Development Of Bacterial Mechanosensitive Channels As Nanodevices In Liposome Systems For Targeted Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$502,341.00
Summary
Liposomes are among the most advanced mainstream particulate drug carriers in modern medicine. They vary in complexity, but in their most basic form consist of naturally occurring phospholipid vesicles, capable of encapsulating a wide range of drugs. Such liposomes provide a high degree of biocompatibility and a physical barrier that protects the drug cargo from degradative enzymes in the patient. Furthermore, liposomes provide an effective, non-toxic method to solubilise hydrophobic drugs and a ....Liposomes are among the most advanced mainstream particulate drug carriers in modern medicine. They vary in complexity, but in their most basic form consist of naturally occurring phospholipid vesicles, capable of encapsulating a wide range of drugs. Such liposomes provide a high degree of biocompatibility and a physical barrier that protects the drug cargo from degradative enzymes in the patient. Furthermore, liposomes provide an effective, non-toxic method to solubilise hydrophobic drugs and administer potent and even highly toxic drugs such as the anthracyclines, Doxorubicin and Daunorubicin (clinically approved anti-cancer treatments), Amphotericin B (fungal disease therapy) and Taxol (cancer therapy).The focus of this project is to incorporate nanovalves into these drug delivery systems, in the form of bacterial mechanosensitive (MS) channels, to facilitate the controlled and rapid release of encapsulated drugs at targeted tumours or disease tissues. The successful completion of this project represents a significant advance on existing liposomal drug delivery systems because MS channels open and release the drug into or onto the target cell immediately following liposome binding. Liposomal drug delivery systems offer the additional advantages that they concentrate the drug inside the target tissue, thereby increasing its efficacy; reduce the exposure of healthy cells to toxic drugs; and increase safety to patients through loading site-specific drugs into site-directed liposomes. Specifically this project will develop: 1. Liposome formulations in which the MS channels are closed, but poised to open upon binding to the target cell. 2. Customised MS channels designed to optimize controlled release. 3. Structural information that will assist in the treatment of channelopathies linked to MS channels, i.e. diseases resulting from defects in MS ion channel function (e.g. muscular dystrophy, cardiac arrhythmias, autosomal-dominant polycystic kidney disease).Read moreRead less
The Structural Basis For The Control Of Cardiac And Skeletal Muscle By The Troponin Complex
Funder
National Health and Medical Research Council
Funding Amount
$369,003.00
Summary
Many key physiological processes are controlled by large, multi-protein complexes. These molecular machines ensure that signals transmitted in the body are correctly interpreted and amplified so as to control key body functions. The Troponin protein complex is one such large multi-protein complex which is the switch used to control both heart and skeletal muscle contraction in the body. The Troponin complex responds to increasing cellular calcium levels, switching the muscle on at high calcium. ....Many key physiological processes are controlled by large, multi-protein complexes. These molecular machines ensure that signals transmitted in the body are correctly interpreted and amplified so as to control key body functions. The Troponin protein complex is one such large multi-protein complex which is the switch used to control both heart and skeletal muscle contraction in the body. The Troponin complex responds to increasing cellular calcium levels, switching the muscle on at high calcium. When calcium returns to its normal basal level, the Troponin complex switches the muscle off. Naturally occurring genetic errors can lead to the malfunction of the Troponin complex. This, in turn, can lead to severe and possibly fatal diseases of the heart and muscle systems. To gain an understanding of these molecular diseases, it is important to understand the structure, dynamics and function of the Troponin complex. This project will use a newly-developed magnetic resonance method to monitor changes in the Troponin structure as a function of calcium level. Each component of the Troponin complex will be labeled with magnetic tags, allowing the determination of both structure and dynamics of Troponin, both in solution and in active muscle fibres. The study will result in a molecular understanding of how the Troponin switch works. This will give great insight in how mutations result in cardiac and muscular diseases.Read moreRead less