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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
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.
Su WP, Cheng FY, Shieh DB, Yeh CS, Su WC. Int J Nanomedicine. 2012;7:4269-83. Epub 2012 Aug 3.
Cheng FY, Wang SP, Su CH, Tsai TL, Wu PC, Shieh DB, Chen JH, Hsieh PC, Yeh CS. Biomaterials. 2008, 29, 2104.
Pravin B. Sehgal. Paradigm shifts in the cell biology of STAT signaling. Semin Cell Dev Biol. 2008 August ; 19(4): 329–340