Albumin-based multidrug delivery system enriched in Golgi apparatus against metastatic breast cancer

Breast cancer and metastasis remain great challenges in clinical therapy. Compared with monotherapy, combination therapy, especially mediated by nanomedicine delivery strategy, significantly improves the therapeutic efficacy and reduces undesired toxicity. Cyclooxygenase-2 (COX-2) inhibitors are widely used for adjuvant chemotherapy because COX-2 is overexpressed in virtually all cancer cell lines to regulate tumor progression by catalyzing prostaglandin E₂ (PGE₂) synthesis. This drug combination strategy is still required to be improved due to some unsatisfactory clinical trial results. Intricate processes of tumor growth and metastasis are orchestrated by multiple proteins in addition to COX-2, which are modified and transported by Golgi apparatus. Hence, disrupting the structure and function of Golgi apparatus can inhibit the secretion of tumor-related proteins and further suppress carcinoma progression and metastasis. Since COX-2 is also enriched within Golgi apparatus in tumor cells, COX-2 inhibitors and Golgi disrupting agents can be co-delivered to Golgi apparatus to maximize the synergy. In this work, we developed a human serum albumin (HSA) nanoparticle encapsulating pirarubicin (THP), retinoic acid (RA), and indomethacin (IMC), called TIR-HSA, which was observed to be localized in Golgi complex of 4T1 cells. Owing to the synergistic effect of these three drugs, TIR-HSA inhibited the proliferation, migration, and invasion of tumor cells, enhanced the apoptotic rate, and improved the immunosuppressive tumor microenvironment, which remarkably regressed the tumor growth and metastasis and prolonged the survival period of 4T1-bearing mice.