Journal of Pharmaceutical Investigation

, Volume 48, Issue 1, pp 77–87 | Cite as

Cell-penetrating peptide-based non-invasive topical delivery systems

  • Tru Van Nguyen
  • Meong Cheol Shin
  • Kyoung Ah Min
  • Yongzhuo Huang
  • Euichaul Oh
  • Cheol MoonEmail author


Cell-penetrating peptides (CPPs) have been receiving much attention over the last few decades due to their unique ability to translocate across plasma membranes efficiently and carry the wide range of macromolecular cargoes with them. Although their intracellular delivery mechanism has not been fully elucidated, CPP-based cellular uptake, mainly mediated by direct transduction or endocytosis, depends on structural characteristics of CPPs, the type and concentration of CPPs or cargoes, and cell types being treated. To overcome the intrinsic drawbacks of CPPs including lack of cell or tissue specificity, short plasma half-life, and endosomal sequestration, various strategies have been suggested such as activatable CPPs (ACPPs), introduction of targeting moieties and fusion peptides, and topical delivery systems for clinical application. In this review, we provide an overview of up-to-date knowledge of intracellular delivery mechanisms of CPPs and introduce potential topical applications of CPPs such as transdermal, nasal and ocular delivery for non-invasive delivering the therapeutic proteins or peptides.


Cell-penetrating peptides Intracellular delivery Topical delivery Ocular delivery Protein delivery 



This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1D1A1B03028732), by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science, ICT & Future Planning (2013M3A9B5075840), and in part by a research grant funded by the Sunchon Research Center for Natural Medicines. The authors gratefully appreciate the assistance of Mr. Jeonghyun Moon for editing and proofreading this manuscript.

Compliance with ethical standards

Conflict of the interest

All authors declare that they have no conflict of interest.

Research involving human and animal participants

This article does not contain any studies with human and animal subjects performed by any of the authors.


  1. Agrawa P, Bhalla S, Usmani SS, Singh S, Chaudhary K, Raghava GP, Gautam A (2016) CPPsite 2.0: a repository of experimentally validated cell-penetrating peptides. Nucleic Acids Res 44(D1):D1098-D1103Google Scholar
  2. Aguilera TA, Olson ES, Timmers MM, Jiang T, Tsien RY (2009) Systemic in vivo distribution of activatable cell penetrating peptides is superior to that of cell penetrating peptides. Integr Biol 1(5–6):371–381Google Scholar
  3. Akita H, Masuda T, Nishio T, Niikura K, Ijiro K, Harashima H (2011) Improving in vivo hepatic transfection activity by controlling intracellular trafficking: the function of GALA and maltotriose. Mol Pharm 8(4):1436–1442PubMedGoogle Scholar
  4. Åmand HL, Rydberg HA, Fornander LH, Lincoln P, Nordén B, Esbjörner EK (2012) Cell surface binding and uptake of arginine-and lysine-rich penetratin peptides in absence and presence of proteoglycans. Biochim Biophys Acta 1818(11):2669–2678PubMedGoogle Scholar
  5. Auger I (1993) Computational techniques to predict amphipathic helical segments. In: Epand RM (ed) The amphipathic helix. CRC Press, Florida, pp 7-19Google Scholar
  6. Bae HD, Lee J, Jin XH, Lee K (2016) Potential of translationally controlled tumor protein-derived protein transduction domains as antigen carriers for nasal vaccine delivery. Mol Pharm 13(9):3196–3205PubMedGoogle Scholar
  7. Barua S, Mitragotri S (2014) Challenges associated with penetration of nanoparticles across cell and tissue barriers: a review of current status and future prospects. Nano Today 9(2):223–243PubMedPubMedCentralGoogle Scholar
  8. Bashyal S, Noh S, Keum T, Choi TW, Lee S (2016) Cell penetrating peptides as an innovative approach for drug delivery; then, present and the future. J Pharm Invest 46(3):205–220Google Scholar
  9. Borkenstein M, Zobel V (1985) Treatment of cryptorchism with LHRH nasal spray. Wien Klin Wochenschr 97(9):414–416PubMedGoogle Scholar
  10. Brock R (2014) The uptake of arginine-rich cell-penetrating peptides: putting the puzzle together. Bioconjug Chem 25(5):863–868PubMedGoogle Scholar
  11. Cashman SM, Sadowski SL, Morris DJ, Frederick J, Kumar-Singh R (2002) Intercellular trafficking of adenovirus-delivered HSV VP22 from the retinal pigment epithelium to the photoreceptors—implications for gene therapy. Mol Ther 6(6):813–823PubMedGoogle Scholar
  12. Cashman SM, Morris DJ, Kumar-Singh R (2003) Evidence of protein transduction but not intercellular transport by proteins fused to HIV tat in retinal cell culture and in vivo. Mol Ther 8(1):130–142PubMedGoogle Scholar
  13. Choi JK, Jang JH, Jang WH, Kim J, Bae IH, Bae J, Park JH, Kim BJ, Lim KM, Park JW (2012) The effect of epidermal growth factor (EGF) conjugated with low-molecular-weight protamine (LMWP) on wound healing of the skin. Biomaterials 33(33):8579–8590PubMedGoogle Scholar
  14. Console S, Marty C, García-Echeverría C, Schwendener R, Ballmer-Hofer K (2003) Antennapedia and HIV transactivator of transcription (TAT)“protein transduction domains” promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans. J Biol Chem 278(37):35109–35114PubMedGoogle Scholar
  15. de Cogan F, Hill LJ, Lynch A, Morgan-Warren PJ, Lechner J, Berwick MR, Peacock AF, Chen M, Scott RA, Xu H (2017) Topical delivery of Anti-VEGF drugs to the ocular posterior segment using cell-penetrating peptides CPP delivery of anti-VEGF drugs to the retina. Invest Ophthalmol Vis Sci 58(5):2578–2590PubMedGoogle Scholar
  16. Derossi D, Joliot AH, Chassaing G, Prochiantz A (1994) The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem 269(14):10444–10450PubMedGoogle Scholar
  17. Deshayes S, Heitz A, Morris MC, Charnet P, Divita G, Heitz F (2004) Insight into the mechanism of internalization of the cell-penetrating carrier peptide Pep-1 through conformational analysis. Biochemistry 43(6):1449–1457PubMedGoogle Scholar
  18. Dinca A, Chien WM. Chin MT (2016) Intracellular delivery of proteins with cell-penetrating peptides for therapeutic uses in human disease. Int J Mol Sci 17(2):263PubMedPubMedCentralGoogle Scholar
  19. Dom G, Shaw-Jackson C, Matis C, Bouffioux O, Picard JJ, Prochiantz A, Mingeot-Leclercq MP, Brasseur R, Rezsohazy R (2003) Cellular uptake of antennapedia penetratin peptides is a two-step process in which phase transfer precedes a tryptophan-dependent translocation. Nucleic Acids Res 31(2):556–561PubMedPubMedCentralGoogle Scholar
  20. Duchardt F, Fotin-Mleczek M, Schwarz H, Fischer R, Brock R (2007) A comprehensive model for the cellular uptake of cationic cell-penetrating peptides. Traffic 8(7):848–866PubMedGoogle Scholar
  21. Durzyńska J, Przysiecka Ł, Nawrot R, Barylski J, Nowicki G, Warowicka A, Musidlak O, Goździcka-Józefiak A (2015) Viral and other cell-penetrating peptides as vectors of therapeutic agents in medicine. J Pharmacol Exp Ther 354(1):32–42PubMedGoogle Scholar
  22. Elliott G, O’Hare P (1997) Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell 88(2):223–233PubMedGoogle Scholar
  23. Erazo-Oliveras A, Muthukrishnan N, Baker R, Wang TT, Pellois JP (2012) Improving the endosomal escape of cell-penetrating peptides and their cargoes: strategies and challenges. Pharmaceuticals 5(11):1177–1209PubMedPubMedCentralGoogle Scholar
  24. Erazo-Oliveras A, Najjar K, Dayani L, Wang TY, Johnson GA, Pellois JP (2014) Protein delivery into live cells by incubation with an endosomolytic agent. Nat Methods 11(8):861–867PubMedPubMedCentralGoogle Scholar
  25. Favretto ME, Wallbrecher R, Schmidt S, van de Putte R, Brock R (2014) Glycosaminoglycans in the cellular uptake of drug delivery vectors–bystanders or active players? J Control Release 180:81–90PubMedGoogle Scholar
  26. Frankel AD, Pabo CO (1988) Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55(6):1189–1193PubMedGoogle Scholar
  27. Fredrikson S (1996) Nasal spray desmopressin treatment of bladder dysfunction in patients with multiple sclerosis. Acta Neurol Scand 94(1):31–34PubMedGoogle Scholar
  28. Gao W, Yang X, Lin Z, He B, Mei D, Wang D, Zhang H, Zhang H, Dai W, Wang X (2017) The use of electronic-neutral penetrating peptides cyclosporin A to deliver pro-apoptotic peptide: a possibly better choice than positively charged TAT. J Control Release 261:174–186PubMedGoogle Scholar
  29. Garcia-Murray E, Villasenor MLV, Acevedo B, Luna S, Lee J, Waugh JM, Hornfeldt CS (2015) Safety and efficacy of RT002, an injectable botulinum toxin type A, for treating glabellar lines: results of a phase 1/2, open-label, sequential dose-escalation study. Dermatol Surg 41:S47-S55Google Scholar
  30. George EM, Mahdi F, Logue OC, Robinson GG, Bidwell GL III (2016) Corneal penetrating elastin-like polypeptide carriers. J Ocul Pharmacol Ther 32(3):163–171PubMedPubMedCentralGoogle Scholar
  31. Gillmeister MP, Betenbaugh MJ, Fishman PS (2011) Cellular trafficking and photochemical internalization of cell penetrating peptide linked cargo proteins: a dual fluorescent labeling study. Bioconjug Chem 22(4):556–566PubMedGoogle Scholar
  32. Green M, Loewenstein PM (1988) Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 55(6):1179–1188PubMedPubMedCentralGoogle Scholar
  33. Gronewold A, Horn M, Ranđelović I, Tóvári J, Muñoz Vázquez S, Schomäcker K, Neundorf I (2017) Characterization of a cell-penetrating peptide with potential anticancer activity. ChemMedChem 12(1): 42–49PubMedGoogle Scholar
  34. Guidotti G, Brambilla L, Rossi D (2017) Cell-penetrating peptides: from basic research to clinics. Trends Pharmacol Sci 38(4):406–424PubMedGoogle Scholar
  35. Henriques ST, Costa J, Castanho MA (2005) Translocation of β-galactosidase mediated by the cell-penetrating peptide pep-1 into lipid vesicles and human HeLa cells is driven by membrane electrostatic potential. Biochemistry 44(30):10189–10198PubMedGoogle Scholar
  36. Hirose H, Takeuchi T, Osakada H, Pujals S, Katayama S, Nakase I, Kobayashi S, Haraguchi T, Futaki S (2012) Transient focal membrane deformation induced by arginine-rich peptides leads to their direct penetration into cells. Mol Ther 20(5):984–993PubMedPubMedCentralGoogle Scholar
  37. Hsu T, Mitragotri S (2011) Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc Natl Acad Sci 108(38):15816–15821PubMedGoogle Scholar
  38. Huang Y, Park YS, Moon C, David AE, Chung HS, Yang VC (2010) Synthetic skin-permeable proteins enabling needleless immunization. Angew Chem Int Ed 49(15):2724–2727Google Scholar
  39. Illum L (2003) Nasal drug delivery—possibilities, problems and solutions. J Control Release 87(1):187–198PubMedGoogle Scholar
  40. Iwasaki T, Tokuda Y, Kotake A, Okada H, Takeda S, Kawano T, Nakayama Y (2015) Cellular uptake and in vivo distribution of polyhistidine peptides. J Control Release 210:115–124PubMedGoogle Scholar
  41. Januleviciene I, Siaudvytyte L, Barsauskaite R (2012) Ophthalmic drug delivery in glaucoma—a review. Pharmaceutics 4(1):243–251PubMedPubMedCentralGoogle Scholar
  42. Järver P, Mäger I, Langel Ü (2010) In vivo biodistribution and efficacy of peptide mediated delivery. Trends Pharmacol Sci 31(11):528–535PubMedPubMedCentralGoogle Scholar
  43. Jiao CY, Delaroche D, Burlina F, Alves ID, Chassaing G, Sagan S (2009) Translocation and endocytosis for cell-penetrating peptide internalization. J Biol Chem 284(49):33957–33965PubMedPubMedCentralGoogle Scholar
  44. Johnson LN, Cashman SM, Read SP, Kumar-Singh R (2010) Cell penetrating peptide POD mediates delivery of recombinant proteins to retina, cornea and skin. Vision Res 50(7):686–697PubMedGoogle Scholar
  45. Joliot A, Pernelle C, Deagostini-Bazin H, Prochiantz A (1991) Antennapedia homeobox peptide regulates neural morphogenesis. Proc Natl Acad Sci 88(5):1864–1868PubMedGoogle Scholar
  46. Jordán J, Ruíz-Moreno JM (2013) Advances in the understanding of retinal drug disposition and the role of blood–ocular barrier transporters. Expert Opin Drug Metab Toxicol 9(9):1181–1192PubMedGoogle Scholar
  47. Kanazawa T, Akiyama F, Kakizaki S, Takashima Y, Seta Y (2013) Delivery of siRNA to the brain using a combination of nose-to-brain delivery and cell-penetrating peptide-modified nano-micelles. Biomaterials 34(36):9220–9226PubMedGoogle Scholar
  48. Kawaguchi Y, Takeuchi T, Kuwata K, Chiba J, Hatanaka Y, Nakase I, Futaki S (2016) Syndecan-4 is a receptor for clathrin-mediated endocytosis of arginine-rich cell-penetrating peptides. Bioconjug Chem 27(4):1119–1130PubMedGoogle Scholar
  49. Khafagy ES, Morishita M, Isowa K, Imai J, Takayama K (2009) Effect of cell-penetrating peptides on the nasal absorption of insulin. J Control Release 133(2):103–108Google Scholar
  50. Khafagy ES, Morishita M, Takayama K (2010) The role of intermolecular interactions with penetratin and its analogue on the enhancement of absorption of nasal therapeutic peptides. Int J Pharm 388(1):209–212Google Scholar
  51. Kiesgen S, Liebers N, Cremer M, Arnold U, Weber T, Keller A, Herold-Mende C, Dyckhoff G, Jäger D, Kontermann RE (2014) A fusogenic dengue virus-derived peptide enhances antitumor efficacy of an antibody–ribonuclease fusion protein targeting the EGF receptor. Protein Eng Des Sel 27(10):331–338PubMedGoogle Scholar
  52. Kilk K, Mahlapuu R, Soomets U, Langel Ü (2009) Analysis of in vitro toxicity of five cell-penetrating peptides by metabolic profiling. Toxicology 265(3):87–95PubMedGoogle Scholar
  53. Kim YC, Ludovice PJ, Prausnitz MR (2010) Transdermal delivery enhanced by antimicrobial peptides. J Biomed Nanotechnol 6(5):612–620PubMedGoogle Scholar
  54. Kim HY, Yum SY, Jang G, Ahn DR (2015) Discovery of a non-cationic cell penetrating peptide derived from membrane-interacting human proteins and its potential as a protein delivery carrier. Sci Rep 5:11719Google Scholar
  55. Kim CH, Lee SG, Kang MJ, Lee S, Choi YW (2017) Surface modification of lipid-based nanocarriers for cancer cell-specific drug targeting. J Pharm Investig 1–25Google Scholar
  56. Kimura S, Kawano T, Iwasaki T (2017) Short polyhistidine peptides penetrate effectively into Nicotiana tabacum-cultured cells and Saccharomyces cerevisiae cells. Biosci Biotechnol Biochem 81(1):112–118PubMedGoogle Scholar
  57. Koren E, Torchilin VP (2012) Cell-penetrating peptides: breaking through to the other side. Trends Mol Med 18(7):385–393PubMedGoogle Scholar
  58. Krautwald S, Dewitz C, Fändrich F, Kunzendorf U (2016) Inhibition of regulated cell death by cell-penetrating peptides. Cell Mol Life Sci 73(11–12):2269–2284PubMedPubMedCentralGoogle Scholar
  59. Kumar S, Zakrewsky M, Chen M, Menegatti S, Muraski JA, Mitragotri S (2015) Peptides as skin penetration enhancers: mechanisms of action. J Control Release 199:168–178PubMedGoogle Scholar
  60. Langel U (2006) Handbook of cell-penetrating peptides, CRC press, Boca RatonGoogle Scholar
  61. Lee SW, Kim JH, Park MC, Park YB, Chae WJ, Morio T, Lee DH, Yang SH, Lee SK, Lee SK (2012) Alleviation of rheumatoid arthritis by cell-transducible methotrexate upon transcutaneous delivery. Biomaterials 33(5):1563–1572PubMedGoogle Scholar
  62. Liu C, Tai L, Zhang W, Wei G, Pan W, Lu W (2014) Penetratin, a potentially powerful absorption enhancer for noninvasive intraocular drug delivery. Mol Pharm 11(4):1218–1227PubMedGoogle Scholar
  63. Lönn P, Dowdy SF (2015) Cationic PTD/CPP-mediated macromolecular delivery: charging into the cell. Expert Opin Drug Deliv 12(10):1627–1636PubMedGoogle Scholar
  64. Lou G, Zhang Q, Xiao F, Xiang Q, Su Z, Zhang L, Yang P, Yang Y, Zheng Q, Huang Y (2012) Intranasal administration of TAT-haFGF 14–154 attenuates disease progression in a mouse model of Alzheimer’s disease. Neuroscience 223:225–237PubMedGoogle Scholar
  65. Madani F, Lindberg S, Langel Ü, Futaki S, Gräslund A (2011) Mechanisms of cellular uptake of cell-penetrating peptides. J Biophys 2011:414729PubMedPubMedCentralGoogle Scholar
  66. Marks JR, Placone J, Hristova K, Wimley WC (2011) Spontaneous membrane-translocating peptides by orthogonal high-throughput screening. J Am Chem Soc 133(23):8995–9004PubMedPubMedCentralGoogle Scholar
  67. McGowan J, Vig P, Bidwell G (2015) Cell penetrating peptide biopolymers for drug delivery to the central nervous system. FASEB J 29(1 Supplement):834–832Google Scholar
  68. Milletti F (2012) Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov Today 17(15):850–860PubMedGoogle Scholar
  69. Miyata K, Mohri K, Egawa T, Endo R, Morimoto N, Ochiai K, Hiwatari KI, Tsubaki K, Tobita E, Uto T (2016) Demonstration of d-octaarginine-linked polymers as promising adjuvants for mucosal vaccination through influenza virus challenge. Bioconjug Chem 27(8):1865–1871PubMedGoogle Scholar
  70. Moschos SA, Jones SW, Perry MM, Williams AE, Erjefalt JS, Turner JJ, Barnes PJ, Sproat BS, Gait MJ, Lindsay MA (2007) Lung delivery studies using siRNA conjugated to TAT (48–60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug Chem 18(5):1450–1459PubMedPubMedCentralGoogle Scholar
  71. Murayama T, Masuda T, Afonin S, Kawano K, Takatani-Nakase T, Ida H, Takahashi Y, Fukuma T, Ulrich AS, Futaki S (2017) Loosening of lipid packing promotes oligoarginine entry into cells. Angew Chem Int Ed 56(26):7644–7647Google Scholar
  72. Nakase I, Tadokoro A, Kawabata N, Takeuchi T, Katoh H, Hiramoto K, Negishi M, Nomizu M, Sugiura Y, Futaki S (2007) Interaction of arginine-rich peptides with membrane-associated proteoglycans is crucial for induction of actin organization and macropinocytosis. Biochemistry 46(2):492–501PubMedGoogle Scholar
  73. Neundorf I, Rennert R, Hoyer J, Schramm F, Löbner K, Kitanovic I, Wölfl S (2009) Fusion of a short HA2-derived peptide sequence to cell-penetrating peptides improves cytosolic uptake, but enhances cytotoxic activity. Pharmaceuticals 2(2):49–65PubMedPubMedCentralGoogle Scholar
  74. Neutra MR, Kozlowski PA (2006) Mucosal vaccines: the promise and the challenge. Nat Rev Immunol 6(2):148PubMedGoogle Scholar
  75. Niesner U, Halin C, Lozzi L, Günthert M, Neri P, Wunderli-Allenspach H, Zardi L, Neri D (2002) Quantitation of the tumor-targeting properties of antibody fragments conjugated to cell-permeating HIV-1 TAT peptides. Bioconjug Chem 13(4):729–736PubMedGoogle Scholar
  76. Niikura K, Horisawa K, Doi N (2015) A fusogenic peptide from a sea urchin fertilization protein promotes intracellular delivery of biomacromolecules by facilitating endosomal escape. J Control Release 212:85–93PubMedGoogle Scholar
  77. Oehlke J, Krause E, Wiesner B, Beyermann M, Bienert M (1997) Extensive cellular uptake into endothelial cells of an amphipathic β-sheet forming peptide. FEBS Lett 415(2):196–199PubMedGoogle Scholar
  78. Oehlke J, Scheller A, Wiesner B, Krause E, Beyermann M, Klauschenz E, Melzig M, Bienert M (1998) Cellular uptake of an α-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically. Biochim Biophys Acta 1414(1–2):127–139PubMedGoogle Scholar
  79. Patlolla RR, Desai PR, Belay K, Singh MS (2010) Translocation of cell penetrating peptide engrafted nanoparticles across skin layers. Biomaterials 31(21):5598–5607PubMedPubMedCentralGoogle Scholar
  80. Peichl P, Griesmacher A, Kumpan W, Schedl R, Prosquil E, Bröll H (2005) Clinical outcome of salmon calcitonin nasal spray treatment in postmenopausal women after total hip arthroplasty. Gerontology 51(4):242–252PubMedGoogle Scholar
  81. Pescina S, Sala M, Padula C, Scala MC, Spensiero A, Belletti S, Gatti R, Novellino E, Campiglia P, Santi P (2016) Design and synthesis of new cell penetrating peptides: diffusion and distribution inside the cornea. Mol Pharm 13(11):3876–3883PubMedGoogle Scholar
  82. Pooga M, Hällbrink M, Zorko M (1998) Cell penetration by transportan. Fertil Steril 12(1):67–77Google Scholar
  83. Rajfer J, Handelsman DJ, Crum A, Steiner B, Peterson M, Swerdloff RS (1986) Comparison of the efficacy of subcutaneous and nasal spray buserelin treatment in suppression of testicular steroidogenesis in men with prostate cancer. Fertil Steril 46(1):104–110PubMedGoogle Scholar
  84. Reissmann S (2014) Cell penetration: scope and limitations by the application of cell-penetrating peptides. J Pept Sci 20(10):760–784PubMedGoogle Scholar
  85. Rhee M, Davis P (2006) Mechanism of uptake of C105Y, a novel cell penetrating peptide. J Biol Chem 281:1233–1240PubMedGoogle Scholar
  86. Richard JP, Melikov K, Vives E, Ramos C, Verbeure B, Gait MJ, Chernomordik LV, Lebleu B (2003) Cell-penetrating peptides A reevaluation of the mechanism of cellular uptake. J Biol Chem 278(1):585–590PubMedPubMedCentralGoogle Scholar
  87. Richard JP, Melikov K, Brooks H, Prevot P, Lebleu B, Chernomordik LV (2005) Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors. J Biol Chem 280(15):15300–15306PubMedGoogle Scholar
  88. Rothbard JB, Garlington S, Lin Q, Kirschberg T, Kreider E, McGrane PL, Wender PA, Khavari PA (2000) Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat Med 6(11):1253PubMedGoogle Scholar
  89. Rothbard JB, Jessop TC, Lewis RS, Murray BA, Wender PA (2004) Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells. J Am Chem Soc 126(31):9506–9507PubMedGoogle Scholar
  90. Ruan RQ, Wang SS, Wang CL, Zhang L, Zhang YJ, Zhou W, Ding WP, Jin PP, Wei PF, Man N (2013) Transdermal delivery of human epidermal growth factor facilitated by a peptide chaperon. Eur J Med Chem 62:405–409PubMedGoogle Scholar
  91. Sadler K, Eom KD, Yang JL, Dimitrova Y, Tam JP (2002) Translocating proline-rich peptides from the antimicrobial peptide bactenecin 7. Biochemistry 41(48):14150–14157PubMedGoogle Scholar
  92. Sakuma S, Suita M, Inoue S, Marui Y, Nishida K, Masaoka Y, Kataoka M, Yamashita S, Nakajima N, Shinkai N (2012) Cell-penetrating peptide-linked polymers as carriers for mucosal vaccine delivery. Mol Pharm 9(10):2933–2941PubMedGoogle Scholar
  93. Scheller A, Oehlke J, Wiesner B, Dathe M, Krause E, Beyermann M, Melzig M, Bienert M (1999) Structural requirements for cellular uptake of α-helical amphipathic peptides. J Pept Sci 5(4):185–194PubMedGoogle Scholar
  94. Schmidt S, Adjobo-Hermans MJ, Kohze R, Enderle T, Brock R, Milletti F (2016) Identification of short hydrophobic cell-penetrating peptides for cytosolic peptide delivery by rational design. Bioconjug Chem 28(2):382–389PubMedGoogle Scholar
  95. Soomets U, Lindgren M, Gallet X, Hällbrink M, Elmquist A, Balaspiri L, Zorko M, Pooga M, Brasseur R,. Langel Ü (2000) Deletion analogues of transportan. Biochim Biophys Acta 1467(1):165–176PubMedGoogle Scholar
  96. Sudo K, Niikura K, Iwaki K, Kohyama S, Fujiwara K, Doi N (2017) Human-derived fusogenic peptides for the intracellular delivery of proteins. J Control Release 255:1–11PubMedGoogle Scholar
  97. Sullan RMA, Li. JK, Shan Z (2009) Quantification of the nanomechanical stability of ceramide-enriched domains. Langmuir 25(22): 12874–12877PubMedGoogle Scholar
  98. Takeda H, Kurioka T, Kaitsuka T, Tomizawa K, Matsunobu T, Hakim F, Mizutari K, Miwa T, Yamada T, Ise M (2016) Protein transduction therapy into cochleae via the round window niche in guinea pigs. Mol Ther Methods Clin Dev 3:16055PubMedPubMedCentralGoogle Scholar
  99. Tan J, Cheong H, Park YS, Kim H, Zhang M, Moon C, Huang Y (2014) Cell-penetrating peptide-mediated topical delivery of biomacromolecular drugs. Curr Pharm Biotechnol 15(3):231–239PubMedGoogle Scholar
  100. Tünnemann G, Martin RM, Haupt S, Patsch C, Edenhofer F, Cardoso MC (2006) Cargo-dependent mode of uptake and bioavailability of TAT-containing proteins and peptides in living cells. FASEB J 20(11):1775–1784PubMedGoogle Scholar
  101. Tünnemann G, Ter-Avetisyan G, Martin RM, Stöckl M, Herrmann A, Cardoso MC (2008) Live-cell analysis of cell penetration ability and toxicity of oligo-arginines. J Pept Sci 14(4):469–476PubMedGoogle Scholar
  102. Verdurmen WP, Bovee-Geurts PH, Wadhwani P, Ulrich AS, Hällbrink M, van K Th, Brock R (2011) Preferential uptake of L-versus D-amino acid cell-penetrating peptides in a cell type-dependent manner. Chem Biol 18(8):1000–1010PubMedGoogle Scholar
  103. Vij M, Natarajan P, Pattnaik BR, Alam S, Gupta N, Santhiya D, Sharma R, Singh A, Ansari KM, Gokhale RS (2016) Non-invasive topical delivery of plasmid DNA to the skin using a peptide carrier. J Control Release 222:159–168PubMedGoogle Scholar
  104. Vives E, Brodin P, Lebleu B (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272(25):16010–16017PubMedGoogle Scholar
  105. Vivès E, Schmidt J, Pèlegrin A (2008) Cell-penetrating and cell-targeting peptides in drug delivery. Biochim Biophys Acta 1786(2):126–138PubMedGoogle Scholar
  106. Wallbrecher R, Ackels T, Olea RA, Klein MJ, Caillon L, Schiller J, Bovée-Geurts PH, van Kuppevelt TH, Ulrich AS, Spehr M (2017) Membrane permeation of arginine-rich cell-penetrating peptides independent of transmembrane potential as a function of lipid composition and membrane fluidity. J Biol Chem 256:68–78Google Scholar
  107. Wang F, Wang Y, Zhang X, Zhang W, Guo S, Jin F (2014) Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery. J Biol Chem 174:126–136Google Scholar
  108. Wender PA, Mitchell DJ, Pattabiraman K, Pelkey ET, Steinman L, Rothbard JB (2000) The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci 97(24):13003–13008PubMedGoogle Scholar
  109. Yan L, Wang H, Jiang Y, Liu J, Wang Z, Yang Y, Huang S, Huang Y (2013) Cell-penetrating peptide-modified PLGA nanoparticles for enhanced nose-to-brain macromolecular delivery. Macromol Res 21(4):435–441Google Scholar
  110. Yao J, Ma Y, Zhang W, Li L, Zhang Y, Zhang L, Liu H, Ni J, Wang R (2017) Design of new acid-activated cell-penetrating peptides for tumor drug delivery. PeerJ 5:e3429PubMedPubMedCentralGoogle Scholar
  111. Zaro JL, Shen WC (2015) Cationic and amphipathic cell-penetrating peptides (CPPs): their structures and in vivo studies in drug delivery. Front Chem Sci Eng 9(4):407–427Google Scholar
  112. Ziegle A (2008) Thermodynamic studies and binding mechanisms of cell-penetrating peptides with lipids and glycosaminoglycans. Adv Drug Deliv Rev 60(4):580–597Google Scholar
  113. Ziegler A, Seelig S (2008) Binding and clustering of glycosaminoglycans: a common property of mono-and multivalent cell-penetrating compounds. Biophys J 94(6):2142–2149PubMedGoogle Scholar

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© The Korean Society of Pharmaceutical Sciences and Technology 2017

Authors and Affiliations

  • Tru Van Nguyen
    • 1
  • Meong Cheol Shin
    • 2
  • Kyoung Ah Min
    • 3
  • Yongzhuo Huang
    • 4
  • Euichaul Oh
    • 5
  • Cheol Moon
    • 1
    Email author
  1. 1.College of Pharmacy and Research Institute of Life and Pharmaceutical SciencesSunchon National UniversitySuncheonRepublic of Korea
  2. 2.College of Pharmacy and Research Institute of Pharmaceutical SciencesGyeongsang National UniversityJinjuRepublic of Korea
  3. 3.College of Pharmacy and Inje Institute of Pharmaceutical Sciences and ResearchInje UniversityGimhaeRepublic of Korea
  4. 4.Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina
  5. 5.College of Pharmacy and Integrated Research Institute of Pharmaceutical SciencesThe Catholic University of KoreaBucheonRepublic of Korea

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