Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics.

Abstract

Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different applications, including the mitochondria-targeting chemotherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer's disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the drug therapeutic index for cancer, Alzheimer's disease, and obesity compared with the nontargeted construct or the therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction-related diseases.

• Authors: Sean Marrache, Shanta Dhar
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 40 Pg. 16288-93 (Oct 02 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22991470 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Indazoles
• Polymers
• poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer
• Polyglactin 910
• Polyethylene Glycols
• alpha-Tocopherol
• Curcumin
• 2,4-Dinitrophenol
• lonidamine

Topics

• 2,4-Dinitrophenol
• Adipogenesis (physiology)
• Analysis of Variance
• Bioengineering (methods)
• Curcumin
• Drug Delivery Systems (methods)
• Humans
• Indazoles
• Mitochondrial Diseases (drug therapy)
• Nanoparticles (chemistry)
• Polyethylene Glycols (chemical synthesis, chemistry)
• Polyglactin 910 (chemical synthesis, chemistry)
• Polymers (chemistry, metabolism)
• alpha-Tocopherol