Biomimetic PLGA-based nanocomplexes for improved tumor penetration to enhance chemo-photodynamic therapy against metastasis of TNBC

The combination of chemo-photodynamic therapy has become a promising strategy for cancer by overcoming the limitations of chemotherapy. However, hypoxic microenvironment, poor drug penetration, and metastatic malignant tumors still limited the therapeutic efficacy of this strategy on triple-negative breast cancer (TNBC). Hence, we developed a combinational nanosystem for efficient TNBC therapy by programming tumor microenvironment and improving drug penetration ability. First, a hybrid membrane (HM) camouflaged poly lactic-co-glycolic acid (PLGA) nanosystem was developed for tumor-targeted delivery of capsaicin (Cap) to improve the tumor hypoxic microenvironment via dilating tumor blood vessels with oxygenation and promote the accumulation of nano-drugs in the tumor (HM-PLGA@Cap NPs). After administration of HM-PLGA@Cap NPs, the sequential administration of PLGA co-loaded with Gamabufotalin (CS-6) and photosensitizer Chlorin e6 (Ce6) significantly penetrate into tumor core regions (HM-PLGA@GC&CS-6 NPs). Our results demonstrated that the sequential administration strategy not only effectively inhibits tumor growth, but also significantly inhibits the metastasis of primary TNBC by reducing the expression of hypoxia-inducible factor 1-alpha (HIF-1α), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9) in tumor tissues. The study proved a high efficiency of the sequential treatment strategy by combining the vasodilator of capsaicin and tumor-infiltrating biomimetic nano-drugs for TNBC therapy.