Co-Delivery of Hesperetin and Cisplatin via Hyaluronic Acid-Modified Liposome for Targeted Inhibition of Aggression and Metastasis of Triple-Negative Breast Cancer

Having no specific therapy for triple-negative breastcancer (TNBC),this subtype has the lowest survival rate and highest metastatic riskof breast cancer since the tumor inflammatory microenvironment mainlyaccounts for heterogeneity-induced insensitivity to chemotherapy andepithelial-mesenchymal transition (EMT). This study reports hyaluronicacid (HA)-modified liposomes loaded with cisplatin (CDDP) and hesperetin(Hes) (CDDP-HA-Lip/Hes) for active targeting to relieve systematictoxicity and effective anti-tumor/anti-metastasis ability of TNBC.Our results revealed that HA modification promoted the cellular uptakeof the synthesized CDDP-HA-Lip/Hes nanoparticles in MDA-MB-231 cellsand accumulation in tumor sites in vivo, indicatingdeeper tumor penetration. Importantly, CDDP-HA-Lip/Hes inhibited thePI3K/Akt/mTOR pathway to alleviate the inflammation in the tumor andwith a crosstalk to suppress the process of the EMT, increasing thechemosensitivity and inhibiting tumor metastasis. Meanwhile, CDDP-HA-Lip/Hescould significantly inhibit the aggression and metastasis of TNBCwith less side effects on normal tissues. Overall, this study providesa tumor-targeting drug delivery system with great potential for treatingTNBC and its lung metastasis robustly.