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Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer

Vaidhyanathan, Shruthi
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605

Abstract Details

2010, MS, University of Cincinnati, Pharmacy: Pharmaceutical Sciences.
Tumor-selective drug delivery strategies maximize efficacy of pharmacological agents while limiting undesirable, off-target adverse events. The objective of this study was to identify novel peptide ligands that facilitate selective internalization of M13 bacteriophages in metastatic breast cancer and to assess endocytic pathways underlying cellular internalization of phage clones. Phage display technology allows identification of novel ligands for unknown receptors by functional screening of target cells using diverse libraries of peptides and proteins expressed as fusion with viral coat proteins. We performed four consecutive rounds of in vitro screening in the highly invasive, estrogen receptor-negative MDA-MB-231 breast cancer cell line using a cyclic 7-mer peptide library expressed on the M13 bacteriophage platform. The SVP1 phage clone identified at the end of the screening expressed the cyclic CFSGGPFWC peptide as N-terminal fusion in the pIII coat protein of the M13 bacteriophage. Functional uptake studies found the SVP1 phage to be 6-fold more efficiently internalized in MDA-MB-231 breast cancer cells than the M13K07 control phage which did not express a targeting peptide. Preferential selectivity of the SVP1 phage clone for estrogen receptor-negative MDA-MB-231 cells was confirmed by comparing cellular uptake in estrogen-receptor positive MCF-7 breast cancer, PC-3 prostate cancer, ES-2 ovarian cancer, and Ishikawa endometrial cancer cells. To identify underlying mechanisms that contribute to SVP1 phage endocytosis, cellular uptake studies were performed using inhibitors of molecular regulators of different endocytosis pathways. The results from these studies suggest that the intracellular uptake of the SVP1 phage clone is ATP-dependent and requires functional dynamin, microfilament, and microtubule architecture. In addition our data support a significant contribution of macropinocytosis in the uptake of SVP1 phage in estrogen receptor-negative MDA-MB-231 breast cancer cells. Further experiments will explore therapeutic applications of chemically synthesized CFSGGPFWC ligand for targeted drug delivery systems in invasive breast cancer.
Giovanni Pauletti, PhD (Committee Chair)
Arthur Buckley, PhD (Committee Member)
Pankaj Desai, PhD (Committee Member)
100 p.
Pharmaceuticals
phage display; drug delivery; novel ligands; peptide; breast cancer; endocytosis

Recommended Citations

Citations

  • Vaidhyanathan, S. (2010). Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605

    APA Style (7th edition)

  • Vaidhyanathan, Shruthi. Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer. 2010. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605.

    MLA Style (8th edition)

  • Vaidhyanathan, Shruthi. "Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer." Master's thesis, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605

    Chicago Manual of Style (17th edition)

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© 2010, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.