Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells

Folia Histochemica et Cytobiologica

Volumn 52, Issue 4, 2014, Pages 257-269

  Ruczynski, Jaroslaw ^a   Wierzbicki, Piotr M ^b   Kogut Wierzbicka, Marzena ^b   Mucha, Piotr ^a   Siedlecka Kroplewska, Kamila ^b   Rekowski, Piotr ^a  

^a UNIVERSITY OF GDA SK   (Poland)

^b MEDICAL UNIVERSITY OF GDANSK   (Poland)

Author keywords

Anti cancer drug delivery; Cell penetrating peptides; Covalent and noncovalent delivery strategy; Endocytosis; Membrane transduction peptides

Indexed keywords

ARGINYLGLYCYLASPARTIC ACID; AZURIN; BETA3 INTEGRIN; BOTULINUM TOXIN A; CELL PENETRATING PEPTIDE; CROTAMINE; CYCLOSPORIN A; DOXORUBICIN; FIBROBLAST GROWTH FACTOR; GLYCOPROTEIN GP 41; HEAT SHOCK PROTEIN 20; HISTONE H1; HISTONE H2A; HISTONE H2B; IMMUNOGLOBULIN LIGHT CHAIN; LIPOSOME; MASTOPARAN; MELITTIN; MORPHOLINO OLIGONUCLEOTIDE; PACLITAXEL; PENETRATIN; PEPTIDE NUCLEIC ACID; PROTEIN KINASE C INHIBITOR; PROTEIN P28; PROTEIN VP22; STRESS ACTIVATED PROTEIN KINASE INHIBITOR; SUPPRESSOR OF CYTOKINE SIGNALING 3; TRANSACTIVATOR PROTEIN; UNINDEXED DRUG; VINCRISTINE SULFATE;

AMINO ACID SEQUENCE; BRAIN INFARCTION; BRAIN METASTASIS; BRAIN NECROSIS; CELL MEMBRANE TRANSPORT; CELL TRANSPORT; COVALENT BOND; CYTOTOXICITY; DRUG CONJUGATION; DRUG DELIVERY SYSTEM; DUCHENNE MUSCULAR DYSTROPHY; ENDOCYTOSIS; ENERGY; HEARING IMPAIRMENT; HEART INFARCTION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INFLAMMATION; INTERNALIZATION; LIPID MEMBRANE; MEMBRANE PERMEABILITY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PSORIASIS; REVIEW; SCAR; SOLID TUMOR; SPINAL CORD INJURY; TRANSPORT KINETICS; ANIMAL; BIOLOGICAL MODEL; CHEMISTRY; DRUG ADMINISTRATION ROUTE; METABOLISM;

ANIMALS; CELL-PENETRATING PEPTIDES; DRUG ADMINISTRATION ROUTES; HUMANS; MODELS, BIOLOGICAL;

EID: 84921828869     PISSN: 02398508     EISSN: 18975631     Source Type: Journal    
DOI: 10.5603/FHC.a2014.0034     Document Type: Review

References (104)

1. El-Andaloussi S, Holm T, Langel U. Cell-penetrating peptides: mechanisms and applications. Curr Pharm Des. 2005; 11: 3597-3611.
2. Green M, Loewenstein PM. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell. 1988; 55: 1179-1188.
3. Viscidi RP, Mayur K, Lederman HM, Frankel AD. Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science. 1989; 246: 1606-1608.
4. Joliot A, Pernelle C, Deagostini-Bazin H, Prochiantz A. Antennapedia homeobox peptide regulates neural morphogenesis. Proc Natl Acad Sci USA. 1991; 88: 1864-1868.
5. Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem. 1994; 269: 10444-10450.
6. Vives E, Brodin P, Lebleu B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem. 1997; 272: 16010-16017.
7. Mae M, Langel U. Cell-penetrating peptides as vectors for peptide, protein and oligonucleotide delivery. Curr Opin Pharmacol. 2006; 6: 509-514.
8. El-Andaloussi S, Johansson HJ, Holm T, Langel U. A novel cell-penetrating peptide, M918, for efficient delivery of proteins and peptide nucleic acids. Mol Ther. 2007; 15: 1820-1826.
9. Reissmann S. Cell penetration: scope and limitations by the application of cell-penetrating peptides. J Pept Sci. 2014; 20: 760-784.
10. Song J, Kai M, Zhang W et al. Cellular uptake of transportan 10 and its analogs in live cells: Selectivity and structure-activity relationship studies. Peptides. 2011; 32: 1934-1941.
11. Zorko M, Langel U. Cell-penetrating peptides: mechanism and kinetics of cargo delivery. Adv Drug Deliv Rev. 2005; 57: 529-545.
12. Elmquist A, Lindgren M, Bartfai T, Langel U. VE-cadherin-derived cell-penetrating peptide, pVEC, with carrier functions. Exp Cell Res. 2001; 269: 237-244.
13. Madani F, Lindberg S, Langel U, Futaki S, Graslund A. Mechanisms of cellular uptake of cell-penetrating peptides. J Biophys. 2011; 2011: 414729.
14. Futaki S, Suzuki T, Ohashi W et al. Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem. 2001; 276: 5836-5840.
15. Avrahami D, Shai Y. Bestowing antifungal and antibacterial activities by lipophilic acid conjugation to D, L-amino acid-containing antimicrobial peptides: a plausible mode of action. Biochemistry. 2003; 42: 14946-14956.
16. Zhang L, Torgerson TR, Liu XY et al. Preparation of functionally active cell-permeable peptides by single-step ligation of two peptide modules. Proc Natl Acad Sci USA. 1998; 95: 9184-9189.
17. Bleifuss E, Kammertoens T, Hutloff A et al. The translocation motif of hepatitis B virus improves protein vaccination. Cell Mol Life Sci. 2006; 63: 627-635.
18. Rennert R, Neundorf I, Jahnke HG et al. Generation of carrier peptides for the delivery of nucleic acid drugs in primary cells. ChemMedChem. 2008; 3: 241-253.
19. Trabulo S, Cardoso AL, Mano M, de Lima MC. Cell-penetrating peptides-Mechanisms of cellular uptake and generation of delivery Systems. Pharmaceuticals (Basel). 2010; 3: 961-993.
20. Soomets U, Lindgren M, Gallet X et al. Deletion analogues of transportan. Biochim Biophys Acta. 2000; 1467: 165-176.
21. Radis-Baptista G, Kerkis I. Crotamine, a small basic polypeptide myotoxin from rattlesnake venom with cell-penetrating properties. Curr Pharm Des. 2011; 17: 4351-4361.
22. Wender PA, Mitchell DJ, Pattabiraman K, Pelkey ET, Steinman L, Rothbard JB. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci USA. 2000; 97: 13003-13008.
23. Huq I, Ping YH, Tamilarasu N, Rana TM. Controlling human immunodeficiency virus type 1 gene expression by unnatural peptides. Biochemistry. 1999; 38: 5172-5177.
24. Derossi D, Calvet S, Trembleau A, Brunissen A, Chassaing G, Prochiantz A. Cell internalization of the third helix of the Antennapedia homeodomain is receptor-independent. J Biol Chem. 1996; 271: 18188-18193.
25. Matsuzaki K, Yoneyama S, Murase O, Miyajima K. Transbilayer transport of ions and lipids coupled with mastoparan X translocation. Biochemistry. 1996; 35: 8450-8456.
26. Deshayes S, Morris MC, Divita G, Heitz F. Interactions of amphipathic CPPs with model membranes. Biochim Biophys Acta. 2006; 1758: 328-335.
27. Duchardt F, Fotin-Mleczek M, Schwarz H, Fischer R, Brock R. A comprehensive model for the cellular uptake of cationic cell-penetrating peptides. Traffic. 2007; 8: 848-866.
28. Kosuge M, Takeuchi T, Nakase I, Jones AT, Futaki S. Cellular internalization and distribution of arginine-rich peptides as a function of extracellular peptide concentration, serum, and plasma membrane associated proteoglycans. Bioconjug Chem. 2008; 19: 656-664.
29. Berlose JP, Convert O, Derossi D, Brunissen A, Chassaing G. Conformational and associative behaviours of the third helix of antennapedia homeodomain in membrane-mimetic environments. Eur J Biochem. 1996; 242: 372-386.
30. Binder H, Lindblom G. A molecular view on the interaction of the trojan peptide penetratin with the polar interface of lipid bilayers. Biophys J. 2004; 87: 332-343.
31. Ziegler A, Blatter XL, Seelig A, Seelig J. Protein transduction domains of HIV-1 and SIV TAT interact with charged lipid vesicles. Binding mechanism and thermodynamic analysis. Biochemistry. 2003; 42: 9185-9194.
32. Astriab-Fisher A, Sergueev D, Fisher M, Shaw BR, Juliano RL. Conjugates of antisense oligonucleotides with the Tat and antennapedia cell-penetrating peptides: effects on cellular uptake, binding to target sequences, and biologic actions. Pharm Res. 2002; 19: 744-754.
33. Lindberg M, Jarvet J, Langel U, Graslund A. Secondary structure and position of the cell-penetrating peptide transportan in SDS micelles as determined by NMR. Biochemistry. 2001; 40: 3141-3149.
34. Dathe M, Wieprecht T. Structural features of helical antimicrobial peptides: their potential to modulate activity on model membranes and biological cells. Biochim Biophys Acta. 1999; 1462: 71-87.
35. Yang L, Harroun TA, Weiss TM, Ding L, Huang HW. Barrel-stave model or toroidal model? A case study on melittin pores. Biophys J. 2001; 81: 1475-1485.
36. Lundberg P, Langel U. A brief introduction to cell-penetrating peptides. J Mol Recognit. 2003; 16: 227-233.
37. Mishra A, Gordon VD, Yang L, Coridan R, Wong GC. HIV TAT forms pores in membranes by inducing saddle-splay curvature: potential role of bidentate hydrogen bonding. Angew Chem Int Ed Engl. 2008; 47: 2986-2989.
38. Ziegler A. Thermodynamic studies and binding mechanisms of cell-penetrating peptides with lipids and glycosaminoglycans. Adv Drug Deliv Rev. 2008; 60: 580-597.
39. Mitchell DJ, Kim DT, Steinman L, Fathman CG, Rothbard JB. Polyarginine enters cells more efficiently than other polycationic homopolymers. J Pept Res. 2000; 56: 318-325.
40. Herce HD, Garcia AE. Molecular dynamics simulations suggest a mechanism for translocation of the HIV-1 TAT peptide across lipid membranes. Proc Natl Acad Sci USA. 2007; 104: 20805-20810.
41. Bjorklund J, Biverstahl H, Graslund A, Maler L, Brzezinski P. Real-time transmembrane translocation of penetratin driven by light-generated proton pumping. Biophys J. 2006; 91: 29-31.
42. Rothbard JB, Jessop TC, Lewis RS, Murray BA, Wender PA. Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells. J Am Chem Soc. 2004; 126: 9506-9507.
43. Richard JP, Melikov K, Vives E et al. Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. J Biol Chem. 2003; 278: 585-590.
44. Afonin S, Frey A, Bayerl S et al. The cell-penetrating peptide TAT(48-60) induces a non-lamellar phase in DMPC membranes. Chemphyschem. 2006; 7: 2134-2142.
45. Wierzbicki PM, Kogut M, Ruczynski J et al. Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines. Folia Histochem Cytobiol. 2014; 4. doi: 10. 5603/FHC. a2014. 0035.
46. Petrescu AD, Vespa A, Huang H, McIntosh AL, Schroeder F, Kier AB. Fluorescent sterols monitor cell penetrating peptide Pep-1 mediated uptake and intracellular targeting of cargo protein in living cells. Biochim Biophys Acta. 2009; 1788: 425-441.
47. Ferrari A, Pellegrini V, Arcangeli C, Fittipaldi A, Giacca M, Beltram F. Caveolae-mediated internalization of extracellular HIV-1 tat fusion proteins visualized in real time. Mol Ther. 2003; 8: 284-294.
48. Jiang Y, Li M, Zhang Z, Gong T, Sun X. Cell-penetrating peptides as delivery enhancers for vaccine. Curr Pharm Biotechnol. 2014; 15: 256-266.
49. Kaplan IM, Wadia JS, Dowdy SF. Cationic TAT peptide trans-duction domain enters cells by macropinocytosis. J Control Release. 2005; 102: 247-253.
50. Gump JM, June RK, Dowdy SF. Revised role of glycosaminoglycans in TAT protein transduction domain-mediated cellular transduction. J Biol Chem. 2010; 285: 1500-1507.
51. Richard JP, Melikov K, Brooks H, Prevot P, Lebleu B, Chernomordik LV. Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors. J Biol Chem. 2005; 280: 15300-15306.
52. Futaki S, Niwa M, Nakase I et al. Arginine carrier peptide bearing Ni(II) chelator to promote cellular uptake of histidine-tagged proteins. Bioconjug Chem. 2004; 15: 475-481.
53. Tunnemann G, Martin RM, Haupt S, Patsch C, Edenhofer F, Cardoso MC. Cargo-dependent mode of uptake and bioavailability of TAT-containing proteins and peptides in living cells. FASEB J. 2006; 20: 1775-1784.
54. Dupont E, Prochiantz A, Joliot A. Identification of a signal peptide for unconventional secretion. J Biol Chem. 2007; 282: 8994-9000.
55. Vives E, Schmidt J, Pelegrin A. Cell-penetrating and cell-targeting peptides in drug delivery. Biochim Biophys Acta. 2008; 1786: 126-138.
56. Amand HL, Fant K, Norden B, Esbjorner EK. Stimulated endocytosis in penetratin uptake: effect of arginine and lysine. Biochem Biophys Res Commun. 2008; 371: 621-625.
57. Xia H, Gao X, Gu G et al. Penetratin-functionalized PEG-PLA nanoparticles for brain drug delivery. Int J Pharm. 2012; 436: 840-850.
58. Gait MJ. Peptide-mediated cellular delivery of antisense oligonucleotides and their analogues. Cell Mol Life Sci. 2003; 60: 844-853.
59. Moulton HM, Nelson MH, Hatlevig SA, Reddy MT, Iversen PL. Cellular uptake of antisense morpholino oligomers conjugated to arginine-rich peptides. Bioconjug Chem. 2004; 15: 290-299.
60. Zatsepin TS, Turner JJ, Oretskaya TS, Gait MJ. Conjugates of oligonucleotides and analogues with cell penetrating peptides as gene silencing agents. Curr Pharm Des. 2005; 11: 3639-3654.
61. Futaki S, Ohashi W, Suzuki T et al. Stearylated arginine-rich peptides: a new class of transfection systems. Bioconjug Chem. 2001; 12: 1005-1011.
62. Pooga M, Soomets U, Hallbrink M et al. Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat Biotechnol. 1998; 16: 857-861.
63. Abes R, Arzumanov AA, Moulton HM et al. Cell-penetrating-peptide-based delivery of oligonucleotides: an overview. Biochem Soc Trans. 2007; 35: 775-779.
64. Meade BR, Dowdy SF. Exogenous siRNA delivery using peptide transduction domains/cell penetrating peptides. Adv Drug Deliv Rev. 2007; 59: 134-140.
65. Juliano R, Alam MR, Dixit V, Kang H. Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Res. 2008; 36: 4158-4171.
66. Deshayes S, Morris MC, Divita G, Heitz F. Cell-penetrating peptides: tools for intracellular delivery of therapeutics. Cell Mol Life Sci. 2005; 62: 1839-1849.
67. Chugh A, Amundsen E, Eudes F. Translocation of cell-penetrating peptides and delivery of their cargoes in triticale microspores. Plant Cell Rep. 2009; 28: 801-810.
68. Simeoni F, Morris MC, Heitz F, Divita G. Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells. Nucleic Acids Res. 2003; 31: 2717-2724.
69. Morris MC, Deshayes S, Heitz F, Divita G. Cell-penetrating peptides: from molecular mechanisms to therapeutics. Biol Cell. 2008; 100: 201-217.
70. Tünnemann G. Toxicity, uptake and applications of intracellular delivery by cell penetrating peptides. München: Fakultät für Biologie, Ludwig-Maximilians-Universität; 2009.
71. Hallbrink M, Floren A, Elmquist A, Pooga M, Bartfai T, Langel U. Cargo delivery kinetics of cell-penetrating peptides. Biochim Biophys Acta. 2001; 1515: 101-109.
72. Saar K, Lindgren M, Hansen M, et al. Cell-penetrating peptides: a comparative membrane toxicity study. Anal Biochem. 2005; 345: 55-65.
73. Jones SW, Christison R, Bundell K et al. Characterisation of cell-penetrating peptide-mediated peptide delivery. Br J Pharmacol. 2005; 145: 1093-1102.
74. El-Andaloussi S, Jarver P, Johansson HJ, Langel U. Cargo-dependent cytotoxicity and delivery efficacy of cell-penetrating peptides: a comparative study. Biochem J. 2007; 407: 285-292.
75. Cardozo AK, Buchillier V, Mathieu M et al. Cell-permeable peptides induce dose-and length-dependent cytotoxic effects. Biochim Biophys Acta. 2007; 1768: 2222-2234.
76. Silhol M, Tyagi M, Giacca M, Lebleu B, Vives E. Different mechanisms for cellular internalization of the HIV-1 Tat-derived cell penetrating peptide and recombinant proteins fused to Tat. Eur J Biochem. 2002; 269: 494-501.
77. Snyder EL, Saenz CC, Denicourt C et al. Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anticancer peptides. Cancer Res. 2005; 65: 10646-10650.
78. Bernardes N, Ribeiro AS, Abreu S et al. High-throughput molecular profiling of a P-cadherin overexpressing breast cancer model reveals new targets for the anti-cancer bacterial protein azurin. Int J Biochem Cell Biol. 2014; 50: 1-9.
79. Zhang Y, Xia L, Zhang X, Ding X, Yan F, Wu F. Escherichia coli Nissle 1917 targets and restrains mouse B16 melanoma and 4T1 breast tumors through expression of azurin protein. Appl Environ Microbiol. 2012; 78: 7603-7610.
80. Ramachandran S, Mandal M. Induction of apoptosis of azurin synthesized from P. aeruginosa MTCC 2453 against Dalton's lymphoma ascites model. Biomed Pharmacother. 2011; 65: 461-466.
81. Bernardes N, Ribeiro AS, Abreu S et al. The bacterial protein azurin impairs invasion and FAK/Src signaling in P-cadherin-overexpressing breast cancer cell models. PLoS One. 2013; 8: e69023.
82. Moschos SA, Jones SW, Perry MM et al. 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. 2007; 18: 1450-1459.
83. Amantana A, Moulton HM, Cate ML et al. Pharmacokinetics, biodistribution, stability and toxicity of a cell-penetrating peptide-morpholino oligomer conjugate. Bioconjug Chem. 2007; 18: 1325-1331.
84. Tanaka S, Pero SC, Taguchi K et al. Specific peptide ligand for Grb7 signal transduction protein and pancreatic cancer metastasis. J Natl Cancer Inst. 2006; 98: 491-498.
85. Krajewska M, Kim H, Kim C et al. Analysis of apoptosis protein expression in early-stage colorectal cancer suggests opportunities for new prognostic biomarkers. Clin Cancer Res. 2005; 11: 5451-5461.
86. Jang YL, Yun UJ, Lee MS et al. Cell-penetrating peptide mimicking polymer-based combined delivery of paclitaxel and siRNA for enhanced tumor growth suppression. Int J Pharm. 2012; 434: 488-493.
87. Moulton HM. Cell-penetrating peptides enhance systemic delivery of antisense morpholino oligomers. Methods Mol Biol. 2012; 867: 407-414.
88. Gao X, Zhao J, Han G et al. Effective dystrophin restoration by a novel muscle-homing peptide-morpholino conjugate in dystrophin-deficient mdx mice. Mol Ther. 2014; 22: 1333-1341.
89. Shi NQ, Qi XR, Xiang B, Zhang Y. A survey on "Trojan Horse" peptides: Opportunities, issues and controlled entry to "Troy". J Control Release. 2014; 194C: 53-70.
90. Johnson RM, Harrison SD, Maclean D. Therapeutic applications of cell-penetrating peptides. Methods Mol Biol. 2011; 683: 535-551.
91. Lebleu B, Moulton HM, Abes R et al. Cell penetrating peptide conjugates of steric block oligonucleotides. Adv Drug Deliv Rev. 2008; 60: 517-529.
92. Miyaji Y, Walter S, Chen L et al. Distribution of KAI-9803, a novel delta-protein kinase C inhibitor, after intravenous administration to rats. Drug Metab Dispos. 2011; 39: 1946-1953.
93. Cousins MJ, Pickthorn K, Huang S, Critchley L, Bell G. The safety and efficacy of KAI-1678-an inhibitor of epsilon protein kinase C (epsilonPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design. Pain Med. 2013; 14: 533-540.
94. Omotehara Y, Hakuba N, Hato N, Okada M, Gyo K. Protection against ischemic cochlear damage by intratympanic administration of AM-111. Otol Neurotol. 2011; 32: 1422-1427.
95. Zou LL, Ma JL, Wang T, Yang TB, Liu CB. Cell-penetrating Peptide-mediated therapeutic molecule delivery into the central nervous system. Curr Neuropharmacol. 2013; 11: 197-208.
96. Cecchelli R, Berezowski V, Lundquist S et al. Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug Discov. 2007; 6: 650-661.
97. Aarts M, Liu Y, Liu L et al. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science. 2002; 298: 846-850.
98. Jo D, Liu D, Yao S, Collins RD, Hawiger J. Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nat Med. 2005; 11: 892-898.
99. Kurzrock R, Gabrail N, Chandhasin C et al. Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors. Mol Cancer Ther. 2012; 11: 308-316.
100. Che C, Yang G, Thiot C et al. New Angiopep-modified doxorubicin (ANG1007) and etoposide (ANG1009) chemotherapeutics with increased brain penetration. J Med Chem. 2010; 53: 2814-2824.
101. Drin G, Cottin S, Blanc E, Rees AR, Temsamani J. Studies on the internalization mechanism of cationic cell-penetrating peptides. J Biol Chem. 2003; 278: 31192-31201.
102. Pauwels EK, Erba P, Mariani G, Gomes CM. Multidrug resistance in cancer: its mechanism and its modulation. Drug News Perspect. 2007; 20: 371-377.
103. Farkhani SM, Valizadeh A, Karami H, Mohammadi S, Sohrabi N, Badrzadeh F. Cell penetrating peptides: efficient vectors for delivery of nanoparticles, nanocarriers, therapeutic and diagnostic molecules. Peptides. 2014; 57: 78-94.
104. Kilk K. Cell-penetrating peptides and bioactive cargoes. Strategies and mechanisms. Stockholm: Department of Neurochemistry and Neurotoxicology Arrhenius Laboratories for Natural Sciences, Stockholm University; 2004.