ChE PhD Dissertation Defense: Rudolf Abdelmessih

Name:
Rudolf Abdelmessih

Title:

Investigating Strategies for Engineering More Efficient Drug Nanocarriers for Treatment of Human Metastatic Breast Cancer the Impact of Hydrophobic Drug Encapsulation on the Properties of Lipid-Based Nanoparticles and Drug Bioavailability

Date:
11/04/2024

Time:
1:00:00 PM

Committee Members:
Prof. Debra T. Auguste (Advisor)
Prof. Rebecca Carrier
Prof. Stephen Hatfield
Prof. Francisco Hung
Prof. Benjamin Woolston

Location:
EXP 401-A

Abstract:
A significant challenge in cancer treatment is the delivery of water-insoluble, hydrophobic drugs to tumor tissue at concentrations that are therapeutically effective. One way to address this challenge is by encapsulating hydrophobic drugs into drug delivery systems that would allow them to circulate with blood and diffuse into tumor tissue. Lipid-based nanoparticles (LNPs) constitute most of the drug delivery systems currently approved for clinical use, owing to their degradability, lack of toxicity and their wide range of tunable properties. Liposomes are one example of LNPs; they are spherical vesicles comprised of a bilayer phospholipid membrane surrounding an aqueous core, that can be used to encapsulate hydrophobic drugs. However, hydrophobic drug encapsulation can change the structure and mechanical properties of the lipid
membrane of liposomes, and the way they interact with cancer cells. Herein, we investigated the impact of encapsulating different hydrophobic, anticancer drugs into liposomes on cellular uptake, tumor accumulation, gene expression and tumor growth, in metastatic breast cancer (MBC).

Our data show that the encapsulation of an LPA receptor antagonist (Ki16425) into liposomes decreased the stiffness of the lipid membrane, and enhanced their cellular internalization, and tumor accumulation. Moreover, we show that the encapsulation of an HDAC inhibitor (NVP) into liposomes increased their cellular uptake, upregulated the expression of tumor suppressor genes, and led to a significant cell death in MBC cells. Similarly, we tested the effect of encapsulating an adenosine receptor antagonist (KW-6002) in a liposomal formulation that can activate cancer-related immune responses.

In conclusion, our results offer insights into the chemical and mechanical behavior of drug-lipid complexes that can impact cellular internalization and tumor delivery, and may aid in the treatment of MBC.