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Huifeng Wu,1 Xiaodong Wu,2 Mengdan Zhao,3 Jingjing Yan,3 Chaoqun Li,3 Zhewei Zhang,1 Sangsang Tang,2 Rong Wang,3 Weidong Fei3 1Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China; 3Department of Pharmacy, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of ChinaCorrespondence: Weidong Fei; Rong Wang, Email feiweidong@zju.edu.cn; 5521085@zju.edu.cnAbstract: During the past decade, “membrane lipid therapy”, which involves the regulation of the structure and function of tumor cell plasma membranes, has emerged as a new strategy for cancer treatment. Cholesterol is an important component of the tumor plasma membrane and serves an essential role in tumor initiation and progression. This review elucidates the role of cholesterol in tumorigenesis (including tumor cell proliferation, invasion/metastasis, drug resistance, and immunosuppressive microenvironment) and elaborates on the potential therapeutic targets for tumor treatment by regulating cholesterol. More meaningfully, this review provides an overview of cholesterol-integrated membrane lipid nanotherapeutics for cancer therapy through cholesterol regulation. These strategies include cholesterol biosynthesis interference, cholesterol uptake disruption, cholesterol metabolism regulation, cholesterol depletion, and cholesterol-based combination treatments. In summary, this review demonstrates the tumor nanotherapeutics based on cholesterol regulation, which will provide a reference for the further development of “membrane lipid therapy” for tumors. Keywords: cholesterol, tumor, plasma membrane, nanotherapeutics

Shan Yang,1 Weidong Fei,1 Yunchun Zhao,1 Fengmei Wang,1 Yiqing Ye,1 Fenfen Wang2 1Department of Pharmacy, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, Peoples Republic of China; 2Department of Gynecology Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, Peoples Republic of ChinaCorrespondence: Yiqing Ye; Fenfen Wang, Email yqye@zju.edu.cn; wangfenfen@zju.edu.cnAbstract: Angiogenesis is an essential mechanism for the progression of gynecological cancers. Although approved anti-angiogenic drugs have demonstrated clinical efficacy in treating gynecological cancers, the full potential of therapeutic strategies based on tumor blood vessels has not yet been realized. This review summarizes the latest angiogenesis mechanisms involved in the progression of gynecological cancers and discusses the current clinical practice of approved anti-angiogenic drugs and related clinical trials. Given the close relationship between gynecological cancers and blood vessels, we highlight more delicate strategies for regulating tumor vessels, including wise drug combinations and smart nano-delivery platforms to achieve highly efficient drug delivery and overall vessel microenvironment regulation. We also address current challenges and future opportunities in this field. We aim to generate interest in therapeutic strategies that target blood vessels as a key entry point and offer new potential and inspiration for combating gynecological cancers.Keywords: gynecological cancers, tumor blood vessel, tumor vascularization, anti-angiogenic, clinical trials, nano-delivery platforms, nanoparticles

Yun-Chun Zhao,1 Hai-Li Zheng,2 Xiao-Rong Wang,1 Xiao-Ling Zheng,1 Yue Chen,1 Wei-Dong Fei,1 Yong-Quan Zheng,1 Wen-Xi Wang,2 Cai-Hong Zheng1 1Pharmacy Department, Zhejiang University, Women’s Hospital, School of Medicine, Hangzhou, People’s Republic of China; 2College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, People’s Republic of ChinaCorrespondence: Cai-Hong ZhengZhejiang University, Women’s Hospital, School of Medicine, 1 Xueshi Road, Hangzhou 310006, People’s Republic of ChinaTel +86-0571-89991730Email chzheng@zju.edu.cnWen-Xi WangCollege of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou 310014, People’s Republic of ChinaTel +86-0571-88320320Email yjw@zjut.edu.cnBackground: Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N′,N′-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed.Materials and Methods: DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments.Results: In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a

Yun-Chun Zhao,1 Hai-Li Zheng,2 Xiao-Rong Wang,1 Xiao-Ling Zheng,1 Yue Chen,1 Wei-Dong Fei,1 Yong-Quan Zheng,1 Wen-Xi Wang,2 Cai-Hong Zheng1 1Pharmacy Department, Zhejiang University, Women’s Hospital, School of Medicine, Hangzhou, People’s Republic of China; 2College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, People’s Republic of ChinaCorrespondence: Cai-Hong ZhengZhejiang University, Women’s Hospital, School of Medicine, 1 Xueshi Road, Hangzhou 310006, People’s Republic of ChinaTel +86-0571-89991730Email chzheng@zju.edu.cnWen-Xi WangCollege of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou 310014, People’s Republic of ChinaTel +86-0571-88320320Email yjw@zjut.edu.cnBackground: Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N′,N′-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed.Materials and Methods: DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments.Results: In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a