Abstract

Cancer is caused by the uncontrolled growth and spread of abnormal cells resulting in 1 in 6 deaths every day. The most common treatment methods include surgery, chemotherapy, and radiation. These techniques are invasive, aggressive, and non-specific to cancer cells. Therefore, alternative therapies which are both potent and does not interfere with the quality of living are on a rise. Photodynamic Therapy (PDT) is an approved alternative remedy in the treatment of cancer. The efficacy of PDT depends on the penetration power of the photosensitizer (PS) when injected into to the site of tumor. However, due to complexity involved in the structure of the PS molecules and its interaction with the cancerous cells, the potential of this therapy is not fully realized.

The PS molecules exhibit biological effect because of direct interaction with the cell membranes. Therefore, it is important to investigate this interaction and its effect on the physicochemical properties of membranes. The focus of this work is to understand the fundamental mechanism of this interaction with the cell membranes. However, due to the complexities associated on working with the human cell membrane it is appropriate to conduct experiments with model cell membranes, commonly known as liposomes. Additionally, liposomes are extremely biocompatible and are used as drug delivery vehicles or encapsulating agents.

The work reported in this dissertation is divided into two parts. In the first part, the interaction mechanism of hydrophilic riboflavin with liposomes was studied as to create a baseline. It was found out that the hydrophilic nature of riboflavin does not penetrate the hydrophobic lipid bilayer by using a combination of laser scattering and calorimetric techniques. To further the bilayer permeation capacity of any hydrophilic PS, the idea of conjugation of hydrophobic alkyl tail chains to hydrophilic PS molecules was explored. Thereby, hydrophobicity was induced to amino methyl coumarin, a potent PS molecule, based on the setbacks of the existing hydrophilic photosensitizers. The interaction between this molecule and model cancerous cell membranes was investigated using combination of biophysical techniques and MD simulations. Our findings indicated that the addition of alkyl chains to fluorophores improves their cellular uptake and targeted delivery. It was concluded that the at longer chain coumarin fluorophore perturbs the lipid bilayer at higher concentrations by flip-flop mechanism leading to membrane thinning. Preliminary in-vitro activity reveals the photoactive potential of these amphiphilic coumarin molecules.

In the second part, alternative strategies such as encapsulation using liposomes was proposed, for FDA approved existing PS molecules (viz. HPPH and Riboflavin) to increase their efficacy during treatment. Long circulating liposome formulations of poly ethyl glycol (PEG) conjugated lipids, polymerizable lipids and cholesterol. The stability and composition of each component in the formulations was examined using biophysical methods. It was found that PEGylation increases the stability of liposomal formulation by preventing aggregation through thermal and physical stability. It was also concluded that cholesterol does not contribute to the increase in stability of PEGylated formulations. In- vitro and in- vivo studies conducted by our collaborators at NIH confirmed the efficiency of PEGylated liposome-based carriers demonstrated through longer circulation times and specificity towards tumor.

Library of Congress Subject Headings

Photochemotherapy; Cancer--Treatment; Liposomes; Photosensitizing compounds

Publication Date

8-3-2020

Document Type

Dissertation

Student Type

Graduate

Degree Name

Engineering (Ph.D.)

Department, Program, or Center

Engineering (KGCOE)

Advisor

Anju R. Gupta

Advisor/Committee Member

Satish G. Kandlikar

Advisor/Committee Member

Amlan Ganguly

Campus

RIT – Main Campus

Plan Codes

ENGR-PHD

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