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 triplenegative 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 (HMPLGA@Cap NPs). After administration of HM-PLGA@Cap NPs, the sequential administration of PLGA coloaded 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-1a), 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.(c) 2022 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).