblast proliferation and activity against Staphylococcus aureus. In vivo, VCM-NPs/Gel (with 10 mg vancomycin per rabbit) was used to treat rabbits with osteomyelitis. The VCM-NPs/Gel showed excellent anti-infection properties and accelerating bone repair under osteomyelitis conditions. CONCLUSION: The reported multifunctional NPs hydrogel system for local antibiotic delivery (VCM-NPs/Gel) showed bone regeneration promotion and anti-infection properties, demonstrating significant potential as a scaffold for effective treatment of osteomyelitis.