Abstract
Cell-penetrating peptides (CPPs) have emerged as a promising strategy for enhancing the membrane permeability of bioactive molecules, particularly in the treatment of central nervous system diseases. CPPs possess the ability to deliver a diverse array of bioactive molecules into cells using either covalent or non-covalent approaches, with a preference for non-covalent methods to preserve the biological activity of the transported molecules. By effectively traversing various physiological barriers, CPPs have exhibited significant potential in preclinical and clinical drug development. The discovery of CPPs represents a valuable solution to the challenge of limited membrane permeability of bioactive molecules and will continue to exert a crucial influence on the field of biomedical science.
References
Guidotti G, Brambilla L, Rossi D. Cell-Penetrating Peptides: From Basic Research to Clinics. Trends Pharmacol Sci. 2017;38(4):406-424. doi:10.1016/j.tips.2017.01.003
Demeule M, Régina A, Ché C, et al. Identification and design of peptides as a new drug delivery system for the brain. J Pharmacol Exp Ther. 2008;324(3):1064-1072. doi:10.1124/jpet.107.131318
Zhang F, Xu CL, Liu CM. Drug delivery strategies to enhance the permeability of the blood-brain barrier for treatment of glioma. Drug Des Devel Ther. 2015;9:2089-2100. doi:10.2147/DDDT.S79592
Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988;55(6):1189-1193. doi:10.1016/0092-8674(88)90263-2
Green M, Loewenstein PM. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell. 1988;55(6):1179-1188. doi:10.1016/0092-8674(88)90262-0
Joliot A, Pernelle C, Deagostini-Bazin H, Prochiantz A. Antennapedia homeobox peptide regulates neural morphogenesis. Proc Natl Acad Sci U S A. 1991;88(5):1864-1868. doi:10.1073/pnas.88.5.1864
Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem. 1994;269(14):10444-10450.
Vivès 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(25):16010-16017. doi:10.1074/jbc.272.25.16010
Park J, Ryu J, Kim KA, et al. Mutational analysis of a human immunodeficiency virus type 1 Tat protein transduction domain which is required for delivery of an exogenous protein into mammalian cells. J Gen Virol. 2002;83(Pt 5):1173-1181. doi:10.1099/0022-1317-83-5-1173
Elliott G, O’Hare P. Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell. 1997;88(2):223-233. doi:10.1016/s0092-8674(00)81843-7
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(8):5836-5840. doi:10.1074/jbc.M007540200
Oehlke J, Scheller A, Wiesner B, et al. Cellular uptake of an alpha-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically. Biochim Biophys Acta. 1998;1414(1-2):127-139. doi:10.1016/s0005-2736(98)00161-8
Ramsey JD, Flynn NH. Cell-penetrating peptides transport therapeutics into cells. Pharmacol Ther. 2015;154:78-86. doi:10.1016/j.pharmthera.2015.07.003
Raucher D, Ryu JS. Cell-penetrating peptides: strategies for anticancer treatment. Trends in Molecular Medicine. 2015;21(9):560-570. doi:10.1016/j.molmed.2015.06.005
Bechara C, Sagan S. Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett. 2013;587(12):1693-1702. doi:10.1016/j.febslet.2013.04.031
Copolovici DM, Langel K, Eriste E, Langel Ü. Cell-penetrating peptides: design, synthesis, and applications. ACS Nano. 2014;8(3):1972-1994. doi:10.1021/nn4057269
Heitz F, Morris MC, Divita G. Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics. Br J Pharmacol. 2009;157(2):195-206. doi:10.1111/j.1476-5381.2009.00057.x
Regberg J, Srimanee A, Langel U. Applications of cell-penetrating peptides for tumor targeting and future cancer therapies. Pharmaceuticals (Basel). 2012;5(9):991-1007. doi:10.3390/ph5090991
Wang T, Meng Z, Kang Z, et al. Peptide Gene Delivery Vectors for Specific Transfection of Glioma Cells. ACS Biomater Sci Eng. 2020;6(12):6778-6789. doi:10.1021/acsbiomaterials.0c01336
Wu J, Han H, Jin Q, Li Z, Li H, Ji J. Design and Proof of Programmed 5‑Aminolevulinic Acid Prodrug Nanocarriers for Targeted Photodynamic Cancer Therapy. ACS applied materials & interfaces. 2017;9(17):14596-14605. doi:10.1021/acsami.6b15853
Yang H, Liu S, Cai H, et al. Chondroitin sulfate as a molecular portal that preferentially mediates the apoptotic killing of tumor cells by penetratin-directed mitochondria-disrupting peptides. J Biol Chem. 2010;285(33):25666-25676. doi:10.1074/jbc.M109.089417
Xie J, Bi Y, Zhang H, et al. Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application. Front Pharmacol. 2020;11:697. doi:10.3389/fphar.2020.00697
Bera S, Kar RK, Mondal S, Pahan K, Bhunia A. Structural Elucidation of the Cell-Penetrating Penetratin Peptide in Model Membranes at the Atomic Level: Probing Hydrophobic Interactions in the Blood-Brain Barrier. Biochemistry. 2016;55(35):4982-4996. doi:10.1021/acs.biochem.6b00518
Ostenson CG, Zaitsev S, Berggren PO, Efendic S, Langel U, Bartfai T. Galparan: a powerful insulin-releasing chimeric peptide acting at a novel site. Endocrinology. 1997;138(8):3308-3313. doi:10.1210/endo.138.8.5307
Alaybeyoglu B, Sariyar Akbulut B, Ozkirimli E. Insights into membrane translocation of the cell-penetrating peptide pVEC from molecular dynamics calculations. J Biomol Struct Dyn. 2016;34(11):2387-2398. doi:10.1080/07391102.2015.1117396
Bobone S, Piazzon A, Orioni B, et al. The thin line between cell-penetrating and antimicrobial peptides: the case of Pep-1 and Pep-1-K. J Pept Sci. 2011;17(5):335-341. doi:10.1002/psc.1340
Deshayes S, Plénat T, Charnet P, Divita G, Molle G, Heitz F. Formation of transmembrane ionic channels of primary amphipathic cell-penetrating peptides. Consequences on the mechanism of cell penetration. Biochim Biophys Acta. 2006;1758(11):1846-1851. doi:10.1016/j.bbamem.2006.08.010
Silva S, Kurrikoff K, Langel Ü, Almeida AJ, Vale N. A Second Life for MAP, a Model Amphipathic Peptide. Int J Mol Sci. 2022;23(15):8322. doi:10.3390/ijms23158322
Rydström A, Deshayes S, Konate K, et al. Direct translocation as major cellular uptake for CADY self-assembling peptide-based nanoparticles. PLoS One. 2011;6(10):e25924. doi:10.1371/journal.pone.0025924
Rhee M, Davis P. Mechanism of uptake of C105Y, a novel cell-penetrating peptide. J Biol Chem. 2006;281(2):1233-1240. doi:10.1074/jbc.M509813200
Guha S, Ferrie RP, Ghimire J, et al. Applications and evolution of melittin, the quintessential membrane active peptide. Biochem Pharmacol. 2021;193:114769. doi:10.1016/j.bcp.2021.114769
Kim Y, Lillo A, Moss JA, Janda KD. A contiguous stretch of methionine residues mediates the energy-dependent internalization mechanism of a cell-penetrating peptide. Mol Pharm. 2005;2(6):528-535. doi:10.1021/mp050035b
Vasconcelos L, Pärn K, Langel U. Therapeutic potential of cell-penetrating peptides. Ther Deliv. 2013;4(5):573-591. doi:10.4155/tde.13.22
Deloche C, Lopez-Lazaro L, Mouz S, Perino J, Abadie C, Combette JM. XG-102 administered to healthy male volunteers as a single intravenous infusion: a randomized, double-blind, placebo-controlled, dose-escalating study. Pharmacol Res Perspect. 2014;2(1):e00020. doi:10.1002/prp2.20
Brandt F, O’Connell C, Cazzaniga A, Waugh JM. Efficacy and safety evaluation of a novel botulinum toxin topical gel for the treatment of moderate to severe lateral canthal lines. Dermatol Surg. 2010;36 Suppl 4:2111-2118. doi:10.1111/j.1524-4725.2010.01711.x
Cirak S, Arechavala-Gomeza V, Guglieri M, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011;378(9791):595-605. doi:10.1016/S0140-6736(11)60756-3
Cousins MJ, Pickthorn K, Huang S, Critchley L, Bell G. The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (εPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design. Pain Med. 2013;14(4):533-540. doi:10.1111/pme.12058
Delfín DA, Xu Y, Peterson JM, Guttridge DC, Rafael-Fortney JA, Janssen PM. Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy. J Transl Med. 2011;9:68. doi:10.1186/1479-5876-9-68
De Coupade C, Fittipaldi A, Chagnas V, et al. Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules. Biochem J. 2005;390(Pt 2):407-418. doi:10.1042/BJ20050401
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 U S A. 2000;97(24):13003-13008. doi:10.1073/pnas.97.24.13003
Tünnemann G, Ter-Avetisyan G, Martin RM, Stöckl M, Herrmann A, Cardoso MC. Live-cell analysis of cell penetration ability and toxicity of oligo-arginines. J Pept Sci. 2008;14(4):469-476. doi:10.1002/psc.968
Koren E, Torchilin VP. Cell-penetrating peptides: breaking through to the other side. Trends Mol Med. 2012;18(7):385-393. doi:10.1016/j.molmed.2012.04.012
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(31):9506-9507. doi:10.1021/ja0482536
Binder H, Lindblom G. Charge-dependent translocation of the Trojan peptide penetratin across lipid membranes. Biophys J. 2003;85(2):982-995. doi:10.1016/S0006-3495(03)74537-8
Futaki S. Oligoarginine vectors for intracellular delivery: design and cellular-uptake mechanisms. Biopolymers. 2006;84(3):241-249. doi:10.1002/bip.20421
Kim GC, Cheon DH, Lee Y. Challenge to overcome current limitations of cell-penetrating peptides. Biochim Biophys Acta Proteins Proteom. 2021;1869(4):140604. doi:10.1016/j.bbapap.2021.140604
Morris MC, Vidal P, Chaloin L, Heitz F, Divita G. A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res. 1997;25(14):2730-2736. doi:10.1093/nar/25.14.2730
Wang T, Wang C, Zheng S, et al. Insight into the Mechanism of Internalization of the Cell-Penetrating Carrier Peptide Pep-1 by Conformational Analysis. J Biomed Nanotechnol. 2020;16(7):1135-1143. doi:10.1166/jbn.2020.2950
Morris MC, Deshayes S, Heitz F, Divita G. Cell-penetrating peptides: from molecular mechanisms to therapeutics. Biol Cell. 2008;100(4):201-217. doi:10.1042/BC20070116
Eiríksdóttir E, Konate K, Langel U, Divita G, Deshayes S. Secondary structure of cell-penetrating peptides controls membrane interaction and insertion. Biochim Biophys Acta. 2010;1798(6):1119-1128. doi:10.1016/j.bbamem.2010.03.005
Crombez L, Aldrian-Herrada G, Konate K, et al. A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Mol Ther. 2009;17(1):95-103. doi:10.1038/mt.2008.215
Elmquist A, Hansen M, Langel U. Structure-activity relationship study of the cell-penetrating peptide pVEC. Biochim Biophys Acta. 2006;1758(6):721-729. doi:10.1016/j.bbamem.2006.05.013
Schmidt S, Adjobo-Hermans MJW, Kohze R, Enderle T, Brock R, Milletti F. Identification of Short Hydrophobic Cell-Penetrating Peptides for Cytosolic Peptide Delivery by Rational Design. Bioconjug Chem. 2017;28(2):382-389. doi:10.1021/acs.bioconjchem.6b00535
Soomets U, Lindgren M, Gallet X, et al. Deletion analogues of transportan. Biochim Biophys Acta. 2000;1467(1):165-176. doi:10.1016/s0005-2736(00)00216-9
Kamide K, Nakakubo H, Uno S, Fukamizu A. Isolation of novel cell-penetrating peptides from a random peptide library using in vitro virus and their modifications. Int J Mol Med. 2010;25(1):41-51.
Sandgren S, Cheng F, Belting M. Nuclear targeting of macromolecular polyanions by an HIV-Tat derived peptide. Role for cell-surface proteoglycans. J Biol Chem. 2002;277(41):38877-38883. doi:10.1074/jbc.M205395200
Ziegler A, Seelig J. Interaction of the protein transduction domain of HIV-1 TAT with heparan sulfate: binding mechanism and thermodynamic parameters. Biophys J. 2004;86(1 Pt 1):254-263. doi:10.1016/S0006-3495(04)74101-6
Gandhi NS, Mancera RL. The structure of glycosaminoglycans and their interactions with proteins. Chem Biol Drug Des. 2008;72(6):455-482. doi:10.1111/j.1747-0285.2008.00741.x
Ghibaudi E, Boscolo B, Inserra G, et al. The interaction of the cell-penetrating peptide penetratin with heparin, heparansulfates and phospholipid vesicles investigated by ESR spectroscopy. J Pept Sci. 2005;11(7):401-409. doi:10.1002/psc.633
Gonçalves E, Kitas E, Seelig J. Binding of oligoarginine to membrane lipids and heparan sulfate: structural and thermodynamic characterization of a cell-penetrating peptide. Biochemistry. 2005;44(7):2692-2702. doi:10.1021/bi048046i
Ponnappan N, Budagavi DP, Chugh A. CyLoP-1: Membrane-active peptide with cell-penetrating and antimicrobial properties. Biochim Biophys Acta Biomembr. 2017;1859(2):167-176. doi:10.1016/j.bbamem.2016.11.002
Console S, Marty C, García-Echeverría C, Schwendener R, Ballmer-Hofer K. 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. 2003;278(37):35109-35114. doi:10.1074/jbc.M301726200
Fuchs SM, Raines RT. Pathway for polyarginine entry into mammalian cells. Biochemistry. 2004;43(9):2438-2444. doi:10.1021/bi035933x
Lin L, Chi J, Yan Y, et al. Membrane-disruptive peptides/peptidomimetics-based therapeutics: Promising systems to combat bacteria and cancer in the drug-resistant era. Acta Pharm Sin B. 2021;11(9):2609-2644. doi:10.1016/j.apsb.2021.07.014
Mäler L. Solution NMR studies of cell-penetrating peptides in model membrane systems. Adv Drug Deliv Rev. 2013;65(8):1002-1011. doi:10.1016/j.addr.2012.10.011
Marion D, Zasloff M, Bax A. A two-dimensional NMR study of the antimicrobial peptide magainin 2. FEBS Lett. 1988;227(1):21-26. doi:10.1016/0014-5793(88)81405-4
Williamson JA, Loria JP, Miranker AD. Helix stabilization precedes aqueous and bilayer-catalyzed fiber formation in islet amyloid polypeptide. J Mol Biol. 2009;393(2):383-396. doi:10.1016/j.jmb.2009.07.077
Butterfield SM, Lashuel HA. Amyloidogenic Protein-Membrane Interactions: Mechanistic Insight from Model Systems. Angewandte Chemie International Edition. 2010;49(33):5628-5654. doi:10.1002/anie.200906670
Epand RM, Vogel HJ. Diversity of antimicrobial peptides and their mechanisms of action. Biochim Biophys Acta. 1999;1462(1-2):11-28. doi:10.1016/s0005-2736(99)00198-4
Huang HW. Molecular mechanism of antimicrobial peptides: the origin of cooperativity. Biochim Biophys Acta. 2006;1758(9):1292-1302. doi:10.1016/j.bbamem.2006.02.001
Jao CC, Hegde BG, Chen J, Haworth IS, Langen R. Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement. Proc Natl Acad Sci U S A. 2008;105(50):19666-19671. doi:10.1073/pnas.0807826105
Shin MC, Zhang J, Min KA, et al. Cell-penetrating peptides: achievements and challenges in application for cancer treatment. J Biomed Mater Res A. 2014;102(2):575-587. doi:10.1002/jbm.a.34859
Cleal K, He L, Watson PD, Jones AT. Endocytosis, intracellular traffic and fate of cell penetrating peptide based conjugates and nanoparticles. Curr Pharm Des. 2013;19(16):2878-2894. doi:10.2174/13816128113199990297
Säälik P, Padari K, Niinep A, et al. Protein delivery with transportans is mediated by caveolae rather than flotillin-dependent pathways. Bioconjug Chem. 2009;20(5):877-887. doi:10.1021/bc800416f
Khan MA, Wu VM, Ghosh S, Uskoković V. Gene delivery using calcium phosphate nanoparticles: Optimization of the transfection process and the effects of citrate and poly(l-lysine) as additives. J Colloid Interface Sci. 2016;471:48-58. doi:10.1016/j.jcis.2016.03.007
Ruseska I, Zimmer A. Internalization mechanisms of cell-penetrating peptides. Beilstein J Nanotechnol. 2020;11:101-123. doi:10.3762/bjnano.11.10
Bevers EM, Comfurius P, Dekkers DW, Harmsma M, Zwaal RF. Regulatory mechanisms of transmembrane phospholipid distributions and pathophysiological implications of transbilayer lipid scrambling. Lupus. 1998;7 Suppl 2:S126-131. doi:10.1177/096120339800700228
Gaspar D, Veiga AS, Castanho MARB. From antimicrobial to anticancer peptides. A review. Front Microbiol. 2013;4:294. doi:10.3389/fmicb.2013.00294
Tan J, Tay J, Hedrick J, Yang YY. Synthetic macromolecules as therapeutics that overcome resistance in cancer and microbial infection. Biomaterials. 2020;252:120078. doi:10.1016/j.biomaterials.2020.120078
Li X, Shen B, Chen Q, et al. Antitumor effects of cecropin B-LHRH’ on drug-resistant ovarian and endometrial cancer cells. BMC Cancer. 2016;16:251. doi:10.1186/s12885-016-2287-0
Deslouches B, Di YP. Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications. Oncotarget. 2017;8(28):46635-46651. doi:10.18632/oncotarget.16743
Duclohier H, Molle G, Spach G. Antimicrobial peptide magainin I from Xenopus skin forms anion-permeable channels in planar lipid bilayers. Biophys J. 1989;56(5):1017-1021. doi:10.1016/S0006-3495(89)82746-8
Gallucci E, Meleleo D, Micelli S, Picciarelli V. Magainin 2 channel formation in planar lipid membranes: the role of lipid polar groups and ergosterol. Eur Biophys J. 2003;32(1):22-32. doi:10.1007/s00249-002-0262-y
Zhang L, Rozek A, Hancock RE. Interaction of cationic antimicrobial peptides with model membranes. J Biol Chem. 2001;276(38):35714-35722. doi:10.1074/jbc.M104925200
Bimbo LM, Peltonen L, Hirvonen J, Santos HA. Toxicological profile of therapeutic nanodelivery systems. Curr Drug Metab. 2012;13(8):1068-1086. doi:10.2174/138920012802850047
Ma N, Ma C, Li C, et al. Influence of nanoparticle shape, size, and surface functionalization on cellular uptake. J Nanosci Nanotechnol. 2013;13(10):6485-6498. doi:10.1166/jnn.2013.7525
Nakase I, Akita H, Kogure K, et al. Efficient intracellular delivery of nucleic acid pharmaceuticals using cell-penetrating peptides. Acc Chem Res. 2012;45(7):1132-1139. doi:10.1021/ar200256e
Treuel L, Jiang X, Nienhaus GU. New views on cellular uptake and trafficking of manufactured nanoparticles. J R Soc Interface. 2013;10(82):20120939. doi:10.1098/rsif.2012.0939
Erazo-Oliveras A, Muthukrishnan N, Baker R, Wang TY, Pellois JP. Improving the endosomal escape of cell-penetrating peptides and their cargos: strategies and challenges. Pharmaceuticals (Basel). 2012;5(11):1177-1209. doi:10.3390/ph5111177
Yang ST, Zaitseva E, Chernomordik LV, Melikov K. Cell-penetrating peptide induces leaky fusion of liposomes containing late endosome-specific anionic lipid. Biophys J. 2010;99(8):2525-2533. doi:10.1016/j.bpj.2010.08.029
El-Sayed A, Futaki S, Harashima H. Delivery of macromolecules using arginine-rich cell-penetrating peptides: ways to overcome endosomal entrapment. AAPS J. 2009;11(1):13-22. doi:10.1208/s12248-008-9071-2
Ladokhin AS, White SH. “Detergent-like” permeabilization of anionic lipid vesicles by melittin. Biochim Biophys Acta. 2001;1514(2):253-260. doi:10.1016/s0005-2736(01)00382-0
Lee MT, Chen FY, Huang HW. Energetics of pore formation induced by membrane active peptides. Biochemistry. 2004;43(12):3590-3599. doi:10.1021/bi036153r
Naito A, Nagao T, Norisada K, Mizuno T, Tuzi S, Saitô H. Conformation and dynamics of melittin bound to magnetically oriented lipid bilayers by solid-state (31)P and (13)C NMR spectroscopy. Biophys J. 2000;78(5):2405-2417. doi:10.1016/S0006-3495(00)76784-1
Vogel H, Jähnig F. The structure of melittin in membranes. Biophys J. 1986;50(4):573-582. doi:10.1016/S0006-3495(86)83497-X
Meyer M, Zintchenko A, Ogris M, Wagner E. A dimethylmaleic acid-melittin-polylysine conjugate with reduced toxicity, pH-triggered endosomolytic activity and enhanced gene transfer potential. J Gene Med. 2007;9(9):797-805. doi:10.1002/jgm.1075
Jones CH, Chen CK, Ravikrishnan A, Rane S, Pfeifer BA. Overcoming nonviral gene delivery barriers: perspective and future. Mol Pharm. 2013;10(11):4082-4098. doi:10.1021/mp400467x
Juliano R, Bauman J, Kang H, Ming X. Biological barriers to therapy with antisense and siRNA oligonucleotides. Mol Pharm. 2009;6(3):686-695. doi:10.1021/mp900093r
Khalil IA, Harashima H. An efficient PEGylated gene delivery system with improved targeting: Synergism between octaarginine and a fusogenic peptide. Int J Pharm. 2018;538(1-2):179-187. doi:10.1016/j.ijpharm.2018.01.007
Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009;8(2):129-138. doi:10.1038/nrd2742
Tarvirdipour S, Huang X, Mihali V, Schoenenberger CA, Palivan CG. Peptide-Based Nanoassemblies in Gene Therapy and Diagnosis: Paving the Way for Clinical Application. Molecules. 2020;25(15):3482. doi:10.3390/molecules25153482
Luan L, Meng Q, Xu L, Meng Z, Yan H, Liu K. Peptide amphiphiles with multifunctional fragments promoting cellular uptake and endosomal escape as efficient gene vectors. J Mater Chem B. 2015;3(6):1068-1078. doi:10.1039/c4tb01353k
Meng Z, Kang Z, Sun C, et al. Enhanced gene transfection efficiency by use of peptide vectors containing laminin receptor-targeting sequence YIGSR. Nanoscale. 2018;10(3):1215-1227. doi:10.1039/c7nr05843h
Meng Z, Luan L, Kang Z, Feng S, Meng Q, Liu K. Histidine-enriched multifunctional peptide vectors with enhanced cellular uptake and endosomal escape for gene delivery. J Mater Chem B. 2017;5(1):74-84. doi:10.1039/c6tb02862d
Wang T, Zou C, Wen N, et al. The effect of structural modification of antimicrobial peptides on their antimicrobial activity, hemolytic activity, and plasma stability. J Pept Sci. 2021;27(5):e3306. doi:10.1002/psc.3306
Yang S, Meng Z, Kang Z, et al. The structure and configuration changes of multifunctional peptide vectors enhance gene delivery efficiency. RSC Adv. 2018;8(50):28356-28366. doi:10.1039/c8ra04101f
Mishra S, Webster P, Davis ME. PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur J Cell Biol. 2004;83(3):97-111. doi:10.1078/0171-9335-00363
Kang Z, Meng Q, Liu K. Peptide-based gene delivery vectors. J Mater Chem B. 2019;7(11):1824-1841. doi:10.1039/c8tb03124j
Alhakamy NA, Nigatu AS, Berkland CJ, Ramsey JD. Noncovalently associated cell-penetrating peptides for gene delivery applications. Ther Deliv. 2013;4(6):741-757. doi:10.4155/tde.13.44
Pack DW, Hoffman AS, Pun S, Stayton PS. Design and development of polymers for gene delivery. Nat Rev Drug Discov. 2005;4(7):581-593. doi:10.1038/nrd1775
Avila LA, Aps LRMM, Sukthankar P, et al. Branched amphiphilic cationic oligopeptides form peptiplexes with DNA: a study of their biophysical properties and transfection efficiency. Mol Pharm. 2015;12(3):706-715. doi:10.1021/mp500524s
Mandal H, Katiyar SS, Swami R, et al. ε-Poly-l-Lysine/plasmid DNA nanoplexes for efficient gene delivery in vivo. Int J Pharm. 2018;542(1-2):142-152. doi:10.1016/j.ijpharm.2018.03.021
Walsh DP, Raftery RM, Castaño IM, et al. Transfection of autologous host cells in vivo using gene activated collagen scaffolds incorporating star-polypeptides. J Control Release. 2019;304:191-203. doi:10.1016/j.jconrel.2019.05.009
Ziady AG, Gedeon CR, Miller T, et al. Transfection of airway epithelium by stable PEGylated poly-L-lysine DNA nanoparticles in vivo. Mol Ther. 2003;8(6):936-947. doi:10.1016/j.ymthe.2003.07.007
Wang G, Gao X, Gu G, et al. Polyethylene glycol-poly(ε-benzyloxycarbonyl-l-lysine)-conjugated VEGF siRNA for antiangiogenic gene therapy in hepatocellular carcinoma. Int J Nanomedicine. 2017;12:3591-3603. doi:10.2147/IJN.S131078
Midoux P, Breuzard G, Gomez JP, Pichon C. Polymer-based gene delivery: a current review on the uptake and intracellular trafficking of polyplexes. Curr Gene Ther. 2008;8(5):335-352. doi:10.2174/156652308786071014
Loughran SP, McCrudden CM, McCarthy HO. Designer peptide delivery systems for gene therapy. European Journal of Nanomedicine. 2015;7(2):85-96. doi:10.1515/ejnm-2014-0037
van Rossenberg SMW, van Keulen ACI, Drijfhout JW, et al. Stable polyplexes based on arginine-containing oligopeptides for in vivo gene delivery. Gene Ther. 2004;11(5):457-464. doi:10.1038/sj.gt.3302183
Kim HH, Choi HS, Yang JM, Shin S. Characterization of gene delivery in vitro and in vivo by the arginine peptide system. Int J Pharm. 2007;335(1-2):70-78. doi:10.1016/j.ijpharm.2006.11.017
Ul Ain Q, Chung H, Chung JY, Choi JH, Kim YH. Amelioration of atherosclerotic inflammation and plaques via endothelial adrenoceptor-targeted eNOS gene delivery using redox-sensitive polymer bearing l-arginine. J Control Release. 2017;262:72-86. doi:10.1016/j.jconrel.2017.07.019
Won YW, Kim HA, Lee M, Kim YH. Reducible poly(oligo-D-arginine) for enhanced gene expression in mouse lung by intratracheal injection. Mol Ther. 2010;18(4):734-742. doi:10.1038/mt.2009.297
Woo J, Bae SH, Kim B, et al. Cardiac Usage of Reducible Poly(oligo-D-arginine) As a Gene Carrier for Vascular Endothelial Growth Factor Expression. PLoS One. 2015;10(12):e0144491. doi:10.1371/journal.pone.0144491
Johnson LN, Cashman SM, Kumar-Singh R. Cell-penetrating peptide for enhanced delivery of nucleic acids and drugs to ocular tissues including retina and cornea. Mol Ther. 2008;16(1):107-114. doi:10.1038/sj.mt.6300324
Kesharwani P, Iyer AK. Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery. Drug Discov Today. 2015;20(5):536-547. doi:10.1016/j.drudis.2014.12.012
Torchilin VP. Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery. Biopolymers. 2008;90(5):604-610. doi:10.1002/bip.20989
Luo K, Li C, Li L, She W, Wang G, Gu Z. Arginine functionalized peptide dendrimers as potential gene delivery vehicles. Biomaterials. 2012;33(19):4917-4927. doi:10.1016/j.biomaterials.2012.03.030
Kozhikhova KV, Andreev SM, Shilovskiy IP, et al. A novel peptide dendrimer LTP efficiently facilitates transfection of mammalian cells. Org Biomol Chem. 2018;16(43):8181-8190. doi:10.1039/c8ob02039f
Yoo J, Lee D, Gujrati V, et al. Bioreducible branched poly(modified nona-arginine) cell-penetrating peptide as a novel gene delivery platform. J Control Release. 2017;246:142-154. doi:10.1016/j.jconrel.2016.04.040
Tang M, Dong H, Li Y, Ren T. Harnessing the PEG-cleavable strategy to balance cytotoxicity, intracellular release and the therapeutic effect of dendrigraft poly-l-lysine for cancer gene therapy. J Mater Chem B. 2016;4(7):1284-1295. doi:10.1039/c5tb02224j
Lehto T, Simonson OE, Mäger I, et al. A peptide-based vector for efficient gene transfer in vitro and in vivo. Mol Ther. 2011;19(8):1457-1467. doi:10.1038/mt.2011.10
Andaloussi SEL, Lehto T, Mäger I, et al. Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo. Nucleic Acids Res. 2011;39(9):3972-3987. doi:10.1093/nar/gkq1299
Aldrian G, Vaissière A, Konate K, et al. PEGylation rate influences peptide-based nanoparticles mediated siRNA delivery in vitro and in vivo. J Control Release. 2017;256:79-91. doi:10.1016/j.jconrel.2017.04.012
Rittner K, Benavente A, Bompard-Sorlet A, et al. New basic membrane-destabilizing peptides for plasmid-based gene delivery in vitro and in vivo. Mol Ther. 2002;5(2):104-114. doi:10.1006/mthe.2002.0523
Liu Y, Song Z, Zheng N, Nagasaka K, Yin L, Cheng J. Systemic siRNA delivery to tumors by cell-penetrating α-helical polypeptide-based metastable nanoparticles. Nanoscale. 2018;10(32):15339-15349. doi:10.1039/c8nr03976c
He H, Zheng N, Song Z, et al. Suppression of Hepatic Inflammation via Systemic siRNA Delivery by Membrane-Disruptive and Endosomolytic Helical Polypeptide Hybrid Nanoparticles. ACS Nano. 2016;10(2):1859-1870. doi:10.1021/acsnano.5b05470
Xiang S, Tong H, Shi Q, et al. Uptake mechanisms of non-viral gene delivery. J Control Release. 2012;158(3):371-378. doi:10.1016/j.jconrel.2011.09.093
Liu J, Guo N, Gao C, et al. Effective Gene Silencing Mediated by Polypeptide Nanoparticles LAH4-L1-siMDR1 in Multi-Drug Resistant Human Breast Cancer. J Biomed Nanotechnol. 2019;15(3):531-543. doi:10.1166/jbn.2019.2705
Zhu H, Dong C, Dong H, et al. Cleavable PEGylation and hydrophobic histidylation of polylysine for siRNA delivery and tumor gene therapy. ACS Appl Mater Interfaces. 2014;6(13):10393-10407. doi:10.1021/am501928p
Zhou J, Zhao Y, Simonenko V, et al. Simultaneous silencing of TGF-β1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis. Oncotarget. 2017;8(46):80651-80665. doi:10.18632/oncotarget.20869
Tai Z, Wang X, Tian J, et al. Biodegradable stearylated peptide with internal disulfide bonds for efficient delivery of siRNA in vitro and in vivo. Biomacromolecules. 2015;16(4):1119-1130. doi:10.1021/bm501777a
Yao C, Liu J, Wu X, et al. Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy. J Control Release. 2016;232:203-214. doi:10.1016/j.jconrel.2016.04.034
Khatibi S, Modaresi M, Kazemi Oskuee R, Salehi M, Aghaee-Bakhtiari SH. Genetic modification of cystic fibrosis with ΔF508 mutation of CFTR gene using the CRISPR system in peripheral blood mononuclear cells. Iran J Basic Med Sci. 2021;24(1):73-78. doi:10.22038/ijbms.2020.50051.11415
Zhou Y, Han S, Liang Z, Zhao M, Liu G, Wu J. Progress in arginine-based gene delivery systems. J Mater Chem B. 2020;8(26):5564-5577. doi:10.1039/d0tb00498g
Yong SB, Kim HJ, Kim JK, Chung JY, Kim YH. Human CD64-targeted non-viral siRNA delivery system for blood monocyte gene modulation. Sci Rep. 2017;7:42171. doi:10.1038/srep42171
Manunta MDI, Tagalakis AD, Attwood M, et al. Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis. Sci Rep. 2017;7(1):700. doi:10.1038/s41598-017-00662-2
Amin M, Mansourian M, Koning GA, Badiee A, Jaafari MR, Ten Hagen TLM. Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region. J Control Release. 2015;220(Pt A):308-315. doi:10.1016/j.jconrel.2015.10.039
Adil MM, Erdman ZS, Kokkoli E. Transfection mechanisms of polyplexes, lipoplexes, and stealth liposomes in α₅β₁ integrin bearing DLD-1 colorectal cancer cells. Langmuir. 2014;30(13):3802-3810. doi:10.1021/la5001396
Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev. 2008;60(15):1615-1626. doi:10.1016/j.addr.2008.08.005
Yang H, Li Y, Li T, et al. Multifunctional core/shell nanoparticles cross-linked polyetherimide-folic acid as efficient Notch-1 siRNA carrier for targeted killing of breast cancer. Sci Rep. 2014;4:7072. doi:10.1038/srep07072
Komin A, Russell LM, Hristova KA, Searson PC. Peptide-based strategies for enhanced cell uptake, transcellular transport, and circulation: Mechanisms and challenges. Adv Drug Deliv Rev. 2017;110-111:52-64. doi:10.1016/j.addr.2016.06.002
Kumar P, Wu H, McBride JL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007;448(7149):39-43. doi:10.1038/nature05901
Georgieva JV, Hoekstra D, Zuhorn IS. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier. Pharmaceutics. 2014;6(4):557-583. doi:10.3390/pharmaceutics6040557
Huang S, Li J, Han L, et al. Dual targeting effect of Angiopep-2-modified, DNA-loaded nanoparticles for glioma. Biomaterials. 2011;32(28):6832-6838. doi:10.1016/j.biomaterials.2011.05.064
Somani S, Blatchford DR, Millington O, Stevenson ML, Dufès C. Transferrin-bearing polypropylenimine dendrimer for targeted gene delivery to the brain. J Control Release. 2014;188:78-86. doi:10.1016/j.jconrel.2014.06.006
Vadevoo SMP, Gurung S, Khan F, et al. Peptide-based targeted therapeutics and apoptosis imaging probes for cancer therapy. Arch Pharm Res. 2019;42(2):150-158. doi:10.1007/s12272-019-01125-0
de Araujo CB, Heimann AS, Remer RA, et al. Intracellular Peptides in Cell Biology and Pharmacology. Biomolecules. 2019;9(4):150. doi:10.3390/biom9040150
de Araujo CB, Russo LC, Castro LM, et al. A novel intracellular peptide derived from g1/s cyclin d2 induces cell death. J Biol Chem. 2014;289(24):16711-16726. doi:10.1074/jbc.M113.537118
Wh L, D S. Role of the p16 tumor suppressor gene in cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1998;16(3). doi:10.1200/JCO.1998.16.3.1197
Snyder EL, Meade BR, Saenz CC, Dowdy SF. Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. PLoS Biol. 2004;2(2):E36. doi:10.1371/journal.pbio.0020036
Hosotani R, Miyamoto Y, Fujimoto K, et al. Trojan p16 peptide suppresses pancreatic cancer growth and prolongs survival in mice. Clin Cancer Res. 2002;8(4):1271-1276.
Fulda S, Wick W, Weller M, Debatin KM. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med. 2002;8(8):808-815. doi:10.1038/nm735
Vucic D, Deshayes K, Ackerly H, et al. SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). J Biol Chem. 2002;277(14):12275-12279. doi:10.1074/jbc.M112045200
Stirpe F, Olsnes S, Pihl A. Gelonin, a new inhibitor of protein synthesis, nontoxic to intact cells. Isolation, characterization, and preparation of cytotoxic complexes with concanavalin A. J Biol Chem. 1980;255(14):6947-6953.
Park YJ, Chang LC, Liang JF, Moon C, Chung CP, Yang VC. Nontoxic membrane translocation peptide from protamine, low molecular weight protamine (LMWP), for enhanced intracellular protein delivery: in vitro and in vivo study. FASEB J. 2005;19(11):1555-1557. doi:10.1096/fj.04-2322fje
Kim HY, Kim S, Youn H, Chung JK, Shin DH, Lee K. The cell penetrating ability of the proapoptotic peptide, KLAKLAKKLAKLAK fused to the N-terminal protein transduction domain of translationally controlled tumor protein, MIIYRDLISH. Biomaterials. 2011;32(22):5262-5268. doi:10.1016/j.biomaterials.2011.03.074
Yin J, Liu D, Bao L, et al. Tumor targeting and microenvironment-responsive multifunctional fusion protein for pro-apoptotic peptide delivery. Cancer Lett. 2019;452:38-50. doi:10.1016/j.canlet.2019.03.016
Diener C, Garza Ramos Martínez G, Moreno Blas D, et al. Effective Design of Multifunctional Peptides by Combining Compatible Functions. PLoS Comput Biol. 2016;12(4):e1004786. doi:10.1371/journal.pcbi.1004786
Gronewold A, Horn M, Ranđelović I, et al. Characterization of a Cell-Penetrating Peptide with Potential Anticancer Activity. ChemMedChem. 2017;12(1):42-49. doi:10.1002/cmdc.201600498
Wang K rong, Yan J xi, Zhang B zhi, Song J jing, Jia P fei, Wang R. Novel mode of action of polybia-MPI, a novel antimicrobial peptide, in multi-drug resistant leukemic cells. Cancer Lett. 2009;278(1):65-72. doi:10.1016/j.canlet.2008.12.027
Wang K rong, Zhang B zhi, Zhang W, Yan J xi, Li J, Wang R. Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides. 2008;29(6):963-968. doi:10.1016/j.peptides.2008.01.015
Fázio MA, Jouvensal L, Vovelle F, et al. Biological and structural characterization of new linear gomesin analogues with improved therapeutic indices. Biopolymers. 2007;88(3):386-400. doi:10.1002/bip.20660
Sinthuvanich C, Veiga AS, Gupta K, Gaspar D, Blumenthal R, Schneider JP. Anticancer β-hairpin peptides: membrane-induced folding triggers activity. J Am Chem Soc. 2012;134(14):6210-6217. doi:10.1021/ja210569f
Liu S, Yang H, Wan L, Cheng J, Lu X. Penetratin-mediated delivery enhances the antitumor activity of the cationic antimicrobial peptide Magainin II. Cancer Biother Radiopharm. 2013;28(4):289-297. doi:10.1089/cbr.2012.1328
Thankappan B, Sivakumar J, Asokan S, et al. Dual antimicrobial and anticancer activity of a novel synthetic α-helical antimicrobial peptide. Eur J Pharm Sci. 2021;161:105784. doi:10.1016/j.ejps.2021.105784
Wang C, Zhou Y, Li S, et al. Anticancer mechanisms of temporin-1CEa, an amphipathic α-helical antimicrobial peptide, in Bcap-37 human breast cancer cells. Life Sci. 2013;92(20-21):1004-1014. doi:10.1016/j.lfs.2013.03.016
Xu H, Chen CX, Hu J, et al. Dual modes of antitumor action of an amphiphilic peptide A(9)K. Biomaterials. 2013;34(11):2731-2737. doi:10.1016/j.biomaterials.2012.12.039
Eliassen LT, Berge G, Leknessund A, et al. The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo. Int J Cancer. 2006;119(3):493-500. doi:10.1002/ijc.21886
Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I. Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Jpn J Cancer Res. 1997;88(2):184-190. doi:10.1111/j.1349-7006.1997.tb00364.x
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