International Journal of Nanomedicine (Jan 2025)
Tumor Microenvironment Responsive Key Nanomicelles for Effective Against Invasion and Metastasis in Ovarian Cancer Using Mice Model
Abstract
Yang Liu,1,2 Liang Kong,1,2 Yang Yu,1,2 Juan Zang,1,2 Lu Zhang,1,2 Rui-Bo Guo,1,2 Shu-Tong Li,1,2 Lan Cheng,1,2 Xue-Tao Li,1,2 You-Qiang Chen1,2 1School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, People’s Republic of China; 2Shenyang Key Laboratory of Chinese Medicine Targeted Delivery Key Laboratory, Shenyang, 110847, People’s Republic of ChinaCorrespondence: Xue-Tao Li; You-Qiang Chen, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Shengming 1 Road 77, Double D Port, Dalian, 116600, People’s Republic of China, Tel +86411 8589 0170, Fax +86411 8589 0128, Email [email protected]; [email protected]: 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: nano-drug delivery system, tumor microenvironment, docetaxel, triptolide, epithelial mesenchymal transition, angiogenesis
