Document Type

Dissertation

Date of Award

12-31-2019

Degree Name

Doctor of Philosophy in Chemistry - (Ph.D.)

Department

Chemistry and Environmental Science

First Advisor

Kevin D. Belfield

Second Advisor

James Haorah

Third Advisor

Yong Ick Kim

Fourth Advisor

Mengyan Li

Fifth Advisor

Yuanwei Zhang

Abstract

Mitochondria are essential organelles as the site of respiration in eukaryotic cells and are involved in many crucial functions in cell life. Dysfunction of mitochondrial metabolism and irregular morphology have been frequently found in human cancers. The capability of imaging mitochondria as well as regulating their microenvironment is important both scientifically and clinically. Mitochondria penetrating peptides (MPPs), certain peptides that are composed of cationic and hydrophobic amino acids, are good candidates for mitochondria targeting. Herein, a novel MPP, D-argine-phenylalanine-D-argine-phenylalanine-D-argine-phenylalanine-NH2 (rFrFrF), is conjugated with a rhodamine-based fluorescent chromophore (TAMRA). The TAMRA-rFrFrF probe exhibits advantageous properties for long-term mitochondria tracking of up to three days with low cytotoxicity and high biocompatibility. Mitochondria isolation experiments further confirmed the mitochondria targeting of the TAMRA-rFrFrF probe with minimal perturbation of mitochondrial function.

Mitochondrial function and metabolism are centrally involved in cancer initiation, tumorigenesis, growth, survival, and metastasis. Dysfunction of mitochondria, especially mitochondrial membrane hyperpolarization, plays a key role in drug resistance during cancer treatment. We report a boron-dipyrromethene (BODIPY) triarylsulfonium-based molecule (BD-PAG) as an opto-biomodulator (MOB) to target mitochondria and modulate mitochondrial pH. Significantly, our BD-PAG MOB demonstrates the reduction of drug resistance in cancer cell lines by regulating the mitochondrial pH and depolarizing the mitochondrial membrane.

Share

COinS