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

ACS Appl Mater Interfaces. 2023 Jul 26;15(29):34360-34377. doi: 10.1021/acsami.3c03233. Epub 2023 Jul 11.


Having no specific therapy for triple-negative breast cancer (TNBC), this subtype has the lowest survival rate and highest metastatic risk of breast cancer since the tumor inflammatory microenvironment mainly accounts for heterogeneity-induced insensitivity to chemotherapy and epithelial-mesenchymal transition (EMT). This study reports hyaluronic acid (HA)-modified liposomes loaded with cisplatin (CDDP) and hesperetin (Hes) (CDDP-HA-Lip/Hes) for active targeting to relieve systematic toxicity and effective anti-tumor/anti-metastasis ability of TNBC. Our results revealed that HA modification promoted the cellular uptake of the synthesized CDDP-HA-Lip/Hes nanoparticles in MDA-MB-231 cells and accumulation in tumor sites in vivo, indicating deeper tumor penetration. Importantly, CDDP-HA-Lip/Hes inhibited the PI3K/Akt/mTOR pathway to alleviate the inflammation in the tumor and with a crosstalk to suppress the process of the EMT, increasing the chemosensitivity and inhibiting tumor metastasis. Meanwhile, CDDP-HA-Lip/Hes could significantly inhibit the aggression and metastasis of TNBC with less side effects on normal tissues. Overall, this study provides a tumor-targeting drug delivery system with great potential for treating TNBC and its lung metastasis robustly.

Keywords: anti-metastasis; cisplatin; hesperetin; hyaluronic acid modified liposomes; triple-negative breast cancer; tumor targeting.

MeSH terms

  • Aggression
  • Cell Line, Tumor
  • Cisplatin* / therapeutic use
  • Humans
  • Hyaluronic Acid / therapeutic use
  • Liposomes
  • Phosphatidylinositol 3-Kinases
  • Triple Negative Breast Neoplasms* / metabolism
  • Tumor Microenvironment


  • Cisplatin
  • Liposomes
  • Hyaluronic Acid
  • hesperetin
  • Phosphatidylinositol 3-Kinases