There is a pressing need for more effective and selective therapies for cancer and other diseases. Consequently, much effort is being devoted to the development of alternative experimental approaches based on selective systems, which are designed to be specifically directed against target cells. In addition, a large number of highly potent therapeutic molecules are being discovered. However, they do not reach clinical trials because of their low delivery, poor specificity or their incapacity to bypass the plasma membrane. Cell-penetrating peptides (CPPs) are an open door for cell-impermeable compounds to reach intracellular targets. Putting all these together, research is sailing in the direction of the design of systems with the capacity to transport new drugs into a target cell. Some CPPs show cell type specificity while others require modifications or form part of more sophisticated drug delivery systems. In this review article we summarize several strategies for directed drug delivery involving CPPs that have been reported in the literature.
References
[1]
Hassane, F.S.; Saleh, A.; Abes, R.; Gait, M.; Lebleu, B. Cell-penetrating-peptides: Overview and applications to the delivery of oligonucleotides. Cell. Mol. Life Sci.?2009, 715–726.
[2]
Andaloussi, S.E.; Guterstam, P.; Langel, U. Assessing the delivery efficacy and internalization route of cell-penetrating peptides. Nat. Protocols?2007, 2, 2043–2047.
[3]
Pujals, S.; Fernandez-Carneado, J.; Kogan, M.J.; Martinez, J.; Cavelier, F.; Giralt, E. Replacement of a proline with silaproline causes a 20-fold increase in the cellular uptake of a pro-rich peptide. J. Am. Chem. Soc.?2006, 128, 8479–8483.
Endoh, T.; Ohtsuki, T. Cellular siRNA delivery using cell-penetrating peptides modified for endosomal escape. Adv. Drug Delivery Rev.?2009, 61, 704–709.
Fukuda, M.N.; Ohyama, C.; Lowitz, K.; Matsuo, O.; Pasqualini, R.; Ruoslahti, E.; Fukuda, M. A peptide mimic of E-selectin ligand inhibits Sialyl Lewis X-dependent lung colonization of tumor cells. Cancer Res.?2000, 60, 450–456. 10667600
[15]
Wang, X.; Cao, B.B. Screening of specific internalization Fab fragment from Human Naive Phage Library by combinational bio-panning. Methods Mol. Biol.?2009, 525, 161–174, doi:10.1007/978-1-59745-554-1_8. 19252831
[16]
Kolonin, M.; Pasqualini, R.; Arap, W. Molecular addresses in blood vessels as targets for therapy. Curr. Opin. Chem. Biol.?2001, 5, 308–313.
[17]
Laakkonen, P.; Zhang, L.; Ruoslahti, E. Peptide targeting of tumor lymph vessels. Ann. N. Y. Acad. Sci.?2008, 1131, 37–43.
[18]
Gehlsen, K.; Argraves, W.; Pierschbacher, M.; Ruoslahti, E. Inhibition of in vitro tumor cell invasion by Arg-Gly-Asp-containing synthetic peptides. J. Cell Biol.?1988, 106, 925–930, doi:10.1083/jcb.106.3.925. 2450101
[19]
Paolillo, M.; Russo, M.A.; Serra, M.; Colombo, L.; Schinelli, S. Small molecule integrin antagonists in cancer therapy. Mini-Rev. Med. Chem.?2009, 9, 1439–1446, doi:10.2174/138955709789957404. 19929817
[20]
Lucie, S.; Elisabeth, G.; Stephanie, F.; Guy, S.; Amandine, H.; Corinne, A.-R.; Didier, B.; Catherine, S.; Alexei, G.; Pascal, D.; Jean-Luc, C. Clustering and internalization of Integrin αvβ3 with a tetrameric RGD-synthetic peptide. Mol. Ther.?2009, 17, 837–843.
[21]
Dumy, P.; Eggleston, I.M.; Cervigni, S.; Sila, U.; Sun, X.; Mutter, M. A convenient synthesis of cyclic peptides as regioselectively addressable functionalized templates (RAFT). Tetrahedron Lett.?1995, 36, 1255–1258.
[22]
Koivunen, E.; Gay, D.A.; Ruoslahti, E. Selection of peptides binding to the alpha 5 beta 1 integrin from phage display library. J. Biol. Chem.?1993, 268, 20205–20210. 7690752
[23]
Pasqualini, R.; Koivunen, E.; Kain, R.; Lahdenranta, J.; Sakamoto, M.; Stryhn, A.; Ashmun, R. A.; Shapiro, L.H.; Arap, W.; Ruoslahti, E. Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res.?2000, 60, 722–727. 10676659
[24]
Corti, A.; Curnis, F.; Arap, W.; Pasqualini, R. The neovasculature homing motif NGR: More than meets the eye. Blood?2008, 112, 2628–2635.
[25]
Arap, W.; Pasqualini, R.; Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science?1998, 279, 377–380.
[26]
Pastorino, F.; Brignole, C.; Di Paolo, D.; Nico, B.; Pezzolo, A.; Marimpietri, D.; Pagnan, G.; Piccardi, F.; Cilli, M.; Longhi, R.; Ribatti, D.; Corti, A.; Allen, T.M.; Ponzoni, M. Targeting liposomal chemotherapy via both tumor cell-specific and tumor vasculature-specific ligands potentiates therapeutic efficacy. Cancer Res.?2006, 66, 10073–10082. 17047071
[27]
Pastorino, F.; Brignole, C.; Marimpietri, D.; Cilli, M.; Gambini, C.; Ribatti, D.; Longhi, R.; Allen, T.M.; Corti, A.; Ponzoni, M. Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Res.?2003, 63, 7400–7409. 14612539
Lemeshko, V.V. Potential-dependent membrane permeabilization and mitochondrial aggregation caused by anticancer polyarginine-KLA peptides. Arch. Biochem. Biophys.?2009. in press.
[31]
Sacchi, A.; Gasparri, A.; Curnis, F.; Bellone, M.; Corti, A. Crucial role for interferon γ in the synergism between tumor vasculature-targeted tumor necrosis factor-α (NGR-TNF) and doxorubicin. Cancer Res.?2004, 64, 7150–7155.
[32]
Angelo, C.; Mirco, P. Tumor vascular targeting with Tumor Necrosis Factor α and chemotherapeutic drugs. Ann. N. Y. Acad. Sci.?2004, 1028, 104–112, doi:10.1196/annals.1322.011.
[33]
Curnis, F.; Sacchi, A.; Corti, A. Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J. Clin. Invest.?2002, 110, 475–482.
[34]
Zarovni, N.; Monaco, L.; Corti, A. Inhibition of tumor growth by intramuscular injection of cDNA encoding Tumor Necrosis Factor α coupled to NGR and RGD tumor-homing peptides. Hum. Gene Ther.?2004, 15, 373–382.
[35]
Sacchi, A.; Gasparri, A.; Gallo-Stampino, C.; Toma, S.; Curnis, F.; Corti, A. Synergistic antitumor activity of Cisplatin, Paclitaxel, and Gemcitabine with tumor vasculature-targeted Tumor Necrosis Factor α. Clin. Cancer Res.?2006, 12, 175–182, doi:10.1158/1078-0432.CCR-05-1147. 16397040
[36]
Yumi, Y.; Sundaram, R. Addition of an aminopeptidase N-binding sequence to human endostatin improves inhibition of ovarian carcinoma growth. Cancer?2005, 104, 321–331.
[37]
Meng, J.; Ma, N.; Yan, Z.; Han, W.; Zhang, Y. NGR enhanced the anti-angiogenic activity of tum-5. J. Biochem.?2006, 140, 299–304.
[38]
Meng, J.; Yan, Z.; Wu, J.; Li, L.; Xue, X.; Li, M.; Li, W.; Hao, Q.; Wan, Y.; Qin, X.; Zhang, C.; You, Y.; Han, W.; Zhang, Y. High-yield expression, purification and characterization of tumor-targeted IFN-α2a. Cytotherapy?2007, 9, 60–68.
[39]
Curnis, F.; Gasparri, A.; Sacchi, A.; Cattaneo, A.; Magni, F.; Corti, A. Targeted delivery of IFN-γ to tumor vessels uncouples antitumor from counterregulatory mechanisms. Cancer Res.?2005, 65, 2906–2913.
Porkka, K.; Laakkonen, P.; Hoffman, J.A.; Bernasconi, M.; Ruoslahti, E. A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo. Proc. Natl. Acad. Sci. USA?2002, 99, 7444–7449.
[42]
Bustin, M. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol. Cell. Biol.?1999, 19, 5237–5246.
[43]
Hurley, L.H. DNA and its associated processes as targets for cancer therapy. Nat. Rev. Cancer.?2002, 2, 188–200, doi:10.1038/nrc749. 11990855
[44]
Hong, F.D.; Clayman, G.L. Isolation of a peptide for targeted drug delivery into human head and neck solid tumors. Cancer Res.?2000, 60, 6551–6556. 11118031
[45]
Hoekman, K.; van der Vijgh, W.J.F.; Vermorken, J.B. Clinical and preclinical modulation of chemotherapy-induced toxicity in patients with cancer. Drugs?1999, 57, 133–155, doi:10.2165/00003495-199957020-00002. 10188757
[46]
Kim, Y.; Lillo, A.M.; Steiniger, S.C.J.; Liu, Y.; Ballatore, C.; Anichini, A.; Mortarini, R.; Kaufmann, G.F.; Zhou, B.; Felding-Habermann, B.; Janda, K.D. Targeting Heat Shock Proteins on cancer cells: Selection, characterization, and cell-penetrating properties of a peptidic GRP78 ligand. Biochemistry?2006, 45, 9434–9444. 16878978
[47]
Liu, Y.; Steiniger, S.C.J.; Kim, Y.; Kaufmann, G.F.; Felding-Habermann, B.; Janda, K.D. Mechanistic studies of a peptidic GRP78 ligand for cancer cell-specific drug delivery. Mol. Pharmaceutics?2007, 4, 435–447, doi:10.1021/mp060122j.
[48]
Lee, A.S. The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem. Sci.?2001, 26, 504–510, doi:10.1016/S0968-0004(01)01908-9. 11504627
[49]
Lee, A.S. GRP78 induction in cancer: Therapeutic and prognostic implications. Cancer Res.?2007, 67, 3496–3499, doi:10.1158/0008-5472.CAN-07-0325. 17440054
[50]
Zhang, J.; Jiang, Y.; Jia, Z.; Li, Q.; Gong, W.; Wang, L.; Wei, D.; Yao, J.; Fang, S.; Xie, K. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin. Exp. Metastasis?2006, 23, 401–410.
Dubowchik, G.M.; Firestone, R.A. Cathepsin B-sensitive dipeptide prodrugs. 1. A model study of structural requirements for efficient release of doxorubicin. Bioorg. Med. Chem. Lett.?1998, 8, 3341–3346, doi:10.1016/S0960-894X(98)00609-X. 9873731
[53]
Arap, W.; Haedicke, W.; Bernasconi, M.; Kain, R.; Rajotte, D.; Krajewski, S.; Ellerby, H.M.; Bredesen, D.E.; Pasqualini, R.; Ruoslahti, E. Targeting the prostate for destruction through a vascular address. Proc. Natl. Acad. Sci. USA?2002, 99, 1527–1531.
[54]
Gingrich, J.R.; Barrios, R.J.; Morton, R.A.; Boyce, B.F.; DeMayo, F.J.; Finegold, M.J.; Angelopoulou, R.; Rosen, J.M.; Greenberg, N.M. Metastatic prostate cancer in a transgenic mouse. Cancer Res.?1996, 56, 4096–4102. 8797572
[55]
Tohru, Y.; Arsenio, M.F.; Vasu, P.; Laura, B.; Tapas, K.D.G.; Ananda, M.C. Internalization of bacterial redox protein azurin in mammalian cells: Entry domain and specificity. Cell. Microbiol.?2005, 7, 1418–1431, doi:10.1111/j.1462-5822.2005.00567.x. 16153242
[56]
Taylor, B.N.; Mehta, R.R.; Yamada, T.; Lekmine, F.; Christov, K.; Chakrabarty, A.M.; Green, A.; Bratescu, L.; Shilkaitis, A.; Beattie, C.W.; Das Gupta, T.K. Noncationic peptides obtained from Azurin preferentially enter cancer cells. Cancer Res.?2009, 69, 537–546. 19147567
[57]
Chaudhari, A.; Mahfouz, M.; Fialho, A.M.; Yamada, T.; Granja, A.T.; Zhu, Y.; Hashimoto, W.; Schlarb-Ridley, B.; Cho, W.; Gupta, T.K.D.; Chakrabarty, A.M. Cupredoxin-cancer interrelationship: Azurin binding with EphB2, interference in EphB2 tyrosine phosphorylation, and inhibition of cancer growth. Biochemistry?2007, 46, 1799–1810. 17249693
[58]
Yang, D.-S.; Miao, X.-D.; Ye, Z.-M.; Feng, J.; Xu, R.-Z.; Huang, X.; Ge, F.-F. Bacterial redox protein azurin induce apoptosis in human osteosarcoma U2OS cells. Pharmacol. Res.?2005, 52, 413–421.
[59]
Yamada, T.; Hiraoka, Y.; Ikehata, M.; Kimbara, K.; Avner, B.S.; Das Gupta, T.K.; Chakrabarty, A.M. Apoptosis or growth arrest: Modulation of tumor suppressor p53's specificity by bacterial redox protein azurin. Proc. Natl. Acad. Sci. USA?2004, 101, 4770–4775.
[60]
Laakkonen, P.; ?kerman, M.E.; Biliran, H.; Yang, M.; Ferrer, F.; Karpanen, T.; Hoffman, R.M.; Ruoslahti, E. Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells. Proc. Natl. Acad. Sci. USA?2004, 101, 9381–9386.
[61]
Laakkonen, P.; Porkka, K.; Hoffman, J.A.; Ruoslahti, E. A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat. Med.?2002, 8, 751–755. 12053175
[62]
Kimberly, A.K.; Jones, D.A. Isolation of a colon tumor specific binding peptide using phage display selection. Neoplasia?2003, 5, 437–444. 14670181
[63]
Oi, J.; Terashima, T.; Kojima, H.; Fujimiya, M.; Maeda, K.; Arai, R.; Chan, L.; Yasuda, H.; Kashiwagi, A.; Kimura, H. Isolation of specific peptides that home to dorsal root ganglion neurons in mice. Neurosci. Lett.?2008, 434, 266–272, doi:10.1016/j.neulet.2008.01.062. 18329804
Sadler, K.; Eom, K.D.; Yang, J.-L.; Dimitrova, Y.; Tam, J.P. Translocating proline-rich peptides from the antimicrobial peptide Bactenecin 7. Biochemistry?2002, 41, 14150–14157. 12450378
[66]
Fillon, Y.A.; Anderson, J.P.; Chmielewski, J. Cell-penetrating agents based on a polyproline helix scaffold. J. Am. Chem. Soc.?2005, 127, 11798–11803. 16104758
[67]
Geisler, I.; Chmielewsk, J. Probing length effects and mechanism of cell penetrating agents mounted on a polyproline helix scaffold. Bioorg. Med. Chem. Lett.?2007, 17, 2765–2768, doi:10.1016/j.bmcl.2007.02.077. 17363245
[68]
Geisler, I.; Chmielewski, J. Cationic amphiphilic polyproline helices: Side-chain variations and cell-specific internalization. Chem. Biol. Drug Des.?2009, 73, 39–45.
[69]
M?e, M.; Myrberg, H.; Andaloussi, S.E.; Langel, ü. Design of a tumor homing cell-penetrating peptide for drug delivery. Int. J. Pept. Res. Ther.?2009, 15, 11–15, doi:10.1007/s10989-008-9156-x.
[70]
Nakase, I.; Hirose, H.; Tanaka, G.; Tadokoro, A.; Kobayashi, S.; Takeuchi, T.; Futaki, S. Cell-surface accumulation of flock house virus-derived peptide leads to efficient internalization via macropinocytosis. Mol. Ther.?2009, 17, 1868–1876.
Tan, M.; Lan, K.-H.; Yao, J.; Lu, C.-H.; Sun, M.; Neal, C.L.; Lu, J.; Yu, D. Selective inhibition of ErbB2-overexpressing breast cancer in vivo by a novel TAT-based ErbB2-targeting signal transducers and activators of Transcription 3-Blocking Peptide. Cancer Res.?2006, 66, 3764–3772. 16585203
Dihua, Y.; Mien-Chie, H. Role of ErbB2 in breast cancer chemosensitivity. BioEssays?2000, 22, 673–680.
[75]
Tan, M.; Jing, T.; Lan, K.-H.; Neal, C.L.; Li, P.; Lee, S.; Fang, D.; Nagata, Y.; Liu, J.; Arlinghaus, R.; Hung, M.-C.; Yu, D. Phosphorylation on Tyrosine-15 of p34Cdc2 by ErbB2 Inhibits p34Cdc2 Activation and is Involved in Resistance to Taxol-Induced Apoptosis. Mol. Cell?2002, 9, 993–1004.
[76]
Bromberg, J.; Darnell, J.E. The role of STATs in transcriptional control and their impact on cellular function. Oncogene?2000, 19, 2468–2473, doi:10.1038/sj.onc.1203476. 10851045
[77]
Santra, S.; Yang, H.; Stanley, J.T.; Holloway, P.H.; Moudgil, B.M.; Walter, G.; Mericle, R.A. Rapid and effective labeling of brain tissue using TAT-conjugated CdSMn/ZnS quantum dots. Chem. Commun.?2005, 3144–3146.
[78]
Wadia, J.S.; Dowdy, S.F. Transmembrane delivery of protein and peptide drugs by TAT-mediated transduction in the treatment of cancer. Adv. Drug Delivery Rev.?2005, 57, 579–596, doi:10.1016/j.addr.2004.10.005.
[79]
Melnick, A. Targeting aggressive B-cell lymphomas with cell-penetrating peptides. Biochem. Soc. Trans.?2007, 035, 802–806.
[80]
Essler, M.; Ruoslahti, E. Molecular specialization of breast vasculature: A breast-homing phage-displayed peptide binds to Aminopeptidase P in breast vasculature. Proc. Natl. Acad. Sci. USA?2002, 99, 2252–2257.
Myrberg, H.; Zhang, L.; M?e, M.; Langel, ü. Design of a tumor-homing cell-penetrating peptide. Bioconjugate Chem.?2007, 19, 70–75.
[83]
Menard, S.; Pupa, S.M.; Campiglio, M.; Tagliabue, E. Biologic and therapeutic role of HER2 in cancer. Oncogene?2003, 22, 6570–6578, doi:10.1038/sj.onc.1206779. 14528282
[84]
Dayanidhi, R.; Paige, J.B.; Yee Mon, T.; Ann, R. Role of chemokines in tumor growth. Cancer Lett.?2007, 256, 137–165, doi:10.1016/j.canlet.2007.05.013. 17629396
[85]
Daniel, J.C.; Chang, H.K.; Eugene, C.B. Chemokines in the systemic organization of immunity. Immunol. Rev.?2003, 195, 58–71, doi:10.1034/j.1600-065X.2003.00067.x. 12969310
[86]
Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer.?2004, 4, 540–550.
[87]
Snyder, E.L.; Saenz, C.C.; Denicourt, C.; Meade, B.R.; Cui, X.-S.; Kaplan, I.M.; Dowdy, S.F. Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anticancer peptides. Cancer Res.?2005, 65, 10646–10650. 16322205
[88]
Zhou, N.; Luo, Z.; Luo, J.; Fan, X.; Cayabyab, M.; Hiraoka, M.; Liu, D.; Han, X.; Pesavento, J.; Dong, C.-Z.; Wang, Y.; An, J.; Kaji, H.; Sodroski, J.G.; Huang, Z. Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with d-peptides derived from chemokines. J. Biol. Chem.?2002, 277, 17476–17485. 11880384
[89]
Snyder, E.L.; Meade, B.R.; Saenz, C.C.; Dowdy, S.F. Treatment of terminal Peritoneal Carcinomatosis by a transducible p53-activating peptide. PLoS Biol.?2004, 2, e36, doi:10.1371/journal.pbio.0020036. 14966535
Perea, S.E.; Reyes, O.; Puchades, Y.; Mendoza, O.; Vispo, N.S.; Torrens, I.; Santos, A.; Silva, R.; Acevedo, B.; Lopez, E.; Falcon, V.; Alonso, D.F. Antitumor effect of a novel proapoptotic peptide that impairs the phosphorylation by the Protein Kinase 2 (Casein Kinase 2). Cancer Res.?2004, 64, 7127–7129. 15466209
[92]
Yaylim, I.; Isbir, T. Enhanced casein kinase II (CK II) activity in human lung tumours. Anticancer Res.?2002, 22, 215–218.
[93]
Wang, H.; Davis, A.; Yu, S.; Ahmed, K. Response of cancer cells to molecular interruption of the CK2 signal. Mol. Cell. Biochem.?2001, 227, 167–174.
[94]
Ruzzene, M.; Penzo, D.; Pinna, L.A. Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. Biochem. J.?2002, 364, 41–47. 11988074
[95]
Mueller, J.; Gaertner, F.C.; Blechert, B.; Janssen, K.-P.; Essler, M. Targeting of tumor blood vessels: A phage-displayed tumor-homing peptide specifically binds to matrix metalloproteinase-2-processed collagen IV and blocks angiogenesis in vivo. Mol. Cancer Res.?2009, 7, 1078–1085, doi:10.1158/1541-7786.MCR-08-0538. 19584266
[96]
Jiang, T.; Olson, E.S.; Nguyen, Q.T.; Roy, M.; Jennings, P.A.; Tsien, R.Y. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc. Natl. Acad. Sci. USA?2004, 101, 17867–17872.
[97]
Roy, R.; Yang, J.; Moses, M.A. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J. Clin. Oncol.?2009, 27, 5287–5297. 19738110
[98]
Morris, M.C.; Deshayes, S.; Heitz, F.; Divita, G. Cell-penetrating peptides: From molecular mechanisms to therapeutics. Biol. Cell.?2008, 100, 201–217, doi:10.1042/BC20070116. 18341479
[99]
Friend, S. p53: A glimpse at the puppet behind the shadow play. Science?1994, 265, 334–335.
[100]
Abarzua, P.; Losardo, J.E.; Gubler, M.L.; Spathis, R.; Lu, Y.-A.; Felix, A.; Nerri, A. Restoration of the transcription activation function to mutant p53 in human cancer cells. Oncogene?1996, 13, 2477–2248. 8957091
[101]
Selivanova, G.; Iotsova, V.; Okan, I.; Fritsche, M.; Strom, M.; Groner, B.; Grafstrom, R.C.; Wiman, K.G. Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat. Med.?1997, 3, 632–638, doi:10.1038/nm0697-632. 9176489
[102]
Senatus, P.B.; Li, Y.; Mandigo, C.; Nichols, G.; Moise, G.; Mao, Y.; Brown, M.D.; Anderson, R.C.; Parsa, A.T.; Brandt-Rauf, P.W.; Bruce, J.N.; Fine, R.L. Restoration of p53 function for selective Fas-mediated apoptosis in human and rat glioma cells in vitro and in vivo by a p53 COOH-terminal peptide. Mol. Cancer Ther.?2006, 5, 20–28. 16432159
[103]
Li, Y.; Mao, Y.; Rosal, R.V.; Dinnen, R.D.; Williams, A.C.; Brandt-Rauf, P.W.; Fine, R.L. Selective induction of apoptosis through the FADD/caspase-8 pathway by a p53 c-terminal peptide in human pre-malignant and malignant cells. Int. J. Cancer?2005, 115, 55–64, doi:10.1002/ijc.20838. 15645452
[104]
Li, Y.; Rosal, R.V.; Brandt-Rauf, P.W.; Fine, R.L. Correlation between hydrophobic properties and efficiency of carrier-mediated membrane transduction and apoptosis of a p53 C-terminal peptide. Biochem. Biophys. Res. Commun.?2002, 298, 439–449, doi:10.1016/S0006-291X(02)02470-1. 12413961
[105]
Vocero-Akbani, A.M.; Heyden, N.V.; Lissy, N.A.; Ratner, L.; Dowdy, S.F. Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein. Nat. Med.?1999, 5, 29–33, doi:10.1038/4710. 9883836
[106]
Semenza, G.L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer?2003, 3, 721–732, doi:10.1038/nrc1187. 13130303
[107]
Kizaka-Kondoh, S.; Tanaka, S.; Hiraoka, M. Imaging and targeting of the hypoxia-inducible factor 1-active microenvironment. Toxicol. Pathol.?2009, 22, 93–100.
[108]
Schwarze, S.R.; Ho, A.; Vocero-Akbani, A.; Dowdy, S.F. In vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse. Science?1999, 285, 1569–1572. 10477521
[109]
Hahn, J.-S. The Hsp90 chaperone machinery: From structure to drug development. BMB Rep.?2009, 42, 623–630.
[110]
Isaacs, J.S.; Xu, W.; Neckers, L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell?2003, 3, 213–217, doi:10.1016/S1535-6108(03)00029-1. 12676580
[111]
Fortugno, P.; Beltrami, E.; Plescia, J.; Fontana, J.; Pradhan, D.; Marchisio, P.C.; Sessa, W.C.; Altieri, D.C. Regulation of survivin function by Hsp90. Proc. Natl. Acad. Sci. USA?2003, 100, 13791–13796.
[112]
Plescia, J.; Salz, W.; Xia, F.; Pennati, M.; Zaffaroni, N.; Daidone, M.G.; Meli, M.; Dohi, T.; Fortugno, P.; Nefedova, Y.; Gabrilovich, D.I.; Colombo, G.; Altieri, D.C. Rational design of shepherdin, a novel anticancer agent. Cancer Cell?2005, 7, 457–468, doi:10.1016/j.ccr.2005.03.035. 15894266
[113]
Caughey, B. Prion protein conversions: insight into mechanisms, TSE transmission barriers and strains. Br. Med. Bull.?2003, 66, 109–120.
[114]
Lundberg, P.; Magzoub, M.; Lindberg, M.; H?llbrink, M.; Jarvet, J.; Eriksson, L.E.G.; Langel, ü.; Gr?slund, A. Cell membrane translocation of the N-terminal (1-28) part of the prion protein. Biochem. Biophys. Res. Commun.?2002, 299, 85–90, doi:10.1016/S0006-291X(02)02595-0. 12435392
[115]
Magzoub, M.; Ogl?cka, K.; Pramanik, A.; Eriksson, L.E.G.; Gr?slund, A. Membrane perturbation effects of peptides derived from the N-termini of unprocessed prion proteins. Biochim. Biophys. Acta Biomembr.?2005, 1716, 126–136, doi:10.1016/j.bbamem.2005.09.009.
Heitz, F.; Morris, M.C.; Divita, G. Twenty years of cell-penetrating peptides: From molecular mechanisms to therapeutics. Br. J. Pharmacol.?2009, 157, 195–206, doi:10.1111/j.1476-5381.2009.00057.x. 19309362
[119]
Meade, B.R.; Dowdy, S.F. Enhancing the cellular uptake of siRNA duplexes following noncovalent packaging with protein transduction domain peptides. Adv. Drug Delivery Rev.?2008, 60, 530–536, doi:10.1016/j.addr.2007.10.004.
[120]
Moschos, S.A.; Jones, S.W.; Perry, M.M.; Williams, A.E.; Erjefalt, J.S.; Turner, J.J.; Barnes, P.J.; Sproat, B.S.; Gait, M.J.; Lindsay, M.A. Lung selivery 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, doi:10.1021/bc070077d. 17711319
[121]
Fonseca, S.B.; Pereira, M.P.; Kelley, S.O. Recent advances in the use of cell-penetrating peptides for medical and biological applications. Adv. Drug Delivery Rev.?2009, 61, 953–964, doi:10.1016/j.addr.2009.06.001.
[122]
Sebbage, V. Cell-penetrating peptides and their therapeutic applications. Biosci. Horiz.?2009, 2, 64–72.
[123]
Turner, J.J.; Jones, S.; Fabani, M.M.; Ivanova, G.; Arzumanov, A.A.; Gait, M.J. RNA targeting with peptide conjugates of oligonucleotides, siRNA and PNA. Blood Cells Mol. Dis.?2007, 38, 1–7, doi:10.1016/j.bcmd.2006.10.003. 17113327
[124]
Crombez, L.; Aldrian-Herrada, G.; Konate, K.; Nguyen, Q.N.; McMaster, G.K.; Brasseur, R.; Heitz, F.; Divita, G. A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Mol. Ther.?2008, 17, 95–103. 18957965
Sethuraman, V.A.; Na, K.; Bae, Y.H. pH-responsive Sulfonamide/PEI system for tumor specific gene delivery: An in vitro study. Biomacromolecules?2005, 7, 64–70, doi:10.1021/bm0503571.
[134]
Sethuraman, V.A.; Bae, Y.H. TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors. J. Control. Release?2007, 118, 216–224, doi:10.1016/j.jconrel.2006.12.008. 17239466
[135]
Tannock, I.F.; Rotin, D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res.?1989, 49, 4373–4384. 2545340
[136]
Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol.?1927, 8, 519–530.
[137]
Semenza, G.L.; Artemov, D.; Bedi, A.; Bhujwalla, Z.; Chiles, K.; Feldser, D.; Laughner, E.; Ravi, R.; Simons, J.; Taghavi, P.; Zhong, H. The metabolism of tumours: 70 years later. In the Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity; Goode, J.A., Chadwick, D.J., Eds.; John Wiley & Sons: Chichester, UK, 2001; pp. 251–264.
Kale, A.A.; Torchilin, V.P. Enhanced transfection of tumor cells in vivo using “Smart” pH-sensitive TAT-modified pegylated liposomes. J. Drug Targeting?2007, 15, 538–545, doi:10.1080/10611860701498203.
[140]
Dewhirst, M.W.; Viglianti, B.L.; Lora-Michiels, M.; Hanson, M.; Hoopes, P.J. Basic principles of thermal dosimetry and thermal thresholds for tissue damage from hyperthermia. Int. J. Hyperthermia?2003, 19, 267–294, doi:10.1080/0265673031000119006. 12745972
[141]
Meyer, D.E.; Shin, B.C.; Kong, G.A.; Dewhirst, M.W.; Chilkoti, A. Drug targeting using thermally responsive polymers and local hyperthermia. J. Control. Release?2001, 74, 213–224, doi:10.1016/S0168-3659(01)00319-4. 11489497
Hart, D.S.; Gehrke, S.H. Thermally associating polypeptides designed for drug delivery produced by genetically engineered cells. J. Pharm. Sci.?2007, 96, 484–516, doi:10.1002/jps.20755. 17080413
[144]
Meyer, D.E.; Kong, G.A.; Dewhirst, M.W.; Zalutsky, M.R.; Chilkoti, A. Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia. Cancer Res.?2001, 61, 1548–1554. 11245464
[145]
Bidwell, G.L.; Raucher, D. Application of thermally responsive polypeptides directed against c-Myc transcriptional function for cancer therapy. Mol. Cancer Ther.?2005, 4, 1076–1085, doi:10.1158/1535-7163.MCT-04-0253. 16020665
[146]
Massodi, I.; Bidwell III, G.L.; Raucher, D. Evaluation of cell penetrating peptides fused to elastin-like polypeptide for drug delivery. J. Control. Release?2005, 108, 396–408, doi:10.1016/j.jconrel.2005.08.007. 16157413
[147]
Manceur, A.P.; Driscoll, B.D.; Sun, W.; Audet, J. Selective enhancement of the uptake and bioactivity of a TAT-conjugated peptide inhibitor of Glycogen Synthase Kinase-3. Mol. Ther.?2008, 17, 500–507. 19107119
[148]
Rothbard, J.B.; Garlington, S.; Lin, Q.; Kirschberg, T.; Kreider, E.; McGrane, P.L.; Wender, P.A.; Khavari, P.A. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat. Med.?2000, 6, 1253–1257. 11062537
[149]
Koo, J. A randomized, double-blind study comparing the efficacy, safety and optimal dose of two formulations of Cyclosporin, Neoral and Sandimmun, in patients with severe psoriasis. Br. J. Dermatol.?1998, 139, 88–95, doi:10.1046/j.1365-2133.1998.02319.x. 9764154
[150]
Naeyaert, J.M.; Lachapelle, J.M.; Degreef, H.; de la Brassinne, M.; Heenen, M.; Lambert, J. Cyclosporin in Atopic Dermatitis. Dermatology?1999, 198, 145–152, doi:10.1159/000018091. 10325461
[151]
McCusker, C.T.; Wang, Y.; Shan, J.; Kinyanjui, M.W.; Villeneuve, A.; Michael, H.; Fixman, E.D. Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT-6 peptide. J. Immunol.?2007, 179, 2556–2564. 17675518
[152]
Kuperman, D.A.; Huang, X.; Koth, L.L.; Chang, G.H.; Dolganov, G.M.; Zhu, Z.; Elias, J.A.; Sheppard, D.; Erle, D.J. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med.?2002, 8, 885–889. 12091879
[153]
Heckl, S.; Pipkorn, R.; Waldeck, W.; Spring, H.; Jenne, J.; von der Lieth, C.-W.; Corban-Wilhelm, H.; Debus, J.; Braun, K. Intracellular visualization of prostate cancer using magnetic resonance imaging. Cancer Res.?2003, 63, 4766–4772.
[154]
Louie, A.Y.; Huber, M.M.; Ahrens, E.T.; Rothbacher, U.; Moats, R.; Jacobs, R.E.; Fraser, S.E.; Meade, T.J. In vivo visualization of gene expression using magnetic resonance imaging. Nat. Biotech.?2000, 18, 321–325.
[155]
Lewin, M.; Carlesso, N.; Tung, C.-H.; Tang, X.-W.; Cory, D.; Scadden, D.T.; Weissleder, R. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat. Biotech.?2000, 18, 410–414.
[156]
Sherr, C.J. Cancer cell cycles. Science?1996, 274, 1672–1677.
[157]
Tan, M.L.; Choong, P.F.M.; Dass, C.R. Recent developments in liposomes, microparticles and nanoparticles for protein and peptide drug delivery. Peptides?2010, 184–193. 19819278
[158]
Malam, Y.; Loizidou, M.; Seifalian, A.M. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol. Sci.?2009, 30, 592–599, doi:10.1016/j.tips.2009.08.004. 19837467
[159]
Fanciullino, R.; Ciccolini, J. Liposome-encapsulated anticancer drugs: Still waiting for the magic bullet? Curr. Med. Chem.?2009, 16, 4361–4373, doi:10.2174/092986709789712916. 19835568
Ko, Y.T.; Hartner, W.C.; Kale, A.; Torchilin, V.P. Gene delivery into ischemic myocardium by double-targeted lipoplexes with anti-myosin antibody and TAT peptide. Gene Ther.?2008, 16, 52–59. 18701915
[162]
Sheikh, F.; Sontag, D.P.; Fandrich, R.R.; Kardami, E.; Cattini, P.A. Overexpression of FGF-2 increases cardiac myocyte viability after injury in isolated mouse hearts. Am. J. Physiol. Heart Circ. Physiol.?2001, 280, H1039–H1050. 11179045
[163]
Jayakumar, J.; Suzuki, K.; Sammut, I.A.; Smolenski, R.T.; Khan, M.; Latif, N.; Abunasra, H.; Murtuza, B.; Amrani, M.; Yacoub, M.H. Heat Shock Protein 70 gene transfection protects mitochondrial and ventricular function against ischemia-reperfusion injury. Circulation?2001, 104, I303–I307. 11568073
[164]
Mack, C.A.; Patel, S.R.; Schwarz, E.A.; Zanzonico, P.; Hahn, R.T.; Ilercil, A.; Devereux, R.B.; Goldsmith, S.J.; Christian, T.F.; Sanborn, T.A.; Kovesdi, I.; Hackett, N.; Isom, O.W.; Crystal, R.G.; Rosengart, T.K. Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart. J. Thorac. Cardiovasc. Surg.?1998, 115, 168–177, doi:10.1016/S0022-5223(98)70455-6. 9451061
[165]
Keiji, I.; Yoshiki, S.; Satoru, K.-S.; Naomasa, K.; Nariaki, M.; Toshikazu, N.; Hikaru, M. Gene transfection of hepatocyte growth factor attenuates the progression of cardiac remodeling in the hypertrophied heart. J. Thorac. Cardiovasc. Surg.?2005, 130, 719–725.
[166]
Khaw, B.A.; Mattis, J.A.; Melincoff, G.; Strauss, H.W.; Gold, H.K.; Haber, E. Monoclonal antibody to cardiac myosin: Imaging of experimental myocardial infarction. Hybridoma?1984, 3, 11–23, doi:10.1089/hyb.1984.3.11. 6469268
[167]
Dass, C.R.; Choong, P.F.M. Selective gene delivery for cancer therapy using cationic liposomes: In vivo proof of applicability. J. Control. Release?2009, 113, 155–163.
[168]
Leonie, B.; Klaas, P.; Grietje, M.; Dirk, K.F.M. Targeting of sugar- and charge-modified albumins to fibrotic rat livers: The accessibility of hepatic cells after chronic bile duct ligation. J. Hepatol.?1998, 29, 579–588, doi:10.1016/S0168-8278(98)80153-0. 9824267
[169]
Tuan Giam Chuang, V.; Kragh-Hansen, U.; Otagiri, M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharm. Res.?2002, 19, 569–577.
[170]
Zoltán, S.; Alisa, E.K. Vascular endothelium and immune responses: Implications for inflammation and angiogenesis. Rheum. Dis. Clin. North Am.?2004, 30, 97–114, doi:10.1016/S0889-857X(03)00116-9. 15061570
[171]
Temming, K.; Lacombe, M.; van der Hoeven, P.; Prakash, J.; Gonzalo, T.; Dijkers, E.C.F.; Orfi, L.; Keri, G.; Poelstra, K.; Molema, G.; Kok, R.J. Delivery of the p38 MAPkinase inhibitor SB202190 to angiogenic endothelial cells: Development of novel RGD-Equipped and PEGylated drug-albumin conjugates using platinum(II)-based drug linker technology. Bioconjugate Chem.?2006, 17, 1246–1255, doi:10.1021/bc0600158.
[172]
Temming, K.; Meyer, D.L.; Zabinski, R.; Senter, P.D.; Poelstra, K.; Molema, G.; Kok, R.J. Improved efficacy of αvβ3-targeted albumin conjugates by conjugation of a novel Auristatin derivative. Mol. Pharmaceutics?2007, 4, 686–694, doi:10.1021/mp0700312.
[173]
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, 13–22.
[174]
Singh, R.; Kostarelos, K. Designer adenoviruses for nanomedicine and nanodiagnostics. Trends Biotechnol.?2009, 27, 220–229.
[175]
Zochowska, M.; Paca, A.; Schoehn, G.; Andrieu, J.-P.; Chroboczek, J.; Dublet, B.; Szolajska, E. Adenovirus Dodecahedron, as a drug delivery vector. PLoS One?2009, 4, e5569.
[176]
Ogris, M.; Wagner, E. Targeting tumors with non-viral gene delivery systems. Drug Discov. Today?2002, 7, 479–485.
[177]
J?rver, P.; Langel, ü. The use of cell-penetrating peptides as a tool for gene regulation. Drug Discov. Today?2004, 9, 395–402, doi:10.1016/S1359-6446(04)03042-9. 15081956
[178]
Mintzer, M.A.; Simanek, E.E. Nonviral vectors for gene delivery. Chem. Rev.?2008, 109, 259–302.
[179]
Torchilin, V.P. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug. Discov.?2005, 4, 145–160, doi:10.1038/nrd1632. 15688077
[180]
Boeckle, S.; Wagner, E. Optimizing targeted gene delivery: Chemical modification of viral vectors and synthesis of artificial virus vector systems. AAPS J.?2006, 8, 731–742.
[181]
Kreppel, F.; Gackowski, J.; Schmidt, E.; Stefan, K. Combined genetic and chemical capsid modifications enable flexible and efficient de- and retargeting of Adenovirus vectors. Mol. Ther.?2005, 12, 107–117.
[182]
Frankel, A.D.; Pabo, C.O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell?1988, 55, 1189–1193, doi:10.1016/0092-8674(88)90263-2. 2849510
[183]
Chen, L.; Harrison, S.D. Cell-penetrating peptides in drug development: Enabling intracellular targets. Biochem. Soc. Trans.?2007, 35, 821–825, doi:10.1042/BST0350821. 17635156
[184]
Moulton, H.M.; Moulton, M.J. Antisense morpholino oligomers and theirs peptide conjugates. In Therapeutic Oligonucleotide; Kurreck, J., Ed.; Royal Society of Chemistry: Cambridge, UK, 2008; pp. 43–79.
[185]
Juliano, R.L.; Alam, R.; Dixit, V.; Kang, H.M. Cell-targeting and cell-penetrating peptides for delivery of therapeutic and imaging agents. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol.?2009, 1, 324–335, doi:10.1002/wnan.4. 20049800