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Volkmar Weissig*, Gerard G.M. D’Souza, Sarathi V. Boddapati, Shing-Ming Cheng, Eyad Katrangi
Northeastern University, Bouve College of Health Sciences, Department of Pharmaceutical Sciences, 360 Huntington Avenue, Mugar 211, Boston, MA 02115, USA
*mailto:v.weissig@neu.edu

Mitochondria-specific Nanoassemblies for Drug and DNA delivery to Mitochondria

Mitochondria are being increasingly recognized as a prime target for pharmacological intervention due to their central role in numerous fundamental metabolic pathways. Above all, mitochondria are vital for the cell’s energy metabolism and for the regulation of programmed cell death. In addition, mitochondria are critically involved in the modulation of intracellular calcium concentration and the mitochondrial respiratory chain is the major source of damaging reactive oxygen species. Consequently, mitochondrial dysfunction either causes or at least contributes to a large number of human diseases. Malfunctioning mitochondria are found in several adult-onset diseases, including diabetes, cardiomyopathy, infertility, migraine, blindness, deafness, kidney and liver diseases and stroke. The accumulation of somatic mutations in the mitochondrial genome has been suggested to be involved in aging, in age-related neurodegenerative diseases as well as in cancer. Also, an increasing number of xenobiotics and of pharmaceuticals are being recognized to manifest their toxicity by interfering with mitochondrial functions.

In conclusion, the targeting of both, small drug molecules and large macromolecules to and into mitochondria may provide the basis for a large variety of future cytoprotective and cytotoxic therapies: The delivery of therapeutic DNA and RNA such as antisense oligonucleotides, ribozymes, plasmid DNA expressing mitochondrial encoded genes as well as wild-type mtDNA may provide the basis for treatment of mitochondrial DNA diseases; the targeting of antioxidants into the mitochondrial matrix may protect mitochondria from oxidative stress caused by a variety of insults, perhaps even contribute to slowing down the natural aging process; the mitochondria-specific targeting of naturally occurring toxins or synthetic drugs such as photosensitizers may open up avenues for new anticancer therapies. Moreover, delivering molecules known to trigger apoptosis by directly acting on mitochondria may overcome the apoptosis-resistance of many caner cells and drugs able to target mitochondrial uncoupling proteins may become a basis for treating obesity 1-4.

Amphiphilic cationic compounds with a delocalized charge center are known to accumulate in mitochondria of living cells in response to the mitochondrial membrane potential. Based on the intrinsic mitochondriotropism of such amphiphilic cations we have developed the first universal mitochondria-specific drug delivery system potentially able to deliver small molecules as well as DNA to mitochondria in living cells. For the design of such mitochondriotropic vesicles we have utilized the self-assembly behavior of dequalinium and its derivatives, which are mitochondriotropic amphiphiles resembling “bola”-form electrolytes, i.e. they are symmetric molecules with two charge centers separated by a hydrophobic chain. We found that such “bola”-form like amphiphiles are able to form nanoassemblies, i.e. liposome-like cationic vesicles (“bolasomes”), which we termed “DQAsomes” when prepared from dequalinium 5-7.

This poster presents a summary of earlier and recent data, which demonstrate the capability of mitochondriotropic nanoassemblies to deliver pDNA and apoptotically active small molecules to mitochondria in living mammalian cells.

1. D'Souza GGM, Weissig, V. Approaches to Mitochondrial Gene Therapy. Current Gene Therapy 2004; 4:317-328.
2. Weissig V, Boddapati, S.V., D'Souza, G.G.M., Cheng, S.M. Targeting of Low-Molecular Weight Drugs to Mammalian Mitochondria. Drug Design Reviews - Online 2004; 1:15-28.
3. Weissig V, Cheng, S.-M., D'Souza, G. Mitochondrial Pharmaceutics. Mitochondrion 2004; 3:229-244.
4. Weissig V. Mitochondrial-targeted drug and DNA delivery. Crit Rev Ther Drug Carrier Syst 2003; 20:1-62
5. Weissig V, Lizano C, Ganellin CR, Torchilin VP. DNA binding cationic bolasomes with delocalized charge center: A structure-activity relationship study. S.T.P. Pharma Sciences 2001; 11:91-96.
6. Weissig V, Mogel HJ, Wahab M, Lasch J. Computer simulations of DQAsomes Intl. Symp. Control. Rel. Bioact. Mater. Las Vegas, Nevada, USA: Controlled Release Society, 1998:312.
7. Weissig V, Lasch J, Erdos G, Meyer HW, Rowe TC, Hughes J. DQAsomes: a novel potential drug and gene delivery system made from Dequalinium. Pharm Res 1998; 15:334-337.