Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases

Yamada, Yuma; Harashima, Hideyoshi

doi:10.1016/j.addr.2008.04.016

Cited by 225 publications

(158 citation statements)

References 210 publications

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“…A similar spectrum was observed for the CoQ10/PEG2-PCL3.8-TPPBr mixture in CDCl 3 ( Figure 3C) because it is a good solvent for both of them. In contrast, the spectrum of blank PEG2-PCL3.8-TPPBr micelles in D 2 O showed signals characteristic of PEG protons Figure 3D). In this spectrum, the characteristic signals of the PCL arm protons appear weak and broad due to incorporation into the micelles core and severe loss of movement ( Figure 3D).…”

Section: ■ Results and Discussionmentioning

confidence: 90%

“…1,2 Mitochondrial dysfunction is associated with a variety of human disorders, such as neurodegenerative and neuromuscular diseases, obesity and diabetes, ischemia−reperfusion injury, cancer, and inherited mitochondrial diseases. 2 In many of these diseases, a major cause of damage is mitochondrial overproduction of reactive oxygen species (ROS).…”

Section: ■ Introductionmentioning

confidence: 99%

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Design and Evaluation of Multifunctional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria

et al. 2011

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Impairments of mitochondrial functions have been associated with failure of cellular functions in different tissues, leading to various pathologies. We report here a mitochondria-targeted nanodelivery system for coenzyme Q10 (CoQ10) that can reach mitochondria and deliver CoQ10 in adequate quantities. Multifunctional nanocarriers based on ABC miktoarm polymers (A = poly(ethylene glycol (PEG), B = polycaprolactone (PCL), and C = triphenylphosphonium bromide (TPPBr)) were synthesized using a combination of click chemistry with ring-opening polymerization, self-assembled into nanosized micelles, and were employed for CoQ10 loading. Drug loading capacity (60 wt %), micelle size (25−60 nm), and stability were determined using a variety of techniques. The micelles had a small critical association concentration and were colloidally stable in solution for more than 3 months. The extraordinarily high CoQ10 loading capacity in the micelles is attributed to good compatibility between CoQ10 and PCL, as indicated by the low Flory−Huggins interaction parameter. Confocal microscopy studies of the fluorescently labeled polymer analog together with the mitochondria-specific vital dye label indicated that the carrier did indeed reach mitochondria. The high CoQ10 loading efficiency allowed testing of micelles within a broad concentration range and provided evidence for CoQ10 effectiveness in two different experimental paradigms: oxidative stress and inflammation. Combined results from chemical, analytical, and biological experiments suggest that the new miktoarm-based carrier provides a suitable means of CoQ10 delivery to mitochondria without loss of drug effectiveness. The versatility of the click chemistry used to prepare this new mitochondria-targeting nanocarrier offers a widely applicable, simple, and easily reproducible procedure to deliver drugs to mitochondria or other intracellular organelles.

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Section: ■ Results and Discussionmentioning

confidence: 90%

Section: ■ Introductionmentioning

confidence: 99%

Design and Evaluation of Multifunctional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria

et al. 2011

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“…After mitochondria were incorporated into eukaryotic cells, eukaryotic cells became (DDS) that are specific to mitochondria is an important issue in terms of overcoming these diseases [13], therefore we investigated the use of aptamers that target mitochondria.…”

Section: Organelle-based Selex For Mitochondriamentioning

confidence: 99%

“Programmed packaging” for gene delivery

Hyodo

Sakurai

Akita

et al. 2014

Journal of Controlled Release

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We report on the development of a Multifunctional Envelope-type Nano Device (MEND) based on our packaging concept "Programmed Packaging" to control not only intracellular trafficking but also the biodistribution of encapsulated compounds such as nucleic acids/proteins/peptides. Our strategy for achieving this is based on molecular mechanisms of cell biology such as endocytosis, vesicular trafficking, etc. In this review, we summarize the concept of programmed packaging and discuss some of our recent successful examples of using MENDs. Systematic evolution of ligands by exponential enrichment (SELEX) was applied as a new methodology for identifying a new ligand toward cell or mitochondria. The delivery of siRNA to tumors and the tumor vasculature was achieved using pH sensitive lipid (YSK05), which was newly designed and optimized under in vivo conditions. The efficient delivery of pDNA to immune cells such as dendritic cells has also been developed using the KALA ligand, which can be a breakthrough technology for DNA vaccine. Finally, ss-cleavable and pH-activated lipid-like surfactant (ssPalm) which is a lipid like material with pH-activatable and SS-cleavable properties is also introduced as a proof of our concept.

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“…In addition, for the strategy to be successful, it will be necessary to deliver therapeutic/diagnostic agents into the innermost mitochondrial space, the mitochondrial matrix, where the mtDNA pool is located. A number of systems for delivering cargoes to mitochondria have been reported to date [11][12][13]. However, reports of mitochondrial genome targeting by means of an artificial gene vector are limited, although endogenous mitochondrial importing signal RNA can deliver exogenous RNA to mitochondria in mammalian cells [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…The DF-MITO-Porter, which possesses mitochondria-fusogenic inner and endosome-fusogenic outer envelopes, has the ability to pass through endosomal and mitochondrial membranes via step-wise membrane fusion ( Figure 1) [21]. Octaarginine (R8) functions as a cell-uptake device [22,23] in the outer envelope and as a mitochondrial targeting device [12,24,25] in the inner envelope. In this experiment, we attempted to deliver DNase I protein to mitochondria in living cells.…”

Section: Introductionmentioning

confidence: 99%

Delivery of bioactive molecules to the mitochondrial genome using a membrane-fusing, liposome-based carrier, DF-MITO-Porter

Yamada

Harashima

2012

Biomaterials

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Mitochondrial dysfunction has been implicated in a variety of human diseases. It is now well accepted that mutations and defects in the mitochondrial genome form the basis of these diseases. Therefore, mitochondrial gene therapy and diagnosis would be expected to have great medical benefits. To achieve such an innovative a strategy, it will be necessary to deliver therapeutic agents into mitochondria in living cells. We report here on a novel an approach to accomplish this via the use of a Dual Function (DF)-MITO-Porter, aimed at the mitochondrial genome, so-called mitochondrial DNA (mtDNA). The DF-MITO-Porter, an innovative a nano carrier for mitochondrial delivery, has the ability to penetrate the endosomal and mitochondrial membranes via step-wise membrane fusion. We first constructed a DF-MITO-Porter encapsulating DNase I protein as a bioactive cargo. It was expected that mtDNA would be digested, when the DNase I was delivered to the mitochondria.We observed the intracellular trafficking of the carriers, and then measured mitochondrial activity and mtDNA-levels after the delivery of DNase I by the DF-MITO-Porter. The findings confirm that the DF-MITO-Porter effectively delivered the DNase I into the mitochondria, and provides a demonstration of its potential use in therapies that are selective for the mitochondrial genome. 3

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Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases

Cited by 225 publications

References 210 publications

Design and Evaluation of Multifunctional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria

Design and Evaluation of Multifunctional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria

“Programmed packaging” for gene delivery

Delivery of bioactive molecules to the mitochondrial genome using a membrane-fusing, liposome-based carrier, DF-MITO-Porter

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