Advertisement

AAPS PharmSciTech

, 20:287 | Cite as

Role of Ceramides in Drug Delivery

  • Hamad Alrbyawi
  • Ishwor Poudel
  • Ranjeet Prasad Dash
  • Nuggehally R. Srinivas
  • Amit K Tiwari
  • Robert D. ArnoldEmail author
  • R. Jayachandra BabuEmail author
Review Article Theme: Translational Multi-Disciplinary Approach for the Drug and Gene Delivery Systems
Part of the following topical collections:
  1. Translational Multi-Disciplinary Approach for the Drug and Gene Delivery

Abstract

Ceramides belong to the sphingolipid group of lipids, which serve as both intracellular and intercellular messengers and as regulatory molecules that play essential roles in signal transduction, inflammation, angiogenesis, and metabolic disorders such as diabetes, neurodegenerative diseases, and cancer cell degeneration. Ceramides also play an important structural role in cell membranes by increasing their rigidity, creating micro-domains (rafts and caveolae), and altering membrane permeability; all these events are involved in the cell signaling. Ceramides constitute approximately half of the lipid composition in the human skin contributing to barrier function as well as epidermal signaling as they affect both proliferation and apoptosis of keratinocytes. Incorporation of ceramides in topical preparations as functional lipids appears to alter skin barrier functions. Ceramides also appear to enhance the bioavailability of drugs by acting as lipid delivery systems. They appear to regulate the ocular inflammation signaling, and external ceramides have shown relief in the anterior and posterior eye disorders. Ceramides play a structural role in liposome formulations and enhance the cellular uptake of amphiphilic drugs, such as chemotherapies. This review presents an overview of the various biological functions of ceramides, and their utility in topical, oral, ocular, and chemotherapeutic drug delivery.

KEY WORDS

ceramides sphingolipids apoptosis drug delivery membrane permeability cell signaling 

Notes

Funding information

This study is financially supported by the Auburn University - Intramural Grant Program (AU-IGP), Auburn University Research Initiative in Cancer (AURIC), and Auburn University Presidential Initiative in Interdisciplinary Research (PAIR) grants.

References

  1. 1.
    Spiegel S, Foster D, Kolesnick R. Signal transduction through lipid second messengers. Curr Opin Cell Biol. 1996;8(2):159–67.PubMedGoogle Scholar
  2. 2.
    Zheng W, Kollmeyer J, Symolon H, Momin A, Munter E, Wang E, et al. Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim Biophys Acta. 2006;1758(12):1864–84.PubMedGoogle Scholar
  3. 3.
    Pruett ST, Bushnev A, Hagedorn K, Adiga M, Haynes CA, Sullards MC, et al. Thematic review series: sphingolipids. Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols. 2008;49(8):1621–39.Google Scholar
  4. 4.
    Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K. Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim Biophys Acta. 2000;1485(2–3):63–99.PubMedGoogle Scholar
  5. 5.
    Ghidoni R, Sala G, Giuliani A. Use of sphingolipid analogs: benefits and risks. Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids. 1999;1439(1):17–39.Google Scholar
  6. 6.
    Kolesnick RN, Goni FM, Alonso A. Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol. 2000;184(3):285–300.PubMedGoogle Scholar
  7. 7.
    Sot J, Aranda FJ, Collado MI, Goni FM, Alonso A. Different effects of long- and short-chain ceramides on the gel-fluid and lamellar-hexagonal transitions of phospholipids: a calorimetric, NMR, and x-ray diffraction study. Biophys J. 2005;88(5):3368–80.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Sot J, Goni FM, Alonso A. Molecular associations and surface-active properties of short- and long-N-acyl chain ceramides. Biochim Biophys Acta 2005;1711(1):12–19.Google Scholar
  9. 9.
    Bieberich E, Hu B, Silva J, MacKinnon S, Yu RK, Fillmore H, et al. Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells. Cancer Lett. 2002;181(1):55–64.PubMedGoogle Scholar
  10. 10.
    Brockman HL, Momsen MM, Brown RE, He L, Chun J, Byun HS, et al. The 4,5-double bond of ceramide regulates its dipole potential, elastic properties, and packing behavior. Biophys J. 2004;87(3):1722–31.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Park JH, Schuchman EH. Acid ceramidase and human disease. Biochim Biophys Acta. 2006;1758(12):2133–8.PubMedGoogle Scholar
  12. 12.
    Maggio B, Fanani ML, Rosetti CM, Wilke N. Biophysics of sphingolipids II. Glycosphingolipids: an assortment of multiple structural information transducers at the membrane surface. Biochimica Et Biophysica Acta-Biomembranes. 2006;1758(12):1922–44.Google Scholar
  13. 13.
    Sullards MC, Allegood JC, Kelly S, Wang E, Haynes CA, Park H, et al. Structure-specific, quantitative methods for analysis of sphingolipids by liquid chromatography–tandem mass spectrometry:“inside-out” sphingolipidomics. 2007;432:83–115.Google Scholar
  14. 14.
    Holland WL, Summers SAJEr. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. 2008;29(4):381–402.Google Scholar
  15. 15.
    Nixon GFJBjop. Sphingolipids in inflammation: pathological implications and potential therapeutic targets. 2009;158(4):982–93.Google Scholar
  16. 16.
    Modrak DE, Gold DV, Goldenberg DMJMCT. Sphingolipid targets in cancer therapy 2006;5(2):200–8.Google Scholar
  17. 17.
    Beckham TH, Elojeimy S, Cheng JC, Turner LS, Hoffman SR, Norris JS, et al. Targeting sphingolipid metabolism in head and neck cancer: rational therapeutic potentials 2010;14(5):529–39.Google Scholar
  18. 18.
    Pyne NJ, Pyne SJNRC. Sphingosine 1-phosphate and cancer. 2010;10(7):489.Google Scholar
  19. 19.
    Tessema EN, Gebre-Mariam T, Paulos G, Wohlrab J, Neubert RHH. Delivery of oat-derived phytoceramides into the stratum corneum of the skin using nanocarriers: formulation, characterization and in vitro and ex-vivo penetration studies. Eur J Pharm Biopharm. 2018;127:260–9.PubMedGoogle Scholar
  20. 20.
    Carneiro R, Salgado A, Raposo S, Marto J, Simões S, Urbano M, et al. Topical emulsions containing ceramides: effects on the skin barrier function and anti-inflammatory properties. Eur J Lipid Sci Technol. 2011;113(8):961–6.Google Scholar
  21. 21.
    Yilmaz E, Borchert H-H. Design of a phytosphingosine-containing, positively-charged nanoemulsion as a colloidal carrier system for dermal application of ceramides. Eur J Pharm Biopharm. 2005;60(1):91–8.PubMedGoogle Scholar
  22. 22.
    Ganta S, Singh A, Kulkarni P, Keeler AW, Piroyan A, Sawant RR, et al. EGFR targeted theranostic nanoemulsion for image-guided ovarian cancer therapy 2015;32(8):2753–63.Google Scholar
  23. 23.
    Kim D-C, Noh S-M, Kim Y-B, Baek K-H, Oh YKJJOPI. Transdermal delivery of ceramide using sodium deoxycholate-based deformable liposomes 2008;38(5):319–23.Google Scholar
  24. 24.
    Tan K-B, Ling L-U, Bunte RM, Chng W-J, Chiu GNJN. Liposomal codelivery of a synergistic combination of bioactive lipids in the treatment of acute myeloid leukemia 2014;9(11):1665–79.Google Scholar
  25. 25.
    Park SN, Lee MH, Kim SJ, Yu ER. Preparation of quercetin and rutin-loaded ceramide liposomes and drug-releasing effect in liposome-in-hydrogel complex system. Biochem Biophys Res Commun. 2013;435(3):361–6.PubMedGoogle Scholar
  26. 26.
    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.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Overbye A, Holsaeter AM, Markus F, Skalko-Basnet N, Iversen TG, Torgersen ML, et al. Ceramide-containing liposomes with doxorubicin: time and cell-dependent effect of C6 and C12 ceramide. Oncotarget. 2017;8(44):76921–34.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Peeters L, Sanders NN, Jones A, Demeester J, De Smedt SC. Post-pegylated lipoplexes are promising vehicles for gene delivery in RPE cells. J Control Release. 2007;121(3):208–17.PubMedGoogle Scholar
  29. 29.
    van Lummel M, van Blitterswijk WJ, Vink SR, Veldman RJ, van der Valk MA, Schipper D, et al. Enriching lipid nanovesicles with short-chain glucosylceramide improves doxorubicin delivery and efficacy in solid tumors. FASEB J. 2011;25(1):280–9.PubMedGoogle Scholar
  30. 30.
    Chen L, Alrbyawi H, Poudel I, Arnold RD, Babu RJJAP. Co-delivery of doxorubicin and ceramide in a liposomal formulation enhances cytotoxicity in murine B16BL6 melanoma cell lines. 2019;20(3):99.Google Scholar
  31. 31.
    Skiba-Lahiani M, Hallouard F, Mehenni L, Fessi H, Skiba M. Development and characterization of oral liposomes of vegetal ceramide based amphotericin B having enhanced dry solubility and solubility. Mater Sci Eng C-Materi Biol Applic. 2015;48:145–9.Google Scholar
  32. 32.
    Noh GY, Suh JY, Park SN. Ceramide-based nanostructured lipid carriers for transdermal delivery of isoliquiritigenin: development, physicochemical characterization, and in vitro skin permeation studies. Korean J Chem Eng. 2016;34(2):400–6.Google Scholar
  33. 33.
    Gaur PK, Mishra S, Verma A, Verma N. Ceramide–palmitic acid complex based curcumin solid lipid nanoparticles for transdermal delivery: pharmacokinetic and pharmacodynamic study. J Exp Nanosci. 2015;11(1):38–53.Google Scholar
  34. 34.
    Battogtokh G, Ko YT. Self-assembled chitosan-ceramide nanoparticle for enhanced oral delivery of paclitaxel. Pharm Res. 2014;31(11):3019–30.PubMedGoogle Scholar
  35. 35.
    Min SK, Lee HC, Song H, Shin HS. Multifunctional chitosan-coated poly(lactic-co-glycolic acid) nanoparticles for spatiotemporally controlled codelivery of ceramide and C-phycocyanin to treat atopic dermatitis. J Bioact Compat Polym. 2019;34(2):163–77.Google Scholar
  36. 36.
    Suhrland C, Truman JP, Obeid LM, Sitharaman BJJOBMRPA. Oxidized graphene nanoparticles as a delivery system for the pro-apoptotic sphingolipid C6 ceramide. 2019;107(1):25–37.Google Scholar
  37. 37.
    van Vlerken LE, Duan Z, Little SR, Seiden MV, Amiji MMJTAj. Augmentation of therapeutic efficacy in drug-resistant tumor models using ceramide coadministration in temporal-controlled polymer-blend nanoparticle delivery systems 2010;12(2):171–80.Google Scholar
  38. 38.
    Wang T, Feng L, Yang S, Liu Y, Zhang N. Ceramide lipid-based nanosuspension for enhanced delivery of docetaxel with synergistic antitumor efficiency. Drug Delivery. 2017;24(1):800–10.PubMedGoogle Scholar
  39. 39.
    Kalén A, Borchardt RA, Bell RM. Elevated ceramide levels in GH4C1 cells treated with retinoic acid. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 1992;1125(1):90–6.Google Scholar
  40. 40.
    Hannun YAJJOBC. The sphingomyelin cycle and the second messenger function of ceramide. 1994;269(5):3125–8.Google Scholar
  41. 41.
    Hannun YA. Functions of ceramide in coordinating cellular responses to stress. Science. 1996;274(5294):1855–9.PubMedGoogle Scholar
  42. 42.
    Pettus BJ, Chalfant CE, Hannun YA. Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta. 2002;1585(2–3):114–25.PubMedGoogle Scholar
  43. 43.
    Adam-Klages S, Adam D, Wiegmann K, Struve S, Kolanus W, Schneider-Mergener J, et al. A novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell. 1996;86(6):937–47.PubMedGoogle Scholar
  44. 44.
    Liu Y-Y, Han T-Y, Giuliano AE, Ichikawa S, Hirabayashi Y, Cabot MC. Glycosylation of ceramide potentiates cellular resistance to tumor necrosis factor-α-induced apoptosis. Exp Cell Res. 1999;252(2):464–70.PubMedGoogle Scholar
  45. 45.
    Coroneos E, Martinez M, McKenna S, Kester M. Differential regulation of sphingomyelinase and ceramidase activities by growth factors and cytokines. Implications for cellular proliferation and differentiation. J Biol Chem. 1995;270(40):23305–9.PubMedGoogle Scholar
  46. 46.
    Merrill AHJJOB. Biomembranes. Cell regulation by sphingosine and more complex sphingolipids. 1991;23(1):83–104.Google Scholar
  47. 47.
    El Bawab S, Mao C, Obeid LM, Hannun YA. Ceramidases in the regulation of ceramide levels and function. In: Quinn PJ, Kagan VE, editors. Phospholipid metabolism in apoptosis. Boston, MA: Springer US; 2002. p. 187–205.Google Scholar
  48. 48.
    Lozano J, Berra E, Municio MM, Diaz-Meco MT, Dominguez I, Sanz L, et al. Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase. J Biol Chem. 1994;269(30):19200–2.PubMedGoogle Scholar
  49. 49.
    Heinrich M, Wickel M, Winoto-Morbach S, Schneider-Brachert W, Weber T, Brunner J, et al. Ceramide as an activator lipid of cathepsin D. Adv Exp Med Biol. 2000;477:305–15.PubMedGoogle Scholar
  50. 50.
    Wolff RA, Dobrowsky RT, Bielawska A, Obeid LM, Hannun YA. Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J Biol Chem. 1994;269(30):19605–9.PubMedGoogle Scholar
  51. 51.
    Siskind LJ. Mitochondrial ceramide and the induction of apoptosis. J Bioenerg Biomembr. 2005;37(3):143–53.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Gault CR, Obeid LM, Hannun YA. An overview of sphingolipid metabolism: from synthesis to breakdown. Sphingolipids as Signaling and Regulatory Molecules: Springer; 2010. p. 1–23.Google Scholar
  53. 53.
    Krut O, Wiegmann K, Kashkar H, Yazdanpanah B, Krönke M. Novel TNF-responsive mammalian neutral sphingomyelinase-3 is a C-tail-anchored protein. J Biol Chem. 2006;281:13784–93.PubMedGoogle Scholar
  54. 54.
    Huang WC, Chen CL, Lin YS, Lin CF. Apoptotic sphingolipid ceramide in cancer therapy. J Lipids. 2011;2011:565316.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Reynolds CP, Maurer BJ, Kolesnick RN. Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett. 2004;206(2):169–80.PubMedGoogle Scholar
  56. 56.
    Ruvolo PP. Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacol Res. 2003;47(5):383–92.PubMedGoogle Scholar
  57. 57.
    Jayadev S, Liu B, Bielawska AE, Lee JY, Nazaire F, Pushkareva MY, et al. Role for ceramide in cell cycle arrest 1995;270(5):2047–2052.Google Scholar
  58. 58.
    Senchenkov A, Litvak DA, Cabot MCJJOTNCI. Targeting ceramide metabolism—a strategy for overcoming drug resistance 2001;93(5):347–57.Google Scholar
  59. 59.
    Uchida Y. Ceramide signaling in mammalian epidermis. Biochim Biophys Acta. 2014;1841(3):453–62.PubMedGoogle Scholar
  60. 60.
    Cha HJ, He CF, Zhao H, Dong YM, An IS, An S. Intercellular and intracellular functions of ceramides and their metabolites in skin (review). Int J Mol Med. 2016;38(1):16–22.PubMedGoogle Scholar
  61. 61.
    Liu Y-Y, Han T-Y, Giuliano AE, Cabot MCJJOBC. Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells 1999;274(2):1140–6.Google Scholar
  62. 62.
    LIU Y-Y, HAN T-Y, GIULIANO AE, Cabot MC. Ceramide glycosylation potentiates cellular multidrug resistance 2001;15(3):719–30.Google Scholar
  63. 63.
    Hinkovska-Galcheva V, Boxer LA, Kindzelskii A, Hiraoka M, Abe A, Goparju S, et al. Ceramide 1-phosphate, a mediator of phagocytosis. J Biol Chem. 2005;280(28):26612–21.PubMedGoogle Scholar
  64. 64.
    Montes LR, Lopez DJ, Sot J, Bagatolli LA, Stonehouse MJ, Vasil ML, et al. Ceramide-enriched membrane domains in red blood cells and the mechanism of sphingomyelinase-induced hot-cold hemolysis. Biochemistry. 2008;47(43):11222–30.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Sonnino S, Prinetti A, Mauri L, Chigorno V, Tettamanti G. Dynamic and structural properties of sphingolipids as driving forces for the formation of membrane domains. Chem Rev. 2006;106(6):2111–25.PubMedGoogle Scholar
  66. 66.
    Grösch S, Schiffmann S, Geisslinger G. Chain length-specific properties of ceramides. Prog Lipid Res. 2012;51(1):50–62.PubMedGoogle Scholar
  67. 67.
    Megha SP, Kolter T, Bittman R, London E. Effect of ceramide N-acyl chain and polar headgroup structure on the properties of ordered lipid domains (lipid rafts). Biochim Biophys Acta Biomembr. 2007;1768(9):2205–12.Google Scholar
  68. 68.
    Nybond S, Björkqvist YJE, Ramstedt B, Slotte JP. Acyl chain length affects ceramide action on sterol/sphingomyelin-rich domains. Biochim Biophys Acta Biomembr. 2005;1718(1):61–6.Google Scholar
  69. 69.
    Contreras FX, Sanchez-Magraner L, Alonso A, Goni FM. Transbilayer (flip-flop) lipid motion and lipid scrambling in membranes. FEBS Lett. 2010;584(9):1779–86.PubMedGoogle Scholar
  70. 70.
    Devaux PF, Herrmann A, Ohlwein N, Koziov MM. How lipid flippases can modulate membrane structure. Biochimica Et Biophysica Acta-Biomembranes. 2008;1778(7–8):1591–600.Google Scholar
  71. 71.
    Waheed AA, Freed EOJVR. Lipids and membrane microdomains in HIV-1 replication. 2009;143(2):162–76.Google Scholar
  72. 72.
    Daleke DL. Regulation of transbilayer plasma membrane phospholipid asymmetry. J Lipid Res. 2003;44(2):233–42.PubMedGoogle Scholar
  73. 73.
    Sanyal S, Menon AKJACB. Flipping lipids: why an’ what’s the reason for? 2009;4(11):895–909.Google Scholar
  74. 74.
    Ogushi F, Ishitsuka R, Kobayashi T, Sugita Y. Rapid flip-flop motions of diacylglycerol and ceramide in phospholipid bilayers. Chem Phys Lett. 2012;522:96–102.Google Scholar
  75. 75.
    Poulsen LR, Lopez-Marques RL, Palmgren MG. Flippases: still more questions than answers. Cell Mol Life Sci. 2008;65(20):3119–25.PubMedGoogle Scholar
  76. 76.
    Woodcock J. Sphingosine and ceramide signalling in apoptosis. IUBMB Life. 2006;58(8):462–6.PubMedGoogle Scholar
  77. 77.
    Kahya N, Scherfeld D, Bacia K, Poolman B, Schwille P. Probing lipid mobility of raft-exhibiting model membranes by fluorescence correlation spectroscopy. J Biol Chem. 2003;278(30):28109–15.PubMedGoogle Scholar
  78. 78.
    KOK JW, BABIA T, KLAPPE K, Gustavo E, HOEKSTRA D. Ceramide transport from endoplasmic reticulum to Golgi apparatus is not vesicle-mediated. Biochem J 1998;333(3):779–786.Google Scholar
  79. 79.
    Lopez-Montero I, Rodriguez N, Cribier S, Pohl A, Velez M, Devaux PF. Rapid transbilayer movement of ceramides in phospholipid vesicles and in human erythrocytes. J Biol Chem. 2005;280(27):25811–9.PubMedGoogle Scholar
  80. 80.
    Meckfessel MH, Brandt S. The structure, function, and importance of ceramides in skin and their use as therapeutic agents in skin-care products. J Am Acad Dermatol. 2014;71(1):177–84.PubMedGoogle Scholar
  81. 81.
    Masukawa Y, Narita H, Shimizu E, Kondo N, Sugai Y, Oba T, et al. Characterization of overall ceramide species in human stratum corneum 2008;49(7):1466–76.Google Scholar
  82. 82.
    Skolova B, Kovacik A, Tesar O, Opalka L, Vavrova K. Phytosphingosine, sphingosine and dihydrosphingosine ceramides in model skin lipid membranes: permeability and biophysics. Biochim Biophys Acta. 2017;1859(5):824–34.Google Scholar
  83. 83.
    Moore TC, Hartkamp R, Iacovella CR, Bunge AL, McCabe C. Effect of ceramide tail length on the structure of model stratum corneum lipid bilayers. Biophys J. 2018;114(1):113–25.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Vávrová K, Kováčik A, Opálka L. Ceramides in the skin barrier. Eur Pharmaceut J. 2017;64(2):28–35.Google Scholar
  85. 85.
    Holleran WM, Takagi Y, Uchida Y. Epidermal sphingolipids: metabolism, function, and roles in skin disorders. FEBS Lett. 2006;580(23):5456–66.PubMedGoogle Scholar
  86. 86.
    Bouwstra JA, Dubbelaar FE, Gooris GS, Weerheim AM, Ponec M. The role of ceramide composition in the lipid organisation of the skin barrier. Biochim Biophys Acta. 1999;1419(2):127–36.PubMedGoogle Scholar
  87. 87.
    Imokawa G. A possible mechanism underlying the ceramide deficiency in atopic dermatitis: expression of a deacylase enzyme that cleaves the N-acyl linkage of sphingomyelin and glucosylceramide. J Dermatol Sci. 2009;55(1):1–9.PubMedGoogle Scholar
  88. 88.
    Nakajima K, Terao M, Takaishi M, Kataoka S, Goto-Inoue N, Setou M, et al. Barrier abnormality due to ceramide deficiency leads to psoriasiform inflammation in a mouse model. J Investig Dermatol. 2013;133(11):2555–65.PubMedGoogle Scholar
  89. 89.
    Alessandrini F, Pfister S, Kremmer E, Gerber J-K, Ring J, Behrendt H. Alterations of glucosylceramide-β-glucosidase levels in the skin of patients with psoriasis vulgaris. J Investig Dermatol. 2004;123(6):1030–6.PubMedGoogle Scholar
  90. 90.
    Alessandrini F, Stachowitz S, Ring J, Behrendt H. The level of prosaposin is decreased in the skin of patients with psoriasis vulgaris. J Investig Dermatol. 2001;116(3):394–400.PubMedGoogle Scholar
  91. 91.
    Jiang YJ, Kim P, Uchida Y, Elias PM, Bikle DD, Grunfeld C, et al. Ceramides stimulate caspase-14 expression in human keratinocytes. Exp Dermatol. 2013;22(2):113–8.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Sinha VR, Kaur MP. Permeation enhancers for transdermal drug delivery. Drug Dev Ind Pharm. 2000;26(11):1131–40.PubMedGoogle Scholar
  93. 93.
    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37.Google Scholar
  94. 94.
    Chen Y, Quan P, Liu X, Wang M, Fang L. Novel chemical permeation enhancers for transdermal drug delivery. Asian J Pharmaceut Sc. 2014;9(2):51–64.Google Scholar
  95. 95.
    Vavrova K, Hrabalek A, Dolezal P, Holas T, Zbytovska J. L-serine and glycine based ceramide analogues as transdermal permeation enhancers: polar head size and hydrogen bonding. Bioorg Med Chem Lett. 2003;13(14):2351–3.PubMedGoogle Scholar
  96. 96.
    Takacs M, Bubenyak M, Varadi A, Blazics B, Horvath P, Kokosi J. Synthesis of novel ceramide-like penetration enhancers. Tetrahedron Lett. 2011;52(16):1863–5.Google Scholar
  97. 97.
    Vávrová K, Hrabálek A, Doležal P, Šámalová L, Palát K, Zbytovská J, et al. Synthetic ceramide analogues as skin permeation enhancers: structure–activity relationships 2003;11(24):5381–90.Google Scholar
  98. 98.
    Schroeter A, Engelbrecht T, Neubert RHH. Influence of short chain ceramides and lipophilic penetration enhancers on the nano-structure of stratum corneum model membranes studied using neutron diffraction. Front Chem Sci Eng. 2013;7(1):29–36.Google Scholar
  99. 99.
    Coderch L, Lopez O, de la Maza A, Parra JL. Ceramides and skin function. Am J Clin Dermatol. 2003;4(2):107–29.PubMedGoogle Scholar
  100. 100.
    Pierre MBR, Lopez RFV, Bentley MVLB. Influence of ceramide 2 on in vitro skin permeation and retention of 5-ALA and its ester derivatives, for photodynamic therapy. Brazilian J Pharmaceut Sci. 2009;45(1):109–16.Google Scholar
  101. 101.
    Skolova B, Janusova B, Vavrova K. Ceramides with a pentadecasphingosine chain and short acyls have strong permeabilization effects on skin and model lipid membranes. Biochimica Et Biophysica Acta-Biomembranes. 2016;1858(2):220–32.Google Scholar
  102. 102.
    Veryser L, Boonen J, Taevernier L, Guillaume J, Risseeuw M, Shah SN, et al. The influence of the acyl chain on the transdermal penetration-enhancing effect of synthetic phytoceramides. Skin Pharmacol Physiol. 2015;28(3):124–36.PubMedGoogle Scholar
  103. 103.
    Ramirez R, Marti M, Barba C, Mendez S, Parra JL, Coderch L. Skin efficacy of liposomes composed of internal wool lipids rich in ceramides. J Cosmet Sci. 2010;61(3):235–45.PubMedGoogle Scholar
  104. 104.
    Su R, Yang L, Wang Y, Yu S, Guo Y, Deng J, et al. Formulation, development, and optimization of a novel octyldodecanol-based nanoemulsion for transdermal delivery of ceramide IIIB. Int J Nanomedicine. 2017;12:5203–21.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Sahle FF, Metz H, Wohlrab J, Neubert RHJPR. Lecithin-based microemulsions for targeted delivery of ceramide AP into the stratum corneum: formulation, characterizations, and in vitro release and penetration studies 2013;30(2):538–51.Google Scholar
  106. 106.
    Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.Google Scholar
  107. 107.
    Stuchlik M, Zak S. Lipid-based vehicle for oral drug delivery. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2001;145(2):17–26.PubMedGoogle Scholar
  108. 108.
    Regnault C, Roch-Arveiller M, Tissot M, Sarfati G, Giroud JP, Postaire E, et al. Effect of encapsulation on the anti-inflammatory properties of superoxide dismutase after oral administration. Clin Chim Acta. 1995;240(2):117–27.PubMedGoogle Scholar
  109. 109.
    Chen MC, Mi FL, Liao ZX, Hsiao CW, Sonaje K, Chung MF, et al. Recent advances in chitosan-based nanoparticles for oral delivery of macromolecules. Adv Drug Deliv Rev. 2013;65(6):865–79.PubMedGoogle Scholar
  110. 110.
    Ueda O, Uchiyama T, Nakashima M. Distribution and metabolism of sphingosine in skin after oral administration to mice. Drug Metab Pharmacokinet. 2010;25(5):456–65.PubMedGoogle Scholar
  111. 111.
    Cholkar K, Patel SP, Vadlapudi AD, Mitra AK. Novel strategies for anterior segment ocular drug delivery. J Ocul Pharmacol Ther. 2013;29(2):106–23.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Daemen MJAP, Thijssen HHW, Struykerboudier HAJ. Pharmacokinetic considerations in local-drug delivery. Adv Drug Deliv Rev. 1991;6(1):1–18.Google Scholar
  113. 113.
    Dartt DA. Regulation of mucin and fluid secretion by conjunctival epithelial cells. Prog Retin Eye Res. 2002;21(6):555–76.PubMedGoogle Scholar
  114. 114.
    Karla PK, Earla R, Boddu SH, Johnston TP, Pal D, Mitra A. Molecular expression and functional evidence of a drug efflux pump (BCRP) in human corneal epithelial cells. Curr Eye Res. 2009;34(1):1–9.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Shi XP, Candia OA. Active sodium and chloride transport across the isolated rabbit conjunctiva. Curr Eye Res. 1995;14(10):927–35.PubMedGoogle Scholar
  116. 116.
    Chen H, Tran J-TA, Brush RS, Saadi A, Rahman AK, Yu M, et al. Ceramide signaling in retinal degeneration. Retinal Degenerative Diseases: Springer; 2012; 553–8.Google Scholar
  117. 117.
    German OL, Miranda GE, Abrahan CE, Rotstein NP. Ceramide is a mediator of apoptosis in retina photoreceptors. Invest Ophthalmol Vis Sci. 2006;47(4):1658–68.PubMedGoogle Scholar
  118. 118.
    Zhu DH, Sreekumar PG, Hinton DR, Kannan R. Expression and regulation of enzymes in the ceramide metabolic pathway in human retinal pigment epithelial cells and their relevance to retinal degeneration. Vis Res. 2010;50(7):643–51.PubMedGoogle Scholar
  119. 119.
    Chen H, Chan AY, Stone DU, Mandal NA. Beyond the cherry-red spot: ocular manifestations of sphingolipid-mediated neurodegenerative and inflammatory disorders. Surv Ophthalmol. 2014;59(1):64–76.PubMedGoogle Scholar
  120. 120.
    Kannan R, Jin M, Gamulescu MA, Hinton DR. Ceramide-induced apoptosis: role of catalase and hepatocyte growth factor. Free Radic Biol Med. 2004;37(2):166–75.PubMedGoogle Scholar
  121. 121.
    Zarbin MA, Green WR, Moser AB, Tiffany C. Increased levels of ceramide in the retina of a patient with Farber's disease. Arch Ophthalmol. 1988;106(9):1163.PubMedGoogle Scholar
  122. 122.
    Pearlman ELV, Kester, M. Case Western Reserve University (Cleveland, OH, US),The Penn State Research Foundation (University Park, PA, US), assignee. Ceramide composition and method of use. United States 2018.Google Scholar
  123. 123.
    Sun Y, Fox T, Adhikary G, Kester M, Pearlman E. Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide. J Leukoc Biol. 2008;83(6):1512–21.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Oskouian B, Saba JD. Cancer treatment strategies targeting sphingolipid metabolism. Sphingolipids as Signaling and Regulatory Molecules: Springer; 2010; 185–205,.Google Scholar
  125. 125.
    Artetxe I, Ugarte-Uribe B, Gil D, Valle M, Alonso A, Garcia-Saez AJ, et al. Does ceramide form channels? The ceramide-induced membrane permeabilization mechanism. Biophys J. 2017;113(4):860–8.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Li F, Zhang N. Ceramide: therapeutic potential in combination therapy for cancer treatment. Curr Drug Metab. 2015;17(1):37–51.Google Scholar
  127. 127.
    Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer. 2013;13(1):51–65.PubMedGoogle Scholar
  128. 128.
    Barth BM, Cabot MC, Kester M. Ceramide-based therapeutics for the treatment of cancer. Anti Cancer Agents Med Chem. 2011;11(9):911–9.Google Scholar
  129. 129.
    Alarif WM, Al-Lihaibi SS, Ayyad SEN, Ghandourah MA, Orif MI, Basaif SA, et al. Cytotoxic ceramides from Antipathes dichotoma. J Chem Soc Pakistan. 2016;38(3):553–7.Google Scholar
  130. 130.
    Henry B, Moller C, Dimanche-Boitrel MT, Gulbins E, Becker KA. Targeting the ceramide system in cancer. Cancer Lett. 2013;332(2):286–94.PubMedGoogle Scholar
  131. 131.
    Kozar N, Kruusmaa K, Bitenc M, Argamasilla R, Adsuar A, Goswami N, et al. Metabolomic profiling suggests long chain ceramides and sphingomyelins as a possible diagnostic biomarker of epithelial ovarian cancer. Clin Chim Acta. 2018;481:108–14.PubMedGoogle Scholar
  132. 132.
    Shabbits JA, Mayer LD. Intracellular delivery of ceramide lipids via liposomes enhances apoptosis in vitro. Biochim Biophys Acta. 2003;1612(1):98–106.PubMedGoogle Scholar
  133. 133.
    Watters RJ, Kester M, Tran MA, Loughran TP Jr, Liu X. Development and use of ceramide nanoliposomes in cancer. Methods Enzymol. 2012;508:89–108.PubMedGoogle Scholar
  134. 134.
    Shen F, Chu S, Bence AK, Bailey B, Xue X, Erickson PA, et al. Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells. J Pharmacol Exp Ther. 2008;324(1):95–102.PubMedGoogle Scholar
  135. 135.
    Sanson C, Schatz C, Le Meins JF, Soum A, Thevenot J, Garanger E, et al. A simple method to achieve high doxorubicin loading in biodegradable polymersomes. J Control Release. 2010;147(3):428–35.PubMedGoogle Scholar
  136. 136.
    Valetti S, Mura S, Stella B, Couvreur P. Rational design for multifunctional non-liposomal lipid-based nanocarriers for cancer management: theory to practice. J Nanobiotechnology. 2013;11(Suppl 1(1)):S6.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Fenske DB, Chonn A, Cullis PR. Liposomal nanomedicines: an emerging field. Toxicol Pathol. 2008;36(1):21–9.PubMedGoogle Scholar
  138. 138.
    Veldman RJ, Zerp S, van Blitterswijk WJ, Verheij M. N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx. Br J Cancer. 2004;90(4):917–25.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Stover T, Kester M. Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells. J Pharmacol Exp Ther. 2003;307(2):468–75.PubMedGoogle Scholar
  140. 140.
    Zolnik BS, Stern ST, Kaiser JM, Heakal Y, Clogston JD, Kester M, et al. Rapid distribution of liposomal short-chain ceramide in vitro and in vivo. Drug Metab Dispos. 2008;36(8):1709–15.PubMedGoogle Scholar
  141. 141.
    Jiang Y, DiVittore NA, Kaiser JM, Shanmugavelandy SS, Fritz JL, Heakal Y, et al. Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer 2011;12(7):574–85.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Hamad Alrbyawi
    • 1
    • 2
  • Ishwor Poudel
    • 1
  • Ranjeet Prasad Dash
    • 1
  • Nuggehally R. Srinivas
    • 3
  • Amit K Tiwari
    • 4
  • Robert D. Arnold
    • 1
    Email author
  • R. Jayachandra Babu
    • 1
    Email author
  1. 1.Department of Drug Discovery and Development, Harrison School of PharmacyAuburn UniversityAuburnUSA
  2. 2.Pharmaceutics and Pharmaceutical Technology Department, College of PharmacyTaibah UniversityMedinaSaudi Arabia
  3. 3.Department of Innovation and TechnologyJubilant Life SciencesNoidaIndia
  4. 4.Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical SciencesUniversity of ToledoToledoUSA

Personalised recommendations