Inhibition of Ovarian Cancer Growth, Metastasis and Reverse the Tumor Microenvironment by Dual Drug-Loaded Polymer Micelle Targeting Tumor Microenvironment

Lu Zhang,1,2 Ruibo Guo,1,2 Muhan Chen,1,2 Mo Liu,1,2 Yang Liu,1,2 Yang Yu,1– 3 Juan Zang,1,2 Liang Kong,1,2,* Xuetao Li1,2,* 1School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, People’s Republic of China; 2Shenyang Key Laboratory of Targeted Delivery of Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, People’s Republic of China; 3Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liang Kong, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Shenyang Key Laboratory of Targeted Delivery of Chinese Medicine, Shengming 1 Road 77, Double D Port, Dalian, 116600, People’s Republic of China, Email [email protected] Xuetao Li, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Shenyang Key Laboratory of Targeted Delivery of Chinese Medicine, Shengming 1 Road 77, Double D Port, Dalian, 116600, People’s Republic of China, Email [email protected]: Ovarian cancer is a malignant tumor that arises in the female reproductive system and is associated with a very high mortality rate. This is primarily due to the highly invasive nature of metastasis and recurrence. Transforming the immune environment from an immunosuppressive state to an anti-tumor state through the phenotypic transformation of tumor-associated macrophages is crucial for inhibiting the growth, metastasis, and recurrence of ovarian cancer.Methods: A polymer micelle (RC-PH-Ms) containing paclitaxel (PTX) and honokiol (HNK) was designed based on high expression of reactive oxygen species in the tumor microenvironment. Once the micelles are actively targeted to the tumor microenvironment characterized by elevated levels of reactive oxygen species, the responsive bond is cleaved, thereby exposing the secondary targeting ligand C7R. The released PTX and HNK facilitate the transformation of relevant macrophages in the tumor microenvironment from an M2 phenotype to an M1 phenotype, which in turn inhibits tumor growth, invasion and metastasis, inhibit angiogenesis and reduce tumor recurrence.Results: The effects of RC-PH-Ms on modulating the immune microenvironment and inhibiting tumor growth, invasion and metastasis, vascularization and recurrence were investigated both in vivo and in vitro.Conclusion: RC-PH-Ms can significantly inhibit the metastasis and recurrence of ovarian cancer, which provides a new perspective for clinical treatment.Keywords: ovarian cancer, tumor metastasis, recrudescence, immunotherapy, polymer micelle