Mitochondrial delivery of biologically active molecules.

Starting in 1988 and throughout the 1990s, a series of keydiscoveries was made which revitalized scientific interest inmitochondria, a thoroughly studied cell organelle firstdescribed over a century ago. Long-time mitochondrialaficionados would argue that the 1990s just broughtmitochondria back into fashion and thereby into morefashionable journals. Both views seem correct. The appear-ance of a textbook image of an electron micrograph of ananimal mitochondrion on the front cover of Science onOctober 22, 1999 serves as verification, and StephenHersh’s commentary in this theme issue properly reflectsthe excitement over this recent development.During the 1990s, the number of human diseases foundto be caused by defective mitochondrial DNA has growndramatically, and nowadays approximately more than 360mitochondrial disorders are known. It has been estimatedthat every 15 min, a child is born who has a mitochondrialDNA disease or will develop one by the age of 5 (UnitedMitochondrial Disease Foundation, Pittsburgh, PA). Everyorgan at any age of onset can be affected. Also during the1990s, mitochondria as the well-known “powerhouse” ofthe cell were accepted as the cell’s “death switch” mirroringtheir recognized key role in programmed cell death(apoptosis). Consequently, around 1998, mitochondria werediscussed for the first time as a novel potential target forcancer chemotherapy. “Talking cancer cells into commit-ting suicide” by turning on the intracellular “death switch”emerged as an intriguing new idea in the war on cancer.Further, mitochondria have been known as a source offree radicals for over 40 years, and the link between avariety of clinical conditions and an increased mitochon-drial production of reactive oxygen species (ROS) underhypoxic conditions has been established. Subsequently, theidea of supplementing mitochondria with antioxidantsalways appeared as an attractive therapeutic approach toprotect cells and tissues from oxidation. Only during the1990s, however, the vulnerability of essential redox sensitivesignaling pathways towards exogenous antioxidants wasrevealed, and the question of mitochondria-specific and,above all, controlled delivery of antioxidants arose. Finally,the key role mitochondria play for the calcium homeostasisof every cell and this organelle’s involvement in almostevery biochemical pathway has been textbook knowledgefor perhaps half a century.By the end of the 1990s, mitochondria had beenestablished as an outstanding prime pharmacological targetfor an enormous variety of cytotoxic and cytoprotectivetherapies providing ample opportunities for drug develop-ment. Among pharmaceutical scientists mainly working inthe area of drug delivery, however, interest in mitochondriaappeared around 2000 as somewhat weak at best. Faultynotions, like once a drug is in the cytosol it will reachmitochondria anyway because there are so many of them inevery cell, were not unheard of. Also, categorizing properlyabstract submissions involving early mitochondrial drugdelivery work to, for example, annual meetings of theAmerican Society of Gene Therapy or the ControlledRelease Society, during those years was somewhat ham-pered due to the lack of the term “mitochondria” in theirofficial key word listings. To draw the attention of a broadaudience in the drug delivery community to this fascinatingcell organelle, Elsevier’s Advanced Drug Delivery Reviewsdedicated in 2001 an entire theme issue to “Drug andDNA Delivery to Mitochondria” (vol. 49, 2001, nos.1–2, V.Weissig, V.P. Torchilin, Eds.). It should not go unmen-