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Using PLGA nanoparticle as a carrier to improve anti-Stat3 strategy 藉由 PLGA 奈米載體改善對抗 STAT3 的策略 Advisor:蘇五洲 老師 Student:葉上瑜 Abstract: Constitutive signal transducer and activator of transcription3 (STAT3) activation and Kras mutation are associated with plenty of human cancers and crosstalk with other signaling pathways that responsible to tumor growth, proliferation and metastasis. In addition to tumor cells, activated STAT3 is also found in immune cells, stromal cells and endothelial cells of tumor microenvironment. The Kras mutation in cancer cells causes high drug resistant and reduces the drug efficiency in clinical treatments. These evidences indicate that STAT3 and Kras are the promising cancer therapeutic targets. Poly (D, L-Lactide-co-glycolide) (PLGA), a macromolecular copolymer of poly (lactic acid) and poly (glycolic acid), has superior biocompatible and degradability. The cells uptake nanoparticle by endocytosis. After uptaken by cells, the PLGA nanoparticle (NPs) can either locate to the endosomal and lysosomal compartments or via cell-surface lipid raft associated domains known as caveolae to avoid the degredative fate by endosomal/lysosomal system. Using PLGA as a drug carrier may change the subcellular location of encapsulated drug and lead to more tumor cell death. We have encapsulated Jak2 inhibitor, AG490 、 the Stat3 inhibitor, S3I-201 and the sphingosine-1-phosphate (S1P) receptors agonist, FTY720 into PLGA nanoparticles with/ without surfactant by two encapsulate methods . We then used AS2、A549、CL1-0、CL1-5、CL1-0 (Kras muant)、H460、 H157、 H1299、H1299-L858R、LL2cell lines to investigate the drug efficacies between free form drug and PLGA-drug. After blocking the Jak/stat3 pathway, we found a rebound activation of Kras/ERK pathway. The different drug encapsulated methods affect the location of nanopraticles in cells and induce different degrees of cell death, indicating that cells utilize kinds of pathways to escape from apoptosis. In some conditions, the PLGA-encapsulated-STAT3- inhibitor NPs suppressed both STAT3 and ERK activation in cancer cells. Further studies to disclose the underlying mechanisms are on-going. Reference: 1. Su WP, Cheng FY, Shieh DB, Yeh CS, Su WC. Int J Nanomedicine. 2012;7:4269-83. Epub 2012 Aug 3. 2. Cheng FY, Wang SP, Su CH, Tsai TL, Wu PC, Shieh DB, Chen JH, Hsieh PC, Yeh CS. Biomaterials. 2008, 29, 2104. 3. Pravin B. Sehgal. Paradigm shifts in the cell biology of STAT signaling. Semin Cell Dev Biol. 2008 August ; 19(4): 329–340