Date

2016

Document Type

Dissertation

Degree

Doctor of Philosophy

Department

Chemistry

First Adviser

Thévenin, Damien

Other advisers/committee members

Robinson, Matthew K.; Pires, Marcos M.; Vezenov, Dmitri

Abstract

Localized delivery is vital for the successful development of novel and effective therapeutics for the treatment of cancer. Currently, most targeting methods are based on cancer markers, such as cell surface receptors. However, this approach suffers from two major drawbacks: biomarkers are not specific to cancer cells, which can result in off-target toxicity, and cancer cells have a tendency to evolve quickly, which can lead to a loss of biomarkers, thus therapy resistance. However, nearly all solid tumors have a low extracellular pH, regardless of their tissue or cellular origin. Moreover, tumors' aggressiveness and metastatic potential are fostered at low extracellular pH. For these reasons, acidosis is a hallmark of tumor progression and may provide an opportunity for tumor-targeted therapy.The targeting and delivery described herein is based on the pH(Low) Insertion Peptide (pHLIP), a unique delivery peptide that can selectively target tumors in mice based solely on their acidity rather than a specific marker. pHLIP is a soluble peptide in aqueous solutions at normal pH, but inserts unidirectionally (C-terminus across) into cell membrane as a transmembrane helix under acidic conditions. My thesis research focused on developing new strategies to inhibit cancer cell growth by delivering therapeutics to cells using pHLIP. We hypothesize that the localized targeting achievable with pHLIP when combined with potent therapeutics will synergize to create an advantageous treatment for cancer. I will present my results in (1) inhibiting cancer cell proliferation and tumor through the delivery of monomethyl auristatin derivatives, (2) modulating the activity of G-Protein coupled receptors by interfering with their cytoplasmic domains, and (3) promoting cancer cells toxicity by inducing mitochondrial membrane disruption through the delivery of antimicrobial peptide analogs.

Available for download on Saturday, October 28, 2017

Included in

Chemistry Commons

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