Ultrasound Triggered Release of Estrone- Targeted Liposomes

A Master of Science thesis in Chemical Engineering by Pierre Kawak entitled, "Ultrasound Triggered Release of Estrone- Targeted Liposomes," submitted in May 2017. Thesis advisor is Dr. Ghaleb Husseini. Soft and hard copy available.

Abstract

The fight against cancer has proven to be a lengthy one. Conventional treatment of cancer usually involves chemotherapy, a therapy known for its detrimental side effects. Doxorubicin, a cytotoxic anthracycline antibiotic, is one example of a chemotherapeutic drug that can cause congestive heart failure and other heart-related problems. Drug Delivery Systems (DDS) solve this problem by guarding healthy cells against the effects of chemotherapeutic drugs, while focusing their effect on the diseased tissue. Breast cancer is known to overexpress estrone receptors. This study deals with one DDS: estrone-targeted liposomes incapsulating doxorubicin and its efficacy when used in conjunction with ultrasound for the treatment of breast cancer. The DDS should protect healthy cells from the drug, transport the drug selectively to the cancer cells and release its contents in response to focused ultrasound (US). Two types of carriers were developed and studied: ES-positive and ES-negative liposomes. These DDS were found to be Large Unilamellar Vesicles, or LUVs, with radii of 97.11 ± 6.46 nm and 77.29 ± 0.43 nm, respectively, with uniform distributions. Release triggered by low frequency US was studied using a 20-kHz frequency probe at three power densities: 0.7, 3.09 and 5.25 mW/cm2. An increase in power density caused an increase in the release rate recorded. Comparing both targeted and non-targeted liposomes, the ES-positive ones were found to be more stable and less sonosensitive. High frequency US was studied as a trigger mechanism and no effect was discerned after an hour and a half of application. Comparisons with previous work showed a lower release rate compared to calcein-incorporating liposomes, as well as to doxorubicin-encapsulating micelles and the implications were discussed. Several drug release models were used to model experimental data and the Higuchi Kinetics model was found to be the best fit indicating diffusion-driven release by US. No statistically significant difference was found between the release rate constants of both liposomes under investigation and the different power densities investigated. The average release rate constant was 0.054 %/s.