Development of the methotrexate-nanogold complex for cancer therapeutics in animal models

碩士 === 國立成功大學 === 生物化學研究所 === 93 ===  Antimetabolites are a clinically important group of cancer drugs used in treatment of a variety of solid tumors and hematological malignancies. The cytotoxicity of antimetabolites stems from its ability to interfere with key enzymatic steps in nucleic acid metab...

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Bibliographic Details
Main Authors: Pong-Yu Huang, 黃鵬宇
Other Authors: Chao-Liang Wu
Format: Others
Language:en_US
Published: 2005
Online Access:http://ndltd.ncl.edu.tw/handle/97997371264400371798
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Summary:碩士 === 國立成功大學 === 生物化學研究所 === 93 ===  Antimetabolites are a clinically important group of cancer drugs used in treatment of a variety of solid tumors and hematological malignancies. The cytotoxicity of antimetabolites stems from its ability to interfere with key enzymatic steps in nucleic acid metabolism. Methotrexate (MTX), structurally similar to folic acid, is a stoichiometric inhibitor of dihydrofolate reductase, displaying significant tumoricidal activity against a variety of neoplasms. However, impaired drug transport into cells and augmented drug export partially result in resistance to MTX. Furthermore, locally injected MTX in aqueous solution form that is rapidly absorbed through capillaries into the circulatory system is not effective. To retain the drug in tumor cells for a long period and alter the pharmacokinetic behavior, we developed a new formulation of MTX that is bound to the drug carrier on the nanometer scale. Colloidal gold nanoparticles (AuNPs) have been extensively used in biological applications due to their biocompatibility, dimension (<50 nm), ease of preparation and characterization, and also have a history of use without inherent cytotoxicity. In this study, we developed the MTX-AuNP complex and examined its antitumor effect in vitro and in vivo. MTX could be directly bound onto gold nanoparticles to form the MTX-AuNP complex and reversibly released from nanoparticles. The accumulation of MTX-AuNP was faster and more than that of free MTX in tumor cells. MTX-AuNP showed dramatically enhanced growth-inhibitory effects in several tumor cell lines compared to the equal dose of free MTX. The administration of MTX-AuNP suppressed tumor growth in mice of ascites LL/2 tumor model; however, the equal dose of free MTX showed no effect on suppression of the tumor growth. In conclusion, combined the nanomaterial as a drug carrier, MTX-AuNP exhibits more effective antitumoral activity than free MTX.