Tumor Microenvironment Responsive Key Nanomicelles for Effective Against Invasion and Metastasis in Ovarian Cancer Using Mice Model

Int J Nanomedicine. 2025 Jan 7:20:215-238. doi: 10.2147/IJN.S470219. eCollection 2025.

Abstract

Background: Ovarian cancer is difficult to detect in its early stages, and it has a high potential for invasion and metastasis, along with a high rate of recurrence. These factors contribute to the poor prognosis and reduced survival times for patients with this disease. The effectiveness of conventional chemoradiotherapy remains limited. Nano-particles, as a novel drug delivery system, have significant potential for improving therapeutic efficacy and overcoming these challenges.

Methods: According to the high expression level of matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, MMP-2 responsive nano-particles (PVGLIG-MTX-D/T-NMs) containing docetaxel and triptolide were prepared by the thin-film dispersion method. The synergistic effect between docetaxel and triptolide was systematically investigated, the ratio of the two drugs was optimized, and the physicochemical properties of the nano-particles and their ability to inhibit ovarian cancer cell growth and metastasis were evaluated in vitro and in vivo.

Results: PVGLIG-MTX-D/T-NMs enhanced the targeting, stability, and bioavailability of the drug, while reducing the dose and toxicity. In addition, by regulating the expression levels of E-Cadherin, N-Cadherin, matrix metalloproteinases (MMPs), hypoxia-inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF), it exhibited an inhibitory effect on epithelial-mesenchymal transformation (EMT) and tumor cell angiogenesis, and effectively inhibited the invasion and metastasis of ovarian cancer cells.

Conclusion: PVGLIG-MTX-D/T-NMs achieved passive targeting of tumor sites by enhancing permeability and retention (EPR) effects. Subsequently, the uptake of the drug by tumor cells was enhanced by MMP-2 responsiveness and the modification of methotrexate targeting ligands. By regulating the expression levels of invasion- and metastasis-related proteins in tumor tissues, the nano-particles affected the EMT process, inhibited tumor angiogenesis, and suppressed the malignant potential of invasion and metastasis in ovarian cancer. These findings provided a new direction for further exploration of tumor-targeted therapy.

Keywords: angiogenesis; docetaxel; epithelial mesenchymal transition; nano-drug delivery system; triptolide; tumor microenvironment.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Diterpenes* / chemistry
  • Diterpenes* / pharmacokinetics
  • Diterpenes* / pharmacology
  • Docetaxel* / administration & dosage
  • Docetaxel* / chemistry
  • Docetaxel* / pharmacokinetics
  • Docetaxel* / pharmacology
  • Epithelial-Mesenchymal Transition / drug effects
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / pharmacology
  • Female
  • Humans
  • Matrix Metalloproteinase 2* / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Micelles*
  • Nanoparticles* / chemistry
  • Neoplasm Invasiveness / prevention & control
  • Neoplasm Metastasis
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Phenanthrenes* / chemistry
  • Phenanthrenes* / pharmacokinetics
  • Phenanthrenes* / pharmacology
  • Tumor Microenvironment* / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Micelles
  • Matrix Metalloproteinase 2
  • Phenanthrenes
  • Docetaxel
  • triptolide
  • Diterpenes
  • Epoxy Compounds
  • Antineoplastic Agents

Grants and funding

This work was supported by the Open fund of Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine [Grant No.zyzx2404, No.zyzx2301], China Postdoctoral Science Foundation [Grant No.2022MD723796], the Doctoral Start-up Foundation of Liaoning Province [Grant No.2023-BS-139], Basic Research Project of Education Department of Liaoning Province [Grant No.JYTQN 2023471], the National Natural Science Foundation of China [Grant No.82204629] and the Liaoning Province Natural Science Foundation doctoral foundation [Grant No.2022-BS-197].