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Inhibitory effect of 5-FU loaded ultrasound microbubbles on tumor growth and angiogenesis
Affiliation:1. Department of Ultrasound Diagnosis, Xijing Hospital, Fourth Military Medical University, Xi''an 710038, China;2. Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China;1. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States;2. Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases (CTEGD), University of Georgia, 120 Green Street, Athens, GA 30602, United States;1. School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa;2. Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA;1. Neuroscience Discovery Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States;2. Process Research and Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States;3. Neuroscience Discovery Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States;4. Department of Metabolism and Pharmcokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States;5. Department of Toxicology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, United States;1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan 610041, China;2. Guangxi Wuzhou Pharmaceutical Co. Ltd, Wuzhou, Guangxi 543000, China;3. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China;1. Graduate School of Science, Osaka Prefecture University, Osaka 599-8531, Japan;2. Whol Institute for Drug Discovery of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot 7610001, Israel;3. Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
Abstract:The anti-neovascularization treatment is one of the effective strategies for tumor molecular target therapy. At present, the target and effect of the anti-neovascularization treatment is limited, and it is urgent to establish a new vascular targeting strategy to effectively treat tumors. In this work, we used high intensity focused ultrasound (HIFU) combined with targeted microbubbles to establish a molecular targeted ultrasound response microbubble for neovascular cells. Furthermore, the effects of drug loaded microbubbles on neovascularization and tumor cells were studied. The tumor vascular targeted and ultrasound-responsive microbubbles of 5-FU@DLL4-MBs were prepared by the thin-film dispersion method. The size and zeta potential of 5-FU@DLL4-MBs was about 1248 nm and −9.1 mV. 5-FU@DLL4-MBs released 5-FU showed an ultrasound-responsive manner, and had better vascular-targeting ability. Furthermore, the 5-FU@DLL4-MBs showed the strongest cytotoxic effect on HUVECs or HepG-2 cells and can be effectively internalized into the HUVECs cells. Thus, 5-FU@DLL4-MBs combined with HIFU can be considered as a potential method for antitumor angiogenesis in the future.
Keywords:Microbubbles (Mbs)  High intensity focused ultrasound (HIFU)  Ultrasound-responsive  Anti-tumor angiogenesis  Hepatic carcinoma
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