The Effect of Ultrasound on the Drug Delivery of RGD-Targeted Liposomes

A Master of Science thesis in Chemical Engineering by Mohamad Mahmoud entitled, “The Effect of Ultrasound on the Drug Delivery of RGD-Targeted Liposomes”, submitted in May 2018. Thesis advisor is Dr. Ghaleb Husseini. Soft and hard copy available.

Abstract

Approaches used to treat cancer, with the most prominent being chemotherapy, have detrimental effects on patients’ health. Doxorubicin, a chemotherapeutic agent, alters normal cellular functions and can cause many fatal side effects, such as cell loss and congestive heart failure. Smart Drug Delivery Systems (DDS), such as liposomes, constitute a novel approach which can deliver a cytotoxic agent to the tumor without affecting healthy cells. A moiety, such as an RGD motif, can be conjugated to the liposome’s surface. This modification increases the efficacy of such liposomes by actively targeting specific receptors which are overexpressed on the surface of cancer cells. Two types of carriers were developed in this study, RGD-positive, and their control counterparts, RGD-negative (NH2 liposomes). The liposomes possessed radii of 88.26 ± 5.55 nm and 79.52 ± 4.81 nm, respectively, which classify them as Large Uni-lamellar Vesicles (LUVs). A 20-kHz ultrasound probe at three power densities, 7.46, 9.85, and 17.31 mW/cm2, equivalent to mechanical index (MI) values of 0.11, 0.12, and 0.16, respectively, was used to trigger the liposomes into releasing their encapsulated fluorescent model-drug, calcein. Both types of liposomes were stable and showed a higher release rate as the power density increased. Nine drug release kinetics models were utilized to model the online release profiles, where the Korsmeyer-Peppas and the Weibull models presented the best fits, predicting diffusion and dissolution driven drug release, respectively. Statistical analysis showed that the release rate constants were significantly affected by changes in power densities and the type of carrier. The calculated average release rate constants were KKP = 5.7291 (s-1.0789) and KW = 5.3734 for NH2 liposomes, and KKP = 9.3574 (s-0.9441) and KW = 6.2857 for RGD liposomes. This thesis presents the preparation of the smart DDS (liposomes), evaluates its stability and storage, and analyzes its drug release and sensitivity to ultrasound. The overall goal is to design a drug delivery system capable of reducing the side effects of conventional chemotherapy and hence improving the quality of life of cancer patients worldwide.