Breast cancer is the most frequent cancer in women in the United States. Although its overall cure rate has been significantly improved, the current cure rate of advanced or recurring breast cancer is below 5%. Chemotherapy is a major strategy to treat breast cancer patients along with surgery and/or radiation therapy. However, chemotherapy is limited by several drawbacks such as systemic toxicity and lack of specificity. Nano- scale particle-based delivery of drugs represents a major improvement for more focused delivery of such therapeutic drugs. Another avenue for increasing the specificity of drug delivery is via stem cells that can serve as delivery vehicles for targeting therapeutic cytokines to tumors. Stem cells we have isolated from the Wharton's jelly of umbilical cord, termed `umbilical cord matrix stem'(UCMS) cells can also traffic selectively to tumors. These UCMS cells can be isolated in large numbers postnatally from an inexhaustible source. Our long term goal is to develop a novel strategy for targeted delivery of therapeutic nanoparticles by loading them into stem cells that home to cancer tissues. To address this goal, experiments are designed to test the stem cell/nanogel/therapeutic agent in vitro and in vivo.
In specific aim 1, we will engineer UCMS cells with a suicide gene (thymidine kinase), load them with several multiple nanogel therapeutic combinations, coculture them with breast cancer cells, and release the particles after addition of the pro-drug ganciclivor (GCV).
In specific aim 2, we will test the optimal therapeutic agent-nanogel combination in a SCID mouse model of metastatic human breast carcinoma (MDA-231) cells. The nanogel utilized to encapsulate therapeutic agents such as the anthraquinone derivative AQ10, tryptycene bisquinone TT24 (both are potent anticancer small molecules developed by Dr. Hua (co- investigator) at Kansas State University), Doxorubricin, and Cisplatin is polyethylene glycol- polyethylenimine (PEG-PEI), with an optimal methylene to proton ratio (>6:1). We will use fluorescent loading (SP-DiI) of stem cells, immunocytochemistry, Western blotting, genetic engineering of stem cells, apoptosis assays and image analysis to address these aims. The proposed research is innovative, novel, and will allow targeted delivery of potent anti-cancer small molecule drugs that have solubility issues or toxic side effects that otherwise limit their utility for human breast cancer patients. Upon successful completion of the proposed study, our procedure will have a high potential for future translational study. Therefore, the proposed work is designed to advance the strategic plan outlined in PAR-07-271. Breast cancer is the most common gender-associated cancer in the United States. The current cure rate of advanced or recurring breast cancer is below 5%. Although chemotherapy is the major strategy to treat breast cancer patients, chemotherapy is limited by several drawbacks such as systemic toxicity and lack of specificity. The primary objective of our proposed research is to develop a practical cancer-targeted chemotherapy for breast cancer by merging stem cell biology and a nanotechnology- based targeted-delivery system. Our treatment strategy proposed here is significantly better than existing therapeutic strategies since we anticipate more efficient therapeutic outcome but much fewer side effects. Once our hypothesis is proven correct, this procedure will be applied to human patients in the future. Therefore, this study should significantly contribute to improve public health.
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