Hydroxypropyl-β-cyclodextrin/hyaluronic acid modified polydopamine nanoparticles co-loaded with BNN6 and epirubicin for synergistic photothermal/gas/chemotherapy of breast cancer

Combination therapy, which integrates diverse treatment modalities to induce synergistic anti-tumor effects, has emerged as a promising strategy in oncology. In this study, we developed a near-infrared (NIR) laser-triggered nitric oxide (NO)-releasing and enzyme-sensitive targeted drug delivery system BNN6/EPI-HA@HP-PDA) for the synergistic treatment of breast cancer via combined chemotherapy, NO gas therapy, and photothermal therapy. The system was constructed based on polydopamine (PDA) nanoparticles modified with hyaluronic acid (HA) and hydroxypropyl-β-cyclodextrin (HP-β-CD), co-loaded with epirubicin (EPI) and the NO donor BNN6 (N, N'-di-sec-butyl-N, N'-dinitroso-1,4-phenylenediamine). The resulting spherical nanoparticles exhibited a uniform size of 180.26 nm and a zeta potential of -27.69 mV, with high drug loading and encapsulation efficiencies of 12.04% and 98.10% for EPI and 46.91% and 88.14% for BNN6, respectively. In vitro release studies confirmed nanoparticles’ responsiveness to hyaluronidase, pH, and NIR irradiation. Cellular assays revealed significantly enhanced cytotoxicity of BNN6/EPI-HA@HP-PDA in both MCF-7 and MCF-7/ADR cells, attributable to the combined effects of PDA-mediated hyperthermia, EPI-induced chemotherapy, and NO-mediated gas therapy. Pharmacokinetic evaluation showed a 4.62-fold increase in the area under the curve of BNN6/EPI-HA@HP-PDA compared to free EPI solution. In vivo experiments further demonstrated potent tumor growth inhibition (96.71%) in MCF-7/ADR tumor-bearing Balb/c mice treated with BNN6/EPI-HA@HP-PDA plus laser irradiation, with no detectable systemic toxicity. In general, BNN6/EPI-HA@HP-PDA presents a combination strategy of photothermal/gas/chemotherapy for the synergistic therapy of breast cancer.