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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA135599-02
Application #
7616679
Study Section
Special Emphasis Panel (ZRG1-NANO-M (01))
Program Officer
Fu, Yali
Project Start
2008-05-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$164,250
Indirect Cost
Name
Kansas State University
Department
Anatomy/Cell Biology
Type
Schools of Veterinary Medicine
DUNS #
929773554
City
Manhattan
State
KS
Country
United States
Zip Code
66506
Kawabata, Atsushi; Ohta, Naomi; Seiler, Garret et al. (2013) Naïve rat umbilical cord matrix stem cells significantly attenuate mammary tumor growth through modulation of endogenous immune responses. Cytotherapy 15:586-97
Prior, A M; Thapa, M; Hua, D H (2012) Aldose reductase inhibitors and nanodelivery of diabetic therapeutics. Mini Rev Med Chem 12:326-36
Basel, Matthew T; Balivada, Sivasai; Wang, Hongwang et al. (2012) Cell-delivered magnetic nanoparticles caused hyperthermia-mediated increased survival in a murine pancreatic cancer model. Int J Nanomedicine 7:297-306
Seo, Gwi-Moon; Rachakatla, Raja Shekar; Balivada, Sivasai et al. (2012) A self-contained enzyme activating prodrug cytotherapy for preclinical melanoma. Mol Biol Rep 39:157-65
Basel, Matthew T; Balivada, Sivasai; Shrestha, Tej B et al. (2012) A cell-delivered and cell-activated SN38-dextran prodrug increases survival in a murine disseminated pancreatic cancer model. Small 8:913-20
Wang, Lei; Liu, Ziyan; Balivada, Sivasai et al. (2012) Interleukin-1? and transforming growth factor-? cooperate to induce neurosphere formation and increase tumorigenicity of adherent LN-229 glioma cells. Stem Cell Res Ther 3:5
Uppalapati, Deepthi; Ohta, Naomi; Zhang, Yongqing et al. (2011) Identification and characterization of unique tumoricidal genes in rat umbilical cord matrix stem cells. Mol Pharm 8:1549-58
Doi, Chiyo; Egashira, Noboru; Kawabata, Atsushi et al. (2010) Angiotensin II type 2 receptor signaling significantly attenuates growth of murine pancreatic carcinoma grafts in syngeneic mice. BMC Cancer 10:67
Maurya, Dharmendra K; Doi, Chiyo; Kawabata, Atsushi et al. (2010) Therapy with un-engineered naive rat umbilical cord matrix stem cells markedly inhibits growth of murine lung adenocarcinoma. BMC Cancer 10:590
Doi, Chiyo; Maurya, Dharmendra Kumar; Pyle, Marla M et al. (2010) Cytotherapy with naive rat umbilical cord matrix stem cells significantly attenuates growth of murine pancreatic cancer cells and increases survival in syngeneic mice. Cytotherapy 12:408-17

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