Download Using PLGA as a carrier to improve anti

Using PLGA as a carrier to improve anti-Stat3 strategy
藉由 PLGA 載體改善對抗 STAT3 的策略
Advisor：Su Wu-Chou, M.D.
Student：Yeh Shang-Yu
Abstract：
Constitutive signal transducer and activator of transcription 3 (STAT3) activation is associated with
plenty of human cancers and mediates the expression of various genes in response 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 which shows Stat3 can be a promising cancer
therapeutic target.
The inactive Stat3 are present in the cytoplasm as free monomers until the cell surface receptors interact
with cytokine or growth factor. Through Jaks activation and endocytosis, the Tyr-phosphorylated Stat3
subsequent dimerizationin the cytoplasm and translocate to the nucleus to regulate target genes
transcriptionally. Sequestration of activated Stat3 to long-lived endosomes in the cytosome to form
“statosome” was observed recently. The “statosome” may have functions such as prolongation of signaling
and/or crosstalk.
Several small molecular inhibitors of Stat3 have been developed, such as 1)the direct interaction with
SH2 domain or dimerization inhibitors (e.g., S3I-201, S3I-2001), 2) the DNA binding domain inhibitors
(e.g., IS3 295), 3) the N-terminal domain inhibitors, and 4) the indirect binding of the upstream components
of the Stat3 pathway (e.g.,AG490, JSI-124). There are also antisense RNA and small interfering RNA
(siRNA), developing to inhibit the Stat3 target gene expression.However, up to date, none of the developed
Stat3 inhibitors have shown potential in vivo efficacy.
Poly (D, L-Lactide-co-glycolide) (PLGA), a macromolecular copolymer of poly (lactic acid) and poly
(glycolic acid), has superior biocompatible and degradability. The final product of degradation has no
toxicity and it is approved to be used in human by the U.S. Food and drug Administration (FDA).The cells
would uptake nanoparticles by endocytosis. The pathways into cells can either lead to the endosomal and
lysosomal compartments or via cell-surface lipid raft associated domains known as caveolae which avoids
the degredative fate of material entering the endosomal/lysosomal system.
In previous investigations, we have successfully conjugatedthe Jak2 inhibitor,AG490, into PLGA, which
induced significantly more cell death compared tofree AG490 in various lung cancer cells.We also plan to
conjugate Stat3 inhibitor (S3I-201) or combine S3I-201 and AG490 together into PLGA material to see
whether there are synergistic effects. In mechanism study, we’d like to know whether the Stat3 inhibitors
interact closely with the “statosome”. When they are carried by PLGA and engulfed into cell through
endocytosis. Weexpect to develop ideal nanodeviceswhich can effectively suppress IL-6/Jak/Stat3 pathway
in cancer cells and cells of tumor microenvironment.
Reference：
Pravin B. Sehgal. Paradigm shifts in the cell biology of STAT signaling.Semin Cell Dev Biol.
2008 August ; 19(4): 329–340