Tumor Microenvironment-Responsive Ternary Nanosystem for Enhanced Antitumor and Antimetastasis Efficacy Against Breast Cancer

Chemotherapy is a cornerstone of breast cancer treatment, but its effectiveness is limited by nonspecific targeting and high toxicity. In this study, hyaluronic acid (HA)-modified polymers were designed and synthesized, which could respond to glutathione (GSH) and reactive oxygen species (ROS). On this basis, a tumor microenvironment (TME) responsive nanocarrier, termed HPPSD, was prepared that was characterized by a uniform diameter of 161.0 ± 1.124 nm with a narrow size distribution (PDI: 0.085 ± 0.032). A series of experiments, including particle size distribution, transmission electron microscopy, in vitro release, temperature stability, antiserum adsorption, antidilution, hemolysis, blood, and histopathological examinations, demonstrated the favorable HAase/GSH/ROS responsiveness, stability, and biocompatibility of HPPSD. The cellular uptake and in vivo delivery studies confirmed the tumor targeting ability of HPPSD, which may be achieved by the receptor–ligand specific recognition on the tumor cell surface. Furthermore, the docetaxel-loaded HPPSD (DTX/HPPSD) ternary nanoparticles were fabricated with particle size and PDI and zeta potentials of 178.97 ± 1.168 nm, 0.113 ± 0.019, and −2.82 ± 0.40 mV, respectively. Notably, DTX/HPPSD exhibited excellent tumor inhibition both in vitro and in vivo and significantly inhibited the liver and lung metastases of breast cancer. Therefore, this nanosystem has excellent performance in targeted drug delivery and TME-responsive drug release in tumors, which possesses promising potential in the treatment of breast cancer and its metastasis.