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From Serendipity to Mitochondria-Targeted Nanocarriers

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ABSTRACT

This review illustrates how a random observation at the laboratory bench has helped pave the way towards the development of organelle-targeted pharmaceutical nanocarriers. A fortuitous discovery in the mid 1990s involving the self-assembly of a molecule, known to accumulate inside mitochondria, has lead to the development of subcellular nanocarriers suited for the selective delivery of biologically active molecules to mitochondria inside living mammalian cells. Applications for mitochondria-specific drug and DNA delivery are described, the current state-of-the-art of mitochondrial drug targeting technology is reviewed, and its future perspectives are discussed.

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REFERENCES

  1. Mobacken H, Romanus M. Microvascular response to local application of dequalinium chloride. A vital microscopical study of hamster’s cheek pouch and a microangiographic study of rabbit’s ear. Br J Dermatol. 1975;92(1):63–72.

    PubMed  CAS  Google Scholar 

  2. Mobacken H, Romanus M, Wengstrom C. Development of strength in dequalinium chloride-treated skin incisions in rat. Dermatologica. 1974;148(3):154–9.

    PubMed  CAS  Google Scholar 

  3. Weiss MJ, Wong JR, Ha CS, Bleday R, Salem RR, Steele Jr GD, et al. Dequalinium, a topical antimicrobial agent, displays anticarcinoma activity based on selective mitochondrial accumulation. Proc Natl Acad Sci USA. 1987;84(15):5444–8.

    PubMed  CAS  Google Scholar 

  4. Christman JE, Miller DS, Coward P, Smith LH, Teng NN. Study of the selective cytotoxic properties of cationic, lipophilic mitochondrial-specific compounds in gynecologic malignancies. Gynecol Oncol. 1990;39(1):72–9.

    PubMed  CAS  Google Scholar 

  5. Steichen JD, Weiss MJ, Elmaleh DR, Martuza RL. Enhanced in vitro uptake and retention of 3H-tetraphenylphosphonium by nervous system tumor cells. J Neurosurg. 1991;74(1):116–22.

    PubMed  CAS  Google Scholar 

  6. Vercesi AE, Bernardes CF, Hoffmann ME, Gadelha FR, Docampo R. Digitonin permeabilization does not affect mitochondrial function and allows the determination of the mitochondrial membrane potential of Trypanosoma cruzi in situ. J Biol Chem. 1991;266(22):14431–4.

    PubMed  CAS  Google Scholar 

  7. Horobin RW, Trapp S, Weissig V. Mitochondriotropics: a review of their mode of action, and their applications for drug and DNA delivery to mammalian mitochondria. J Control Release. 2007;121(3):125–36.

    PubMed  CAS  Google Scholar 

  8. Galanakis D, Davis CA, Del Rey Herrero B, Ganellin CR, Dunn PM, Jenkinson DH. Synthesis and structure-activity relationships of dequalinium analogues as K+ channel blockers. Investigations on the role of the charged heterocycle. J Med Chem. 1995;38(4):595–606.

    PubMed  CAS  Google Scholar 

  9. Zhuo S, Allison WS. Inhibition and photoinactivation of the bovine heart mitochondrial F1-ATPase by the cytotoxic agent, dequalinium. Biochem Biophys Res Commun. 1988;152(3):968–72.

    PubMed  CAS  Google Scholar 

  10. Hait WN. Targeting calmodulin for the development of novel cancer chemotherapeutic agents. Anticancer Drug Des. 1987;2:139–49.

    PubMed  CAS  Google Scholar 

  11. Dong Y, Berners-Price SJ, Thorburn DR, Antalis T, Dickinson J, Hurst T, et al. Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines: targets for therapy. Biochem Pharmacol. 1997;53(11):1673–82.

    PubMed  CAS  Google Scholar 

  12. Manetta A, Emma D, Gamboa G, Liao S, Berman M, DiSaia P. Failure to enhance the in vivo killing of human ovarian carcinoma by sequential treatment with dequalinium chloride and tumor necrosis factor. Gynecol Oncol. 1993;50(1):38–44.

    PubMed  CAS  Google Scholar 

  13. Bleday R, Weiss MJ, Salem RR, Wilson RE, Chen LB, Steele Jr G. Inhibition of rat colon tumor isograft growth with dequalinium chloride. Arch Surg. 1986;121(11):1272–5.

    PubMed  CAS  Google Scholar 

  14. Schneider Berlin KR, Ammini CV, Rowe TC. Dequalinium induces a selective depletion of mitochondrial DNA from HeLa human cervical carcinoma cells. Exp Cell Res. 1998;245(1):137–45.

    PubMed  CAS  Google Scholar 

  15. Schneider-Berlin KR, Bonilla TD, Rowe TC. Induction of petite mutants in yeast Saccharomyces cerevisiae by the anticancer drug dequalinium. Mutat Res. 2005;572(1–2):84–97.

    PubMed  CAS  Google Scholar 

  16. Sancho P, Galeano E, Nieto E, Delgado MD, Garcia-Perez AI. Dequalinium induces cell death in human leukemia cells by early mitochondrial alterations which enhance ROS production. Leuk Res. 2007;31(7):969–78.

    PubMed  CAS  Google Scholar 

  17. Rodrigues JR, Gamboa ND. Effect of dequalinium on the oxidative stress in Plasmodium berghei-infected erythrocytes. Parasitol Res. 2009;104(6):1491–6.

    PubMed  Google Scholar 

  18. Gamboa-Vujicic G, Emma DA, Liao SY, Fuchtner C, Manetta A. Toxicity of the mitochondrial poison dequalinium chloride in a murine model system. J Pharm Sci. 1993;82(3):231–5.

    PubMed  CAS  Google Scholar 

  19. Armijo Moreno M, Gutierrez Salmeron MT, Camacho Martinez F, Naranjo Sintes R, Armijo Lozano R, Garcia Mellado V, et al. Necrosis of the penis caused by dequalinim (2 findings). Actas Dermosifiliogr. 1976;67(7-8):547–52.

    PubMed  CAS  Google Scholar 

  20. Weissig V, Vetro-Widenhouse TS, Rowe TC. Topoisomerase II inhibitors induce cleavage of nuclear and 35-kb plastid DNAs in the malarial parasite Plasmodium falciparum. DNA Cell Biol. 1997;16(12):1483–92.

    PubMed  CAS  Google Scholar 

  21. Khor V, Yowell C, Dame JB, Rowe TC. Expression and characterization of the ATP—binding domain of a malarial Plasmodium vivax gene homologous to the B-subunit of the bacterial topoisomerase DNA gyrase. Mol Biochem Parasitol. 2005;140(1):107–17.

    PubMed  CAS  Google Scholar 

  22. Rowe TC, Weissig V, Lawrence JW. Mitochondrial DNA metabolism targeting drugs. Adv Drug Deliv Rev. 2001;49(1–2):175–87.

    PubMed  CAS  Google Scholar 

  23. Weissig V, Lasch J, Erdos G, Meyer HW, Rowe TC, Hughes J. DQAsomes: a novel potential drug and gene delivery system made from Dequalinium. Pharm Res. 1998;15(2):334–7.

    PubMed  CAS  Google Scholar 

  24. Gulik A, Luzzati V, DeRosa M, Gambacorta A. Tetraether lipid components from a thermoacidophilic archaebacterium. Chemical structure and physical polymorphism. J Mol Biol. 1988;201(2):429–35.

    PubMed  CAS  Google Scholar 

  25. Luzzati V, Gambacorta A, DeRosa M, Gulik A. Polar lipids of thermophilic prokaryotic organisms: chemical and physical structure. Annu Rev Biophys Biophys Chem. 1987;16:25–47.

    PubMed  CAS  Google Scholar 

  26. De Rosa M, Gambacorta A, Gliozzi A. Structure, biosynthesis, and physicochemical properties of archaebacterial lipids. Microbiol Rev. 1986;50(1):70–80.

    PubMed  Google Scholar 

  27. Weissig V, Torchilin VP. Mitochondriotropic cationic vesicles: a strategy towards mitochondrial gene therapy. Curr Pharm Biotechnol. 2000;1(4):325–46.

    PubMed  CAS  Google Scholar 

  28. Weissig V, Moegel H-J, Wahab M, Lasch J. Computer simulation of DQAsomes. Proc Intl Symp Control Rel Bioact Mater. 1998;25:196–7.

    Google Scholar 

  29. Grinberg S, Kolot V, Linder C, Shaubi E, Kas’yanov V, Deckelbaum RJ, et al. Synthesis of novel cationic bolaamphiphiles from vernonia oil and their aggregated structures. Chem Phys Lipids. 2008;153(2):85–97.

    PubMed  CAS  Google Scholar 

  30. Li Q, Mittal R, Huang L, Travis B, Sanders CR. Bolaamphiphile-class surfactants can stabilize and support the function of solubilized integral membrane proteins. Biochemistry. 2009;48(49):11606–8.

    PubMed  CAS  Google Scholar 

  31. Meister A, Drescher S, Garamus VM, Karlsson G, Graf G, Dobner B, et al. Temperature-dependent self-assembly and mixing behavior of symmetrical single-chain bolaamphiphiles. Langmuir. 2008;24(12):6238–46.

    PubMed  CAS  Google Scholar 

  32. Meister A, Weygand MJ, Brezesinski G, Kerth A, Drescher S, Dobner B, et al. Evidence for a reverse U-shaped conformation of single-chain bolaamphiphiles at the air-water interface. Langmuir. 2007;23(11):6063–9.

    PubMed  CAS  Google Scholar 

  33. Puri A, Loomis K, Smith B, Lee JH, Yavlovich A, Heldman E, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit Rev Ther Drug Carrier Syst. 2009;26(6):523–80.

    PubMed  CAS  Google Scholar 

  34. Qiu F, Chen Y, Tang C, Zhou Q, Wang C, Shi YK, et al. De novo design of a bolaamphiphilic peptide with only natural amino acids. Macromol Biosci. 2008;8(11):1053–9.

    PubMed  CAS  Google Scholar 

  35. Fuchtner C, Emma DA, Manetta A, Gamboa G, Bernstein R, Liao SY. Characterization of a human ovarian carcinoma cell line: UCI 101. Gynecol Oncol. 1993;48(2):203–9.

    PubMed  CAS  Google Scholar 

  36. Weissig V, Lizano C, Ganellin CR, Torchilin VP. DNA binding cationic bolasomes with delocalized charge center: a structure-activity relationship study. STP Pharma Sci. 2001;11:91–6.

    CAS  Google Scholar 

  37. Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA. 1987;84(21):7413–7.

    PubMed  CAS  Google Scholar 

  38. TrosdeIlarduya C, Sun Y, Duzgunes N. Gene delivery by lipoplexes and polyplexes. Eur J Pharm Sci. 2010;40(3):159–70.

    CAS  Google Scholar 

  39. Hart SL. Multifunctional nanocomplexes for gene transfer and gene therapy. Cell Biol Toxicol. 2010;26(1):69–81.

    PubMed  CAS  Google Scholar 

  40. He CX, Tabata Y, Gao JQ. Non-viral gene delivery carrier and its three-dimensional transfection system. Int J Pharm. 2010;386(1–2):232–42.

    PubMed  CAS  Google Scholar 

  41. Montier T, Benvegnu T, Jaffres PA, Yaouanc JJ, Lehn P. Progress in cationic lipid—mediated gene transfection: a series of bio-inspired lipids as an example. Curr Gene Ther. 2008;8(5):296–312.

    PubMed  CAS  Google Scholar 

  42. Ma B, Zhang S, Jiang H, Zhao B, Lv H. Lipoplex morphologies and their influences on transfection efficiency in gene delivery. J Control Release. 2007;123(3):184–94.

    PubMed  CAS  Google Scholar 

  43. Duguid JG, Durland RH. DNA packaging in non-viral systems. In: Rolland A, editor. Advanced gene delivery. Amsterdam: Harwood Academic; 1999. p. 45–63.

    Google Scholar 

  44. Sternberg B, Sorgi FL, Huang L. New structures in complex formation between DNA and cationic liposomes visualized by freeze-fracture electron microscopy. FEBS Lett. 1994;356(2–3):361–6.

    PubMed  CAS  Google Scholar 

  45. Lasch J, Meye A, Taubert H, Koelsch R, Mansa-ard J, Weissig V. Dequalinium vesicles form stable complexes with plasmid DNA which are protected from DNase attack. Biol Chem. 1999;380(6):647–52.

    PubMed  CAS  Google Scholar 

  46. Xu Y, Szoka Jr FC. Mechanism of DNA release from cationic liposome/DNA complexes used in cell transfection. Biochemistry. 1996;35(18):5616–23.

    PubMed  CAS  Google Scholar 

  47. Weissig V, Torchilin VP. Towards mitochondrial gene therapy: DQAsomes as a strategy. J Drug Target. 2001;9(1):1–13.

    PubMed  CAS  Google Scholar 

  48. Weissig V, D’Souza GGM. Cationic mitochondriotropic vesicles for DNA delivery to mitochondria. Mol Ther. 2004;9:S259.

    Google Scholar 

  49. Therapy ASfG. KEYWORD INDEX. Molecular Therapy 2004;9:S425–35.

    Google Scholar 

  50. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 1988;242(4884):1427–30.

    PubMed  CAS  Google Scholar 

  51. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988;331(6158):717–9.

    PubMed  CAS  Google Scholar 

  52. Tuppen HA, Blakely EL, Turnbull DM, Taylor RW. Mitochondrial DNA mutations and human disease. Biochim Biophys Acta. 2010;1797(2):113–28.

    PubMed  CAS  Google Scholar 

  53. Naviaux RK. Developing a systematic approach to the diagnosis and classification of mitochondrial disease. Mitochondrion. 2004;4(5–6):351–61.

    PubMed  CAS  Google Scholar 

  54. Claros MG, Perea J, Jacq C. Allotopic expression of yeast mitochondrial maturase to study mitochondrial import of hydrophobic proteins. Methods Enzymol. 1996;264:389–403.

    PubMed  CAS  Google Scholar 

  55. Gray RE, Law RH, Devenish RJ, Nagley P. Allotopic expression of mitochondrial ATP synthase genes in nucleus of Saccharomyces cerevisiae. Methods Enzymol. 1996;264:369–89.

    PubMed  CAS  Google Scholar 

  56. Weissig V, Torchilin VP. Cationic bolasomes with delocalized charge centers as mitochondria-specific DNA delivery systems. Adv Drug Deliv Rev. 2001;49(1–2):127–49.

    PubMed  CAS  Google Scholar 

  57. Zullo SJ, Parks WT, Chloupkova M, Wei B, Weiner H, Fenton WA, et al. Stable transformation of CHO Cells and human NARP cybrids confers oligomycin resistance (oli(r)) following transfer of a mitochondrial DNA-encoded oli(r) ATPase6 gene to the nuclear genome: a model system for mtDNA gene therapy. Rejuvenation Res. 2005;8(1):18–28.

    PubMed  CAS  Google Scholar 

  58. Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwong JQ, Guy J, et al. Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nat Genet. 2002;30(4):394–9.

    PubMed  CAS  Google Scholar 

  59. Oca-Cossio J, Kenyon L, Hao H, Moraes CT. Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics. 2003;165(2):707–20.

    PubMed  CAS  Google Scholar 

  60. de Grey AD. Mitochondrial gene therapy: an arena for the biomedical use of inteins. Trends Biotechnol. 2000;18(9):394–9.

    PubMed  Google Scholar 

  61. Figueroa-Martinez F, Vazquez-Acevedo M, Cortes-Hernandez P, Garcia-Trejo JJ, Davidson E, King MP, et al. What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes. Mitochondrion. 2011;11(1):147–54.

    PubMed  CAS  Google Scholar 

  62. Perales-Clemente E, Fernandez-Silva P, Acin-Perez R, Perez-Martos A, Enriquez JA. Allotopic expression of mitochondrial-encoded genes in mammals: achieved goal, undemonstrated mechanism or impossible task? Nucleic Acids Res. 2011;39(1):225–34.

    PubMed  CAS  Google Scholar 

  63. Yoon YG, Yang YW, Koob MD. PCR-based cloning of the complete mouse mitochondrial genome and stable engineering in Escherichia coli. Biotechnol Lett. 2009;31(11):1671–6.

    PubMed  CAS  Google Scholar 

  64. Yonemura I, Nakada K, Sato A, Hayashi J, Fujita K, Kaneko S, et al. Direct cloning of full-length mouse mitochondrial DNA using a Bacillus subtilis genome vector. Gene. 2007;391(1–2):171–7.

    PubMed  CAS  Google Scholar 

  65. Bigger B, Tolmachov O, Collombet JM, Coutelle C. Introduction of chloramphenicol resistance into the modified mouse mitochondrial genome: cloning of unstable sequences by passage through yeast. Anal Biochem. 2000;277(2):236–42.

    PubMed  CAS  Google Scholar 

  66. Bigger BW, Coutelle C. Trial and error: how the unclonable human mitochondrial genome was cloned in yeast. Pharm Res. 2011;IN PRESS.

  67. Gibson DG, Glass JI, Lartigue C, Noskov VN, Chuang RY, Algire MA, et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science. 2010;329(5987):52–6.

    PubMed  CAS  Google Scholar 

  68. Koulintchenko M, Temperley RJ, Mason PA, Dietrich A, Lightowlers RN. Natural competence of mammalian mitochondria allows the molecular investigation of mitochondrial gene expression. Hum Mol Genet. 2006;15(1):143–54.

    PubMed  CAS  Google Scholar 

  69. Weissig V, Seibel P, Seibel M, Torchilin VP. Binding and release of DNA-peptide conjugates by cationic mitochondriotropic vesicles (DQAsomes). Proc Intl Symp Control Rel Bioact Mater. 2001;28:850–1.

    Google Scholar 

  70. Weissig V, Lizano C, Torchilin VP. Selective DNA release from DQAsome/DNA complexes at mitochondria-like membranes. Drug Deliv. 2000;7(1):1–5.

    PubMed  CAS  Google Scholar 

  71. Weissig V, D’Souza GG, Torchilin VP. DQAsome/DNA complexes release DNA upon contact with isolated mouse liver mitochondria. J Control Release. 2001;75(3):401–8.

    PubMed  CAS  Google Scholar 

  72. D’Souza GG, Rammohan R, Cheng SM, Torchilin VP, Weissig V. DQAsome-mediated delivery of plasmid DNA toward mitochondria in living cells. J Control Release. 2003;92(1–2):189–97.

    PubMed  Google Scholar 

  73. Katrangi E, D’Souza G, Boddapati SV, Kulawiec M, Singh KK, Bigger B, et al. Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function. Rejuvenation Res. 2007;10(4):561–70.

    PubMed  Google Scholar 

  74. Vaidya B, Mishra N, Dube D, Tiwari S, Vyas SP. Targeted nucleic acid delivery to mitochondria. Curr Gene Ther. 2009;9(6):475–86.

    PubMed  CAS  Google Scholar 

  75. Yoon YG, Koob MD, Yoo YH. Re-engineering the mitochondrial genomes in mammalian cells. Anat Cell Biol. 2010;43(2):97–109.

    PubMed  Google Scholar 

  76. Lyrawati D, Trounson A, Cram D. Expression of GFP in the mitochondrial compartment using DQAsome-mediated delivery of an artificial mini-mitochondrial genome. Pharm Res. 2011;IN PRESS.

  77. Lechardeur D, Lukacs GL. Intracellular barriers to non-viral gene transfer. Curr Gene Ther. 2002;2(2):183–94.

    PubMed  CAS  Google Scholar 

  78. Duvvuri M, Feng W, Mathis A, Krise JP. A cell fractionation approach for the quantitative analysis of subcellular drug disposition. Pharm Res. 2004;21(1):26–32.

    PubMed  CAS  Google Scholar 

  79. Duvvuri M, Gong Y, Chatterji D, Krise JP. Weak base permeability characteristics influence the intracellular sequestration site in the multidrug-resistant human leukemic cell line HL-60. J Biol Chem. 2004;279(31):32367–72.

    PubMed  CAS  Google Scholar 

  80. Horobin RW. Uptake, distribution and accumulation of dyes and fluorescent probes within living cells: a structure-activity modelling approach. Adv Colour Sci Technol. 2001;4:101–7.

    CAS  Google Scholar 

  81. Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281(5381):1309–12.

    PubMed  CAS  Google Scholar 

  82. Skulachev VP. Why are mitochondria involved in apoptosis? Permeability transition pores and apoptosis as selective mechanisms to eliminate superoxide-producing mitochondria and cell. FEBS Lett. 1996;397(1):7–10.

    PubMed  CAS  Google Scholar 

  83. Chen G, Wang F, Trachootham D, Huang P. Preferential killing of cancer cells with mitochondrial dysfunction by natural compounds. Mitochondrion. 2010;10(6):614–25.

    PubMed  CAS  Google Scholar 

  84. Biasutto L, Dong LF, Zoratti M, Neuzil J. Mitochondrially targeted anti-cancer agents. Mitochondrion. 2010;10(6):670–81.

    PubMed  CAS  Google Scholar 

  85. Ralph SJ, Rodriguez-Enriquez S, Neuzil J, Moreno-Sanchez R. Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger. Mol Aspects Med. 2010;31(1):29–59.

    PubMed  CAS  Google Scholar 

  86. Guchelaar HJ, Vermes A, Vermes I, Haanen C. Apoptosis: molecular mechanisms and implications for cancer chemotherapy. Pharm World Sci. 1997;19(3):119–25.

    PubMed  CAS  Google Scholar 

  87. Decaudin D, Marzo I, Brenner C, Kroemer G. Mitochondria in chemotherapy-induced apoptosis: a prospective novel target of cancer therapy (review). Int J Oncol. 1998;12(1):141–52.

    PubMed  CAS  Google Scholar 

  88. Andre N, Braguer D, Brasseur G, Goncalves A, Lemesle-Meunier D, Guise S, et al. Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells’. Cancer Res. 2000;60(19):5349–53.

    PubMed  CAS  Google Scholar 

  89. Cheng SM, Pabba S, Torchilin VP, Fowle W, Kimpfler A, Schubert, et al. Towards mitochondria-specific delivery of apoptosis-inducing agents: DQAsomal incorporated paclitaxel. J Drug Del Sci Tech. 2005;15(1):81–6.

    CAS  Google Scholar 

  90. D’Souza GG, Cheng SM, Boddapati SV, Horobin RW, Weissig V. Nanocarrier-assisted sub-cellular targeting to the site of mitochondria improves the pro-apoptotic activity of paclitaxel. J Drug Target. 2008;16(7):578–85.

    PubMed  Google Scholar 

  91. Vaidya B, Paliwal R, Rai S, Khatri K, Goyal AK, Mishra N, et al. Cell-selective mitochondrial targeting: a new approach for cancer therapy. Cancer Ther. 2009;7:141–8.

    CAS  Google Scholar 

  92. Zhang Y, Li RJ, Ying X, Tian W, Yao HJ, Men Y, et al. Targeting therapy with mitosomal daunorubicin plus amlodipine has the potential to circumvent intrinsic resistant breast cancer. Mol Pharm. 2011;8(1):162–75.

    PubMed  CAS  Google Scholar 

  93. Weissig V, Lizano C, Torchilin VP. Micellar delivery system for dequalinium—A lipophilic cationic drug with anticarcinoma activity. J Liposome Res. 1998;8:391–400.

    Google Scholar 

  94. Murphy MP, Smith RA. Drug delivery to mitochondria: the key to mitochondrial medicine. Adv Drug Deliv Rev. 2000;41(2):235–50.

    PubMed  CAS  Google Scholar 

  95. Smith RA, Porteous CM, Coulter CV, Murphy MP. Selective targeting of an antioxidant to mitochondria. Eur J Biochem. 1999;263(3):709–16.

    PubMed  CAS  Google Scholar 

  96. Boddapati SV, Tongcharoensirikul P, Hanson RN, D’Souza GG, Torchilin VP, Weissig V. Mitochondriotropic liposomes. J Liposome Res. 2005;15(1–2):49–58.

    PubMed  CAS  Google Scholar 

  97. Schmidt MF. Fatty acid binding: a new kind of posttranslational modification of membrane proteins. Curr Top Microbiol Immunol. 1983;102:101–29.

    PubMed  CAS  Google Scholar 

  98. Magee AI, Schlesinger MJ. Fatty acid acylation of eucaryotic cell membrane proteins. Biochim Biophys Acta. 1982;694(3):279–89.

    PubMed  CAS  Google Scholar 

  99. Schlesinger MJ, Magee AI. Fatty Acid acylation of membrane proteins. Biophys J. 1982;37(1):126–7.

    PubMed  CAS  Google Scholar 

  100. Weissig V, Lasch J, Klibanov AL, Torchilin VP. A new hydrophobic anchor for the attachment of proteins to liposomal membranes. FEBS Lett. 1986;202(1):86–90.

    PubMed  CAS  Google Scholar 

  101. Weissig V, Lasch J, Gregoriadis G. Covalent coupling of sugars to liposomes. Biochim Biophys Acta. 1989;1003(1):54–7.

    PubMed  CAS  Google Scholar 

  102. Weissig V, Gregoriadis G. Coupling of aminogroup bearing ligands to liposomes. In: Gregoriadis G, editor. Liposome technology. Boca Raton: CRC; 1992. p. 231–48.

    Google Scholar 

  103. Torchilin VP, Weissig V, Martin FJ, Heath TD, News RRC. Surface modification of liposomes. In: Torchilin VP, Weissig V, editors. Liposomes—A practical approach. 2nd ed. Oxford: Oxford University Press; 2003. p. 193–229.

    Google Scholar 

  104. Boddapati SV, D’Souza GG, Erdogan S, Torchilin VP, Weissig V. Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett. 2008;8(8):2559–63.

    PubMed  CAS  Google Scholar 

  105. Martin B, Sainlos M, Aissaoui A, Oudrhiri N, Hauchecorne M, Vigneron JP, et al. The design of cationic lipids for gene delivery. Curr Pharm Des. 2005;11(3):375–94.

    PubMed  CAS  Google Scholar 

  106. Nicolazzi C, Garinot M, Mignet N, Scherman D, Bessodes M. Cationic lipids for transfection. Curr Med Chem. 2003;10(14):1263–77.

    PubMed  CAS  Google Scholar 

  107. Hirko A, Tang F, Hughes JA. Cationic lipid vectors for plasmid DNA delivery. Curr Med Chem. 2003;10(14):1185–93.

    PubMed  CAS  Google Scholar 

  108. Schatzlein AG. Non-viral vectors in cancer gene therapy: principles and progress. Anticancer Drugs. 2001;12(4):275–304.

    PubMed  CAS  Google Scholar 

  109. Kim CK, Haider KH, Lim SJ. Gene medicine: a new field of molecular medicine. Arch Pharm Res. 2001;24(1):1–15.

    PubMed  CAS  Google Scholar 

  110. Siskind LJ, Colombini M. The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J Biol Chem. 2000;275(49):38640–4.

    PubMed  CAS  Google Scholar 

  111. Siskind LJ. Mitochondrial ceramide and the induction of apoptosis. J Bioenerg Biomembr. 2005;37(3):143–53.

    PubMed  CAS  Google Scholar 

  112. Siskind LJ, Feinstein L, Yu T, Davis JS, Jones D, Choi J, et al. Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels. J Biol Chem. 2008;283(11):6622–30.

    PubMed  CAS  Google Scholar 

  113. Stover TC, Sharma A, Robertson GP, Kester M. Systemic delivery of liposomal short—chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin Cancer Res. 2005;11(9):3465–74.

    PubMed  CAS  Google Scholar 

  114. Patel NR, Hatziantoniou S, Georgopoulos A, Demetzos C, Torchilin VP, Weissig V, et al. Mitochondria-targeted liposomes improve the apoptotic and cytotoxic action of sclareol. J Liposome Res. 2010;20(3):244–9.

    PubMed  CAS  Google Scholar 

  115. Dimas K, Hatziantoniou S, Tseleni S, Khan H, Georgopoulos A, Alevizopoulos K, et al. Sclareol induces apoptosis in human HCT116 colon cancer cells in vitro and suppression of HCT116 tumor growth in immunodeficient mice. Apoptosis. 2007;12(4):685–94.

    PubMed  CAS  Google Scholar 

  116. Dimas K, Demetzos C, Vaos V, Ioannidis P, Trangas T. Labdane type diterpenes down—regulate the expression of c-Myc protein, but not of Bcl-2, in human leukemia T-cells undergoing apoptosis. Leuk Res. 2001;25(6):449–54.

    PubMed  CAS  Google Scholar 

  117. Dimas K, Kokkinopoulos D, Demetzos C, Vaos B, Marselos M, Malamas M, et al. The effect of sclareol on growth and cell cycle progression of human leukemic cell lines. Leuk Res. 1999;23(3):217–34.

    PubMed  CAS  Google Scholar 

  118. Paradissis A, Hatziantoniou S, Georgopoulos A, Psarra AM, Dimas K, Demetzos C. Liposomes modify the subcellular distribution of sclareol uptake by HCT-116 cancer cell lines. Biomed Pharmacother. 2007;61(2–3):120–4.

    PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS & DISCLOSURES

All work in the author’s laboratories has been financially supported over the years by the Mitochondrial Disease Association (Tucson, AZ), the United Mitochondrial Disease Foundation (Pittsburgh, PA), the Massachusetts Technology Transfer Center (Boston, MA), Northeastern University (Boston, MA), and Midwestern University Glendale (Glendale, AZ). The author would like to thank all his undergraduate and graduate students who have contributed to these studies. In particular, the author is appreciative for the significant contributions from his former Ph.D. students Dr. Gerard D’Souza, Dr. Sarathi Boddapati, Dr. Ching-Ming Cheng, and Dr. Eyad Katrangi.

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  1. Midwestern University College of Pharmacy Glendale, Glendale, Arizona, USA

    Volkmar Weissig

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  1. Volkmar Weissig
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Correspondence to Volkmar Weissig.

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Weissig, V. From Serendipity to Mitochondria-Targeted Nanocarriers. Pharm Res 28, 2657–2668 (2011). https://doi.org/10.1007/s11095-011-0556-9

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  • DOI: https://doi.org/10.1007/s11095-011-0556-9

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