text: the compositions of the invention provide a universally applicable drug delivery system , which delivers in vitro and in vivo highly water - soluble molecules ( low - molecular weight drugs , peptides , peptide - nucleic acids , saccharides , oligonucleotides ) selectively and exclusively to mitochondria in living mammalian cells including malignant transformed cells . the compositions according to the invention can be used to address the significant problems caused by damaged or diseased mitochondria . recently , more than fourteen groups of potential mitochondrial drugs or mitochondrial drug targets have been summarized ( weissig et al ., 2004 ). the vast majority of the recently published reviews center around drug targets related to the crucial role mitochondria play during apoptosis ( morisaki et al ., 2003 ; kotake et al ., 2003 ; kroemer , 2003 ; malisan et al ., 2003 ; galiegue et al ., 2003 ; o &# 39 ; neil et al ., 2003 ; pastorino et al ., 2003 ; granville et al ., 2003 ; halestrap et al ., 2003 ; waldmeier et al ., 2003 ; crompton , 2003 ; sordet et al ., 2003 ). another area of high interest is the protection of mitochondria from oxidative stress ( james et al ., 2004 ; green et al ., 2004 ; coulter et al ., 2000 ). an additional area of interest is disease caused by mutated mitochondrial dna ( dimauro et al ., 2001 ; wallace , 1992 ; wallace , 2001 ; pulkes et al ., 2001 ; manfredi et al ., 2000 ; d &# 39 ; souza et al ., 2004 ). a large number of treatments have been proposed in this area . certain amphiphilic compounds (“ mitochondriotropics ”) are able to cross both mitochondrial membranes leading to their accumulation in the mitochondrial matrix . fig1 shows the chemical structure of representative mitochondriotropic molecules , rhodamine 123 ( compound a ) has been used extensively as a stain for mitochondria in living cells since its introduction in 1982 ( chen et al ., 1982 ). by 1969 , methyltriphenylphosphonium salts ( compound b ) had been demonstrated to be taken up rapidly by mitochondria in living cells ( lieberman et al ., 1969 ), and the mitochondrial accumulation of dequalinium chloride ( compound c ) was established during the 1980s ( weiss et al ., 1987 ). other examples of mitochondriotropic cations ( structures not shown ) are cyanine dyes such as n , n ′- bis ( 2 - ethyl - 1 , 3 - dioxolane ) kryptocyanine ( oseroff et al ., 1986 ) and victoria blue bo ( morgan et al ., 1998 ). mitochondriotropic molecules have two structural features in common . first , they are all amphiphilic ; that is , they combine a hydrophilic charged center with a hydrophobic core . second , in all structures the n - electron charge density extends over at least three atoms or more instead of being limited to the internuclear region between the heteroatom and the adjacent carbon atom . this causes a distribution of the positive charge density between two or more atoms ; that is , the positive charge is delocalized , thus the terminology “ delocalized cations .” both structural features are widely believed to be crucial for the accumulation of these organic cations inside the matrix of mitochondria . sufficient lipophilicity combined with delocalization of the positive charge on these cations , to reduce the free energy change when the cations move from an aqueous to a hydrophobic environment , are thought to be prerequisites for their mitochondrial accumulation in response to the mitochondrial membrane potential ( weiss et al ., 1987 ). the compositions and methods of the invention make use of these properties of mitochondriotropic molecules by combining the hydrophobized versions of these organic cations with the ideal vesicular delivery system , the liposome . colloidal vesicles composed of phospholipids , or liposomes , are one of the most versatile and most extensively studied drug delivery systems . liposomes can encapsulate an unlimited variety of hydrophilic , amphiphilic and hydrophobic small molecules either in their aqueous inner space or in their lipid bilayer membranes . they are essentially nontoxic , non - immunogenic and biodegradable ; that is , liposomes meet all prerequisites for an ideal drug delivery system . the surface modification of liposomes with polyethylene glycol leads to prolonged circulation times in the bloodstream ( klibanov et al ., 1990 ), which in turn is the basis for a variety of liposome - based drugs that have been approved by the fda and fda - like agencies in europe and asia over the last decade . to utilize the superior drug carrier properties of liposomes for mitochondria - targeted delivery of bioactive molecules , amphiphilic delocalized cations have been hydrophobized according to the invention to form liposomes having surface - linked mitochondriotropic residues . in an exemplary embodiment according to the invention , stearyltriphenylphosphonium bromide ( stpp ) was synthesised by replacing the methyl group in methyltriphenylphosphonium bromide ( fig1 , compound b ) with a stearyl residue to form a hydrophobized amphiphilic delocalized cation . the hydrophobic fatty acid ( stearyl ) residue “ anchors ” the mitochondriotropic triphenylphosphonium cation in the phospholipid bilayer membrane ( i . e ., “ attaches ” it covalently to the liposomal surface ), as shown schematically in fig2 b and 2c . any therapeutic compound , e . g ., a therapeutic compound previously delivered by another delivery system , is a candidate for delivery to a patient by the system of the invention . cyclosporin a ( csa ), for example , has been shown to bind with nanomolar affinity to mitochondrial cyclophilin d , which potentially makes it an interesting anti - ischaemic drug candidate ( woodfield et al ., 1998 ). however , csa also targets at least eight other cyclophilins inside the cell , which are likely to bind a large portion of the administered drug . therefore , the mitochondrial concentration of csa is difficult to predict , and an effective csa treatment may require high , even toxic concentrations to reach the mitochondrial target ( waldmeier et al ., 2003 ). consequently , csa as a potential anti - ischaemic drug would benefit from the mitochondria - specific drug carrier system according to the invention , which would be able to increase its therapeutic index . paclitaxel is a potent antitubulin agent used in the treatment of malignancies ( eisenhauer et al ., 1998 ). it has recently been demonstrated that clinically relevant concentrations of paclitaxel target mitochondria directly and trigger apoptosis by inducing cytochrome c ( cyt c ) release in a permeability transition pore ( ptp )- dependent manner ( andre et al ., 2002 ). unfortunately , paclitaxel has a very narrow therapeutic window ( seligson et al ., 2001 , which most likely reflects the existence of several drug targets inside the cell , thus making only a subset of the drug available for mitochondria ( andre et al ., 2002 ). consequently , paclitaxel as an anticancer drug should greatly benefit from the organelle - specific delivery system according to the invention . ceramide is a major sphingolipid with sphingosine as its basic structure . a lipid - signaling molecule , it helps to regulate the differentiation , proliferation , and death of cells . in the cell , ceramide is degraded with ceramidase to sphingosine , which is then phosphorylated by sphingosine kinase to form sphingosine - 1 - phosphate . phosphorylated sphingosine is able to form special channels in the outer mitochondrial membrane , releasing into the cell factors that trigger apoptosis and , thus , inhibiting cancer cell growth . the organelle - specific delivery system according to the invention should significantly increase the specificity , and thus the activity , of this useful therapeutic compound . the therapeutic compositions of the invention may be administered orally , topically , or parenterally ( e . g ., intranasally , subcutaneously , intramuscularly , intravenously , or intra - arterially ) by routine methods in pharmaceutically acceptable inert carrier substances and solutions . for example , the compositions of the invention may be administered in a sustained release formulation using a biodegradable biocompatible polymer . filled mitochondriotropic phospholipid vesicles according to the invention can be administered in a dosage of 0 . 25 μg / kg / day to 5 mg / kg / day , and preferably 1 μg / kg / day to 500 μg / kg / day . optimal dosage and modes of administration can readily be determined by conventional protocols . the therapeutic compositions may be administered either systemically or in a site - specific manner . additional targeting agents may be added to the surface of the mitochondriotropic liposomes of the invention , where appropriate , for targeted delivery to a specific cell type . in the case of treatment for cancer , carcinoma cells are known to have a higher membrane potential than normal cells , which results in thier preferential uptake of the mitochondriotropic liposomes of the invention . the therapeutic compositions of the invention can be administered independently or co - administered with another active agent . it is contemplated that the therapeutic compositions of the invention will be particularly useful as antineoplastic agents when co - administered with , e . g ., cis - platin or methotrexate . the following examples are presented to illustrate the advantages of the present invention and to assist one of ordinary skill in making and using the same . these examples are not intended in any way otherwise to limit the scope of the disclosure . synthesis and characterization of the bromide salt containing stearyl - triphenylphosphonium cation as a hydrophobized amphiphilic delocalized cation according to the invention stearyl - triphenylphosphonium bromide ( according to fig2 a ) was synthesized by heating stearyl bromide and triphenylphosphine ( fig1 b ) under reflux in xylene according to a protocol for the synthesis of analogous tertiary phosphonium salts ( see , materials and methods ). isolation by column chromatography on silica gel and recrystallization from diethylether yielded a chromatographically pure product , which was identified by 1 h - nmr as described in materials and methods . fig3 shows the 31 p - nmr spectrum of stpp . the observed 31 p chemical shift of stpp is at 25 . 34 ppm , well within the range of 20 . 9 - 26 . 2 ppm as described for a series of alkyl - and aryl triphenylphosphonium salts ( kiddle , 2000 ). in comparison , the 31 p chemical shift of triphenylphosphine was found to be − 4 . 48 ppm , which is in perfect agreement with the published 31 p - nmr data ( allen and taylor , 1982 ). preparation and characterization of liposomes according to the invention with surface - linked triphenylphosphonium cations the preparation of liposomes in the presence of hydrophilic molecules that have been hydrophobized via linkage to fatty acid or phospholipid derivatives results in the covalent “ anchoring ” of the hydrophilic moiety to the liposomal surface . liposomes according to the invention were prepared in the presence of stpp according to standard protocols ( lasch et al ., 2003 ). fig2 b shows schematically the alkyl ( i . e ., stearyl ) residue mediated “ anchoring ” of the triphenylphosphonium cation in the liposomal phospholipid bilayer membrane . stpp liposomes , i . e ., liposomes with surface - linked triphenylphosphonium cations , were isolated using a sephadex g - 15 column and characterized by 31 p - nmr ( fig4 ), size distribution analysis ( fig5 ) and zeta potential measurements ( fig6 ). as expected ( see , fig4 ), the 31 p - nmr spectrum of stpp - liposomes shows two chemical shifts correlating to the phosphorus in the phosphate groups of the lipid ( peak a ) and to the positively charged phosphorus of stpp ( peak b ). no differences in both chemical shifts between the free compounds ( i . e ., free stpp and free phospholipid ) and the liposomal incorporated molecules could be found , indicating that the triphenylphosphonium group of stpp does not seem to interact with the bilayer membrane . this in turn supports the conclusion that stpp is anchored in the lipid membrane as schematically shown in fig3 . the size of liposomes with 20 mol % incorporated stpp ( fig5 ) is 132 . 1 ± 59 . 6 nm , slightly larger than would have been expected for liposomes prepared by probe sonication , an effect that is most - likely due to the presence of the stpp . liposome size did not change significantly upon storage at 4 ° c . over several days . the zeta - potential of stpp - liposomes ( fig6 ) seems to increase linearly with increasing amounts of incorporated stpp until it reaches a plateau between 15 and 20 mol % stpp . whether this observed plateau is due to a limitation of the maximal amount of stpp incorporable in liposomes has not been investigated , but subsequently , for all in vitro studies , liposomes with 20 mol % stpp were used . to study the cellular uptake and intracellular distribution of stpp liposomes , cells of the breast cancer cell line bt 20 were incubated with fluorescence - labeled stpp liposomes for 1 h in serum - free medium . to remove non - internalized liposomes , cells were thoroughly washed and allowed to grow for another hour in complete medium . typically obtained epifluorescence microscopic images are shown in fig7 a and 7b . fig7 a displays cells incubated with stpp liposomes that have been labeled by incorporation of 0 . 5 mol % rhodamine - pe , while fig7 b shows cells , the mitochondria of which have been specifically stained with mitotracker red . on comparing fig7 a with fig7 b , it can be seen that cells incubated with stpp liposomes display the same distinct fluorescence pattern as cells stained with the mitochondria - specific dye . such a comparison of staining patterns has been used by filipovska et al . ( 2004 ) to reveal the localization of labeled thiol proteins inside mitochondria and by geromel et al . ( 2001 ) to show the localization of labeled oligonucleotides at and inside mitochondria within living mammalian cells . based on the fact that the fluorophore in our stpp liposomes was covalently linked to phospholipids and not to the mitochondriotropic entity , i . e ., to stpp , it can be concluded from fig7 a and 7b that at least partially intact phospholipid vesicles have accumulated at or near the site of mitochondria . ceramide encapsulated into mitochondriotropic liposomes according to the invention displays increased apoptotic activity results of a preliminary study suggest that the pro - apoptotic activity of c6 ceramide is increased when formulated in mitochondriotropic , i . e ., stpp , liposomes according to the invention . fig8 represents a micrograph of dna gel separation analysis of cells of the colon cancer cell line colo205 incubated with c6 ceramide - loaded mitochondriotropic liposomes according to the invention for 18 hrs , followed by extraction of their dna . the concentration of ceramide in all samples was 25 μm . lane a — dna marker ; lane b — untreated control ; lane c — ceramide - loaded plain liposomes ; lane d — ceramide loaded stpp liposomes according to the invention ; lane e — free ceramide . black arrows indicate the apoptotic dna ladder . the total amount of dna was identical in all lanes . at identical ceramide concentrations , neither cells treated with ceramide loaded plain liposomes ( lane c , fig8 ) nor cells treated with free ceramide ( lane e , fig8 ) showed the dna laddering typical of apoptosis . cells treated with ceramide encapsulated in stpp liposomes , however , do not seem to have any intact dna anymore ( empty well ), but do display a dna ladder ( degraded dna ) as indicated by the black arrows ( lane d , fig8 ). nude mice were inoculated subcutaneously into the left flank with colo205 colon cancer cells . after the tumor size had reached 2 - 3 mm in diameter , 0 . 1 ml samples of radio - labeled liposomes ( 5 μci total ) were injected into the tail vein and the animals were sacrificed after 24 hours . liposomes carrying polyethylene glycol ( 3 ′ peg5000 ) had a zeta potential of − 10 . 6 , whereas liposomes loaded with 100 stpp as well as with 3 % peg5000 exhibited a zeta potential of + 12 . 1 . referring to fig9 , it can be seen that adding a mitochondriotropic cation to the surface of pegylated liposomes does not change the biodistribution pattern of the liposomes in sites as varied as tumor , blood or muscle . thus , the delivery system of the invention is completely blood compatible . triphenylphosphine ( tpp ), stearyl bromide , and organic solvents were purchased from fisher scientific and used without further purification . egg phosphatidylcholine ( pc ) and cholesterol ( ch ) were obtained from avanti polar lipids . the celltiter aqueous one solution cell proliferation assay kit was purchased from promega , and all fluorescence dyes used in this study were obtained from molecular probes . following a protocol for the synthesis of analogue tertiary phosphonium salts ( rideout et al ., 1989 ), stearyl bromide ( 1 . 93 g , 5 . 5 mmol ) and triphenylphosphine ( 1 . 52 g , 5 . 8 mmol ) were heated under reflux for 20 h in freshly distilled anhydrous xylene ( 30 ml ). the progress of the reaction was monitored by thin layer chromatography ( tlc ) on silica gel plates ( silica gel 60 , f - 254 ) using iodine as detection reagent . the solvent was removed on a rotary evaporator to obtain crude yellowish oil . the crude was purified by silica gel column chromatography ( 75 g ) using methanol : chloroform ( 5 : 95 ) as an eluent . purified stpp , obtained as a colorless oil , crystallized on standing and was recrystallized from ether to yield pure stpp in 35 - 45 % yields . the product was characterized by 1 h - nmr ( cdcl 3 ) and 31 p - nmr ( with external 85 % h 3 po 4 as reference ) on a varian mercury 300 nmr spectrometer : 1 h nmr : 7 . 68 - 7 . 88 ( m , 15h ), 3 . 7 - 3 . 8 ( m , 2h ), 1 . 55 - 1 . 65 ( t , 4h ), 1 . 2 - 1 . 35 ( m , 28h ), 0 . 7 - 0 . 8 ( t , 3h ); 31 p - nmr : 25 . 34 . stpp - liposomes were prepared by probe sonication according to the general method of liposome preparation described in lasch et al . ( 2003 ). briefly , a mixture of lecithin , cholesterol , hydrophobized polyethylene glycol and stpp ( pc / ch / hpeg / stpp = 62 / 15 / 3 / 20 , molar ratio ; final total lipid 25 mg / ml ) was dissolved in chloroform followed by removal of the organic solvent using a rotary evaporator . after the addition of 5 mm hepes ( ph 7 . 4 ) to the dry lipid film , the sample was probe sonicated with a sonic dismembrator ( model 100 , fischer scientific ) at a power output of approximately 10 watts for 30 min . to remove any titanium particles shed from the tip of the probe during sonication , the sample was centrifuged for 10 min at 3000 × g . the formed stpp - liposomes were separated from free , i . e ., non - incorporated stpp , by gel filtration chromatography on a sephadex g - 15 column . the liposomal incorporation of stpp was confirmed by 31 p - nmr spectroscopy . the liposome size and size distribution were determined by quasielastic laser light scattering using a coulter n4 submicron particle size analyzer . the zeta potential of stpp liposomes was determined at 2 . 5 v , 657 nm , 2 . 00 hz and 25 ° c . using the zeta potential analyzer version 3 . 26 from brookhaven instruments corporation . for each measurement , 10 μl liposome solution ( total lipid , 25 mg / ml ; stpp content varying between 0 and 25 mol %) were added into 2 ml hbs , ph 7 . 4 and incubated until temperature equilibration was attained . for analyzing their intracellular distribution pattern by fluorescence microscopy , stpp liposomes ( 20 mol % stpp ) were labeled with 0 . 5 mol % rhodamine - pe ( aex = 550 nm , aem = 590 nm ). bt - 20 cells were grown on 22 mm cover slips in 6 - well plates to about 85 % confluence . after the medium had been replaced with serum - free medium , 35 μl stpp liposomes ( 25 mg / ml lipid ) were added to each well . following a 1 h incubation , the medium containing non - internalized liposomes was removed , cells were thoroughly washed , allowed to grow for another hour in complete medium and analyzed by epifluorescence microscopy using a bx61 olympus model . for visualizing mitochondria in cells not treated with stpp liposomes , cells were co - incubated for 5 - 7 min with mitotracker red cmxros . images were taken with an olympus camera on an olympus bx61 microscope using a tritc filter for mitotracker and for rhodamine . photographs were taken digitally and processed using adobe photoshop 6 . 0 . allen , d . w ., taylor , b . f . 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( 1987 ). dequalinium , a topical antimicrobial . agent , displays anticarcinoma activity based on selective mitochondrial accumulation . proc . natl . acad . sci . u . s . a . 84 ( 15 ): 5444 - 5448 . woodfield , k ., ruck , a ., bridiczka , d ., halestrap , a . p ., ( 1998 ) direct demonstration of a specific interaction between cyclophilin d and the adenine nucleotide translocase confirms their role in the mitrochondrial permeability transition . biochem . j ., 336 : 287 - 290 . while the present invention has been described in conjunction with a preferred embodiment , one of ordinary skill , after reading the foregoing specification , will be able to effect various changes , substitutions of equivalents , and other alterations to the compositions and methods set forth herein . it is therefore intended that the protection granted by letters patent hereon be limited only by the definitions contained in the appended claims and equivalents thereof .