Investigation and Mathematical Modeling of Acoustic Release of Doxorubicin from Micelles

Abstract

Given the growing concern over the increasing number of people diagnosed with cancer and the high prevalence of unwanted side effects associated with chemotherapy on healthy tissues, this thesis aims to provide better, safer, and more effective treatment modalities. In this work, a targeted nanocarrier is loaded with an anti-cancer drug. Results of ultrasound release experiments are used to compare the response of different micellar types to acoustic waves. The investigated micelles include non-targeted micelles, folated micelles, micelles stabilized using an interpenetrating network of N,Ndiethylacrylamide, and micelles formed using PEO-b-poly(NIPAAm-co-HEMAlactaten). Acoustic release of the chemotherapeutic drug Doxorubicin (DOX) from micelles, was investigated using both 70-kHz and 80-kHz ultrasound at the following power densities: 0.76, 2.389, 2.546, 3.540, 5.013, 5.432, and 5.914 W/cm2. Next, mathematical modeling is applied to capture drug release kinetics from these nanovehicles. The investigated models are zero-order, first-order, Higuchi, Hixon- Crowell, Korsmeyer-Peppas, Weibull, Baker-Lonsdale, and Hopfenberg. Using statistics and the rate constants deduced, the effects of temperature, power density, and micellar type on drug release were investigated. Results showed that the release from folated micelles is slightly higher compared to release from non-folated micelles. This may be due to the conjugation of the folate moiety, which renders the micelles more sensitive to ultrasound (sonosensitive), by reducing their stability. Moreover, an increase in any of the experimental variables (mechanical index, temperature, or power density) leads to an increase in the percent of drug released. Finally, the Higuchi model provided the best fit to the experimental data, which means that the acoustic data available conform to this model’s assumptions and release mechanism. In conclusion, using micelles as drug delivery carriers and ultrasound as a trigger modality may reduce the side effects associated with chemotherapy.