Mitochondria-targeted Delivery Systems

S. Dhar
The University of Georgia, US

Keywords: cancer nanotechnology, mitochondria, delivery system

Summary:

The potential benefits of integrating nanomaterials with properties such as biodegradability, magnetization, fluorescence, and near-infrared absorption into a single object of nanoscale dimensions can lead to the development of hybrid nanocarrier platforms for simultaneous targeting, imaging, and combination therapy administration. We are developing hybrid nanoparticle (NP) systems for their potential use in combination therapy of cancer and image-guided therapy of atherothrombotic vascular diseases. Mitochondrial dysfunctions cause many human disorders. A platform technology of carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in therapeutics. We are developing a rationally designed, programmable NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction related diseases. An optimized formulation for maximal mitochondrial uptake was identified through in vitro screening of a library of charge and size varied NPs and the uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with mitochondria-targeted blended NPs. The versatility of this platform was demonstrated by studying a variety of mitochondria-acting therapeutics for different applications. These include mitochondria targeting chemotherapeutics for cancer, mitochondrial antioxidant for Alzheimer’s disease, and mitochondrial uncoupler for obesity. On the cardiovascular front, we are developing a long-circulating hybrid NP platform to selectively target macrophages and sense apoptosis for detection of plaque vulnerable to embolism. References: (1) Pathak, R. K.; Marrache, S.; Choi, J. H.; Berding, T. B.; Dhar, S. An Activable Prodrug Platin-A for Simultaneous Release of Cisplatin and Aspirin. Angew. Chem. Int. Ed., 2014, 53, 1963-1967. (2) Marrache, S.; Tundup, S.; Harn, D. A. and Dhar, S. "Ex vivo programming of dendritic cell by mitochondria-targeted nanoparticles to produce interferon-gamma for cancer immunotherapy" ACS Nano, 2013, 7, 7392-7402. (3) Marrache, S. and Dhar, S. "Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis" Proc. Natl. Acad. Sci. USA, 2013, 110, 9445-9450. (4) Marrache, S.; Choi, J. H.; Tundup, S.; Zaver, D.; Harn, D. A. and Dhar, S. "Immune stimulating photoactive hybrid nanoparticles for metastatic breast cancer" Integr. Biol., 2013, 5, 215-223. (5) Marrache, S. and Dhar, S. "Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics" Proc. Natl. Acad. Sci. USA, 2012, 109, 16288-16293.