Title

Platinum-NGR A Peptide Targeting Conjugate Of Cisplatin: Design, Synthesis, And Efficacy In Breast Cancer Cells

Date of Award

January 2017

Degree Type

Closed Access Thesis

Degree Name

Master of Science (MS)

Department

Biological Sciences

First Advisor

Margaret W. Ndinguri

Second Advisor

Lindsay E. Calderon

Third Advisor

Patrick J. Calie

Abstract

Breast cancer is one of the leading causes of mortality in women worldwide. Platinum based chemotherapeutic drugs, such as cisplatin and carboplatin, are one of the primary therapies employed in the treatment of breast cancer. Adverse side effects caused by untargeted drug delivery of these platinum drugs are often a cause for cessation or interruption of cancer treatment. New targeted drug strategies are being employed to reduce side effects and the development of inherent and acquired drug resistances in the body by the addition of targeting moieties specific to cancer cell receptors. In this study we synthesized a platinum-Asn-Gly-Arg (NGR) peptide conjugate with a long-term goal of reducing adverse effects in patients, as well as combating possible drug resistance compared with other widely available platinum-based chemotherapeutics. NGR peptide motifs are specific to angiogenic endothelial cells and solid tumor cells as a result of their interaction with aminopeptidase N (APN), or CD13, receptors. Fmoc solid phase chemistry was employed via a peptide synthesizer to produce mPeg-CNGRC-mal free peptide that was then cyclized and conjugated to activated cisplatin, producing a conjugated platinum-peptide complex specific to APN receptors. Compound identity was confirmed using mass spectra analysis. Our synthesized drug, cyclic mPeg-CNGRC-Pt, was then employed in in vitro testing in 4T1 breast cancer cell lines that are CD13 positive. Cell viability, drug competition, and drug uptake were assessed in 4T1 cells for cyclic mPeg-CNGRC-Pt versus carboplatin and free peptide. Our results suggest that cyclic mPeg-CNGRC-Pt has increased potency and efficacy in 4T1 cells compared with carboplatin. Mechanism of action for the drug has not yet been determined as drug competition and uptake results are still pending. As 4T1 cells have been determined previously to be CD13+, we anticipate that the drug will demonstrate increased selectivity and uptake in this cell line. Our current results demonstrate that cyclic mPeg-CNGRC-Pt could be useful as a chemotherapeutic tool in future breast cancer studies and in the study of other CD13/APN positive cancers, but first mechanism of action must be determined definitively for the drug.

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