Liposomal drug release using ultrasound and modeling release dynamics for model predictive controller design

Abstract

Chemotherapy is widely used for cancer treatment; however, it causes unwanted side effects in patients such as fatigue, weight loss, pain, hair fall and nausea. Those side effects are due to the fact that most of the currently used therapeutic agents are in fact toxic to several organs, including the heart. In addition, many of them lead to the death of both cancerous and healthy cells. In the traditional way of treatment, when the patient was injected with the drug, a high dosage was required so that enough could reach the cancer cells and destroy them. These high dosages, however, can cause more harm than benefit, since they are responsible for the death of many healthy cells. To avoid these adverse effects, nanocarriers, called liposomes, have been developed, which can be loaded with the chemotherapeutic agents, and can be chemically modified to circulate for long periods in the blood stream while encapsulating the drugs and resisting any premature leakages. Additionally, ligands can be conjugated to their surface, allowing for their specific binding to receptors overexpressed on the surface of cancer cells and the subsequent internalization via endocytosis. Using ultrasound (US) as a triggering mechanism, the release of the drug is controlled temporally and spatially as it is induced inside the cells, hence avoiding drug release in systemic circulation, which in turn reduces the undesired side effects of conventional chemotherapy. US is of great interest to be used as a triggering technique as there is a lot of published work proving its usability in causing release from liposomes. Most of the work uses low frequency US as it causes the release at lower power densities; however, it is hardly focused unlike US at higher frequencies. The developed liposomes were tested against low frequency US (20 kHz) and focused-US at 1 MHz and 3 MHz and the results were compared to the literature. Moreover, the kinetics of the release were modeled to be used for many applications such as control systems and elimination of the need for further exhaustive laboratory experimentation.