Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer

Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer

Bibliographic Details
Main Author: Vaidhyanathan, Shruthi
Language:English
Published: University of Cincinnati / OhioLINK 2010
Subjects:
Pharmaceuticals
phage display
drug delivery
novel ligands
peptide
breast cancer
endocytosis
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605
id ndltd-OhioLink-oai-etd.ohiolink.edu-ucin1282570605
record_format oai_dc
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin12825706052021-08-03T06:14:20Z Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer Vaidhyanathan, Shruthi Pharmaceuticals phage display drug delivery novel ligands peptide breast cancer endocytosis 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. 2010-12-06 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Pharmaceuticals
phage display
drug delivery
novel ligands
peptide
breast cancer
endocytosis
spellingShingle Pharmaceuticals
phage display
drug delivery
novel ligands
peptide
breast cancer
endocytosis
Vaidhyanathan, Shruthi
Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer
author Vaidhyanathan, Shruthi
author_facet Vaidhyanathan, Shruthi
author_sort Vaidhyanathan, Shruthi
title Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer
title_short Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer
title_full Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer
title_fullStr Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer
title_full_unstemmed Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer
title_sort selection and internalization mechanisms of targeting ligands for invasive breast cancer
publisher University of Cincinnati / OhioLINK
publishDate 2010
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605
work_keys_str_mv AT vaidhyanathanshruthi selectionandinternalizationmechanismsoftargetingligandsforinvasivebreastcancer
_version_ 1719433250604056576

Similar Items