Mitochondrial drug delivery and mitochondrial disease therapy--an approach to liposome-based delivery targeted to mitochondria.
Recent progress in genetics and molecular biology has provided useful information regarding the molecular mechanisms associated with the mitochondrial diseases. Genetic approaches were initiated in the late 1980s to clarify the gene responsible for various mitochondrial diseases, and information concerning genetic mutations is currently used in the diagnosis of mitochondrial diseases. Moreover, it was also revealed that mitochondria play a central role in apoptosis, or programmed cell death, which is closely related to the loss of physiological functions of tissues. Therefore, drug therapies targeted to the mitochondria would be highly desirable. In spite of the huge amount of mechanism-based studies of mitochondrial diseases, effective therapies have not yet been established mainly because of the lack of an adequate delivery system. To date, numerous investigators have attempted to establish a mitochondrial drug delivery system. However, many problems remain to be overcome before a clinical application can be achieved. To fulfill a drug delivery targeted to mitochondria, we first need to establish a method to encapsulate various drugs, proteins, peptides, and genes into a drug carrier depending on their physical characteristics. Second, we need to target it to a specific cell. Finally, multi-processes of intracellular trafficking should be sophisticatedly regulated so as to release a drug carrier from the endosome to the cytosol, and thereafter to deliver to the mitochondria. In this review, we describe the current state of the development of mitochondrial drug delivery systems, and discuss the advantage and disadvantage of each system. Our current efforts to develop an efficient method for the packaging of macromolecules and regulating intracellular trafficking are also summarized. Furthermore, novel concept of "Regulation of intramitochondrial trafficking" is proposed herein as a future challenge to the development of a mitochondrial drug delivery system.
Yamada
Yuma
Y
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Sapporo 060-0812, Japan.
Akita
Hidetaka
H
Kogure
Kentaro
K
Kamiya
Hiroyuki
H
Harashima
Hideyoshi
H
D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D004337:Drug Carriers / Q000008:administration & dosage*; D015696:Gene Products, tat / Q000008:administration & dosage; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage*; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D018832:Molecular Chaperones / Q000502:physiology; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use; D020135:Peptide Nucleic Acids / Q000627:therapeutic use; D021381:Protein Transport / Q000502:physiology; D051381:Rats
D004272:DNA, Mitochondrial; D004337:Drug Carriers; D015696:Gene Products, tat; D008081:Liposomes; D018832:Molecular Chaperones; D009838:Oligodeoxyribonucleotides; D020135:Peptide Nucleic Acids; C090759:mitochondrial import stimulation factor, rat