Abstract
Different mammalian tissues in their normal and pathological state have distinct molecular features in the luminal side of the vessels. These features can be targeted with peptides that concentrate, i.e., home to their target tissue. The homing peptides can be used to deliver cargo, such as therapeutic molecules, to the target tissue, or they can help in detecting pathological changes in the tissue. Some of the homing peptides are capable of penetrating to the target tissue and bringing their cargo with them. One of the most studied homing peptides, iRGD, penetrates to its target tissue with the help of the CendR sequence. The homing and penetrating peptides are discovered by screening a peptide library encoded on the surface of bacteriophages. In in vivo biopanning, the library is injected to the circulation of a living animal, and later, unbound phages are washed off during circulation and bound phages are eluted from the target tissue. The eluted phages are amplified and form the library for the second biopanning round. After a few rounds, the phages containing sequences that home to the target tissue are concentrated in the library.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Agemy L, Sugahara KN, Kotamraju VR, Gujraty K, Girard OM, Kono Y, Mattrey RF, Park JH, Sailor MJ, Jimenez AI, Cativiela C, Zanuy D, Sayago FJ, Aleman C, Nussinov R, Ruoslahti E (2010) Nanoparticle-induced vascular blockade in human prostate cancer. Blood 116(15): 2847–2856
Åkerman ME, Chan WCW, Laakkonen P, Bhatia SN, Ruoslahti E (2002) Nanocrystal targeting in vivo. Proc Natl Acad Sci 99(20):12617–12621
Alberici L, Roth L, Sugahara KN, Agemy L, Kotamraju VR, Teesalu T, Bordignon C, Traversari C, Rizzardi GP, Ruoslahti E (2013) De novo design of a tumor-penetrating peptide. Cancer Res 73(2):804–812
AlDeghaither D, Smaglo BG, Weiner LM (2015) Beyond peptides and mAbs – current status and future perspectives for biotherapeutics with novel constructs. J Clin Pharmacol 55(S3):S4–S20
Arap W, Pasqualini R, Ruoslahti E (1998) Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279(5349):377–380
Arap W, Kolonin MG, Trepel M, Lahdenranta J, Cardó-Vila M, Giordano RJ, Minitz PJ, Ardelt PU, Yao VJ, Vidal CI, Chen L, Flamm A, Valtanen H, Weavind LM, Hicks ME, Pollock RE, Botz GH, Bucana DC, Koivunen E, Cahill D, Troncoso P, Baggerly KA, Pentz RD, Do KA, Logothetis CJ, Pasqualini R (2002) Steps toward mapping the human vasculature by phage display. Nat Med 8(2):121–127
Barry MA, Dower WJ, Johnston SA (1996) Toward cell-targeting gene therapy vectors: selection of cell-binding peptides from random peptide-presenting phage libraries. Nat Med 2(3):299–305
Brewis ND, Phelan A, Normand N, Choolun E, O’Hare P (2003) Particle assembly incorporating a VP22-BH3 fusion protein, facilitating intracellular delivery, regulated release, and apoptosis. Mol Ther 7(2):262–270
Brown KC (2010) Peptidic tumor targeting agents: the road from phage display peptide selection to clinical applications. Curr Pharm Des 16(9):1040–1054
Chaurasia CS, Müller M, Dashaw ED, Denfeldt E, Bolinder J, Bullock R, Bungay PM, DeLange ECM, Derendorf H, Elmquist WF, Hammarlund-Udenaes M, Joukhadar C, Kellogg DL, Lunte CE, Nordström CH, Rollema H, Sawchuk RJ, Cheung BWY, Phah VP, Stahle L, Ungerstedt U, Welty DF, Yeo H (2007) AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives. Pharm Res 24(5):1014–1025
Costantini TW, Eliceiri BP, Putnam JG, Bansal V, Baird A, Coimbra R (2012) Intravenous phage display identified peptide sequences that target the burn-injured intestine. Peptides 38(1):94–99
Derfus AM, Chen AA, Min D, Ruoslahti E, Bhatia SN (2007) Targeted quantum dot conjugates for siRNA delivery. Bioconjug Chem 18(5):1391–1396
Elliott G, O’Hare P (1997) Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell 88(2):223–233
Fields S, Song O (1989) A novel genetic system to detect protein-protein interactions. Nature 340(6230):254–256
Fogal V, Zhang L, Krajewski S, Ruoslahti E (2008) Mitochondrial/cell-surface protein p32/gC1qR as a molecular target in tumor cells and tumor stroma. Cancer Res 68(17):7210–7218
Fogal V, Sugahara KN, Ruoslahti E, Christian S (2009) Cell surface nucleolin antagonist causes endothelial cell apoptosis and normalization of tumor vasculature. Angiogenesis 12(1):91–100
Glasgow HL, Whitney MA, Gross LA, Friedman B, Adams SR, Crisp JL, Hussain T, Frei AP, Novy K, Wollscheid B, Nguyen QT, Tsien RY (2016) Laminin targeting of a peripheral nerve-highlighting peptide enables degenerated nerve visualization. Proc Natl Acad Sci 113(45):12774–12779
Gotthardt M, van Eerd-Vismale J, Oyen WJ, de Jong M, Zhang H, Rolleman E, Maecke HR, Béhé M, Boerman O (2007) Indication for different mechanisms of kidney uptake of radiolabeled peptides. J Nucl Med 48(4):596–601
Gupta N, Ibrahim HM, Ahsan F (2014) Peptide-micelle hybrids containing fasudil for targeted delivery to the pulmonary arteries and arterioles to treat pulmonary arterial hypertension. J Pharm Sci 103(11):3743–3753
Hajdin K, D’Alessandro V, Niggli FK, Schäfer BW, Bernasconi M (2010) Furin targeted drug delivery for treatment of rhabdomyosarcoma in a mouse model. PLoS One 5(5):e10445
Hoffman JA, Giraudo E, Singh M, Zhang L, Inoue M, Porkka K, Hanahan D, Ruoslahti E (2003) Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma. Cancer Cell 4(5):383–391
Hoffman JA, Laakkonen P, Porkka K, Bernasconi M, Ruoslahti E (2004) In vivo and ex vivo selections using phage-displayed libraries. In: Clackson T, Lowman HB (eds) Phage display: a practical approach, 1st edn. Oxford University Press, Oxford, pp 171–192
Hong S, Leroueil PR, Majoros IJ, Orr BG, Baker JR Jr, Banaszak Holl MM (2007) The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform. Chem Biol 14(1):107–115
Hsiung P, Hardy J, Friedland S, Soetikno R, Du CB, Wu APW, Sahbaie P, Crawhord JM, Lowe AW, Contag CH, Wang TD (2008) Detection of colonic dysplasia in vivo using a targeted fluorescent septapeptide and confocal microendoscopy. Nat Med 14(4):454–458
Hu S, Guo X, Xie H, Du Y, Pan Y, Shi Y, Wang J, Hong L, Han S, Zhang D, Huang D, Zhang K, Bai F, Jiang H, Zhai H, Nie Y, Wu K, Fan D (2006) Phage display selection of peptides that inhibit metastasis ability of gastric cancer cells with high liver-metastatic potential. Biochem Biophys Res Commun 341(4):964–972
Hussain S, Joo J, Kang J, Kim B, Braun GB, She ZG, Kim D, Mann AP, Mölder T, Teesalu T, Carnazza S, Guglielmino S, Sailor MJ, Ruoslahti E (2018) Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy. Nat Biomed Eng 2(2):95–103
Hyvönen M, Laakkonen P (2015) Identification and characterization of homing peptides using in vivo peptide phage display. Methods Mol Biol 1324:205–222
Hyvönen M, Enbäck J, Huhtala T, Lammi J, Sihto H, Weisell J, Joensuu H, Rosenthal-Aizman K, El-Andaloussi S, Langel U, Närvänen A, Bergers G, Laakkonen P (2014) Novel target for peptide-based imaging and treatment of brain tumors. Mol Cancer Ther 13(4):996–1007
Ikemoto H, Lingasamy P, Willmore AA, Hunt H, Kurm K, Tammik O, Scodeller P, Simón-Gracia L, Kotamraju VR, Lowy AM, Sugahara KN, Teesalu T (2017) Hyaluronan-binding peptide for targeting peritoneal carcinomatosis. Tumor Biol 39(5):1–9
Ikemura T (1981) Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes. J Mol Biol 146(1):1–21
Jain RK (1999) Transport of molecules, particle, and cells in solid tumors. Annu Rev Biomed Eng 1:241–263
Järvinen TA (2012) Design of target-seeking antifibrotic compounds. Methods Enzymol 509: 243–261
Järvinen TAH, Pemmari T (2020) Systemically administered, target-specific, multi-functional therapeutic recombinant proteins in regenerative medicine. Nanomaterials 10:226
Järvinen TAH, Ruoslahti E (2007) Molecular changes in the vasculature of injured tissues. Am J Pathol 171(2):702–711
Järvinen TAH, Ruoslahti E (2010) Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice. Proc Natl Acad Sci 107(50):21671–21676
Järvinen TAH, Ruoslahti E (2019) Generation of a multi-functional, target organ-specific, anti-fibrotic molecule by molecular engineering of the extracellular matrix protein, decorin. Br J Pharmacol 176:16–25
Järvinen TAH, May U, Prince S (2015) Systemically administered, target organ-specific therapies for regenerative medicine. Int J Mol Sci 16:23556–23571
Järvinen TAH, Rashid J, Valmari T, May U, Ahsan F (2017) Systemically administered, target-specific therapeutic recombinant proteins and nanoparticles for regenerative medicine. ACS Biomater Sci Eng 3(7):1273–1282
Joyce JA, Laakkonen P, Bernasconi M, Bergers G, Ruoslahti E, Hanahan D (2003) Stage-specific vascular markers revealed by phage display in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 4(5):393–403
Kaplan IM, Wadia JS, Dowdy SF (2005) Cationic TAT peptide transduction domain enters cells by micropinocytosis. J Control Release 102(1):247–253
Kayushin AL, Korosteleva MD, Miroshnikov AI, Kosch W, Zubov D, Piel N (1996) A convenient approach to the synthesis of trinucleotide phosphoramidites – synthons for the generation of oligonucleotide/peptide libraries. Nucleic Acids Res 24(19):3748–3755
Kean TJ, Duesler L, Young RG, Dadabayev A, Olenyik A, Penn M, wagner J, Fink DJ, Caplan AI, Dennis JE (2012) Development of a peptide-targeted, myocardial ischemia-homing, mesenchymal stem cell. J Drug Target 20(1):23–32
Kelly KA, Bardeesy N, Anbazhagan R, Gurumurthy S, Berger J, Alencar H, Depinho RA, Mahmood U, Weissleder R (2008) Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma. PLoS Med 5(4):e85
Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, McParland B, Cohen PS, Hui AM, Palmieri C, Osman S, Glaser M, Turton D, Al-Nahhas A, Aboagye EO (2008) Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med 49(6):879–886
Klein AF, Varela MA, Arandel L, Holland A, Naouar N, Arzumanov A, Seoane D, Revillod L, Bassez G, Ferry A, Jauvin D, Gourdon G, Puymirat J, Gait MJ, Furling D, Wood MJA (2019) Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice. J Clin Invest 129(11):4739–4744
Krag DN, Shukla GS, Shen GP, Pero S, Ashikaga T, Fuller S, Weaver DL, Durdette-Radoux S, Thomas C (2006) Selection of tumor-binding ligands in cancer patients with phage display libraries. Cancer Res 66(15):7724–7733
Krumpe L, Mori T (2006) The use of phage-displayed peptide libraries to develop tumor-targeting drugs. Int J Pept Res Ther 12(1):79–91
Laakkonen P, Porkka K, Hoffman JA, Ruoslahti E (2002) A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nat Med 8(7):751–755
Laakkonen P, Åkerman ME, Biliran H, Yang M, Ferrer F, Kapanen T, Hoffman RM, Ruoslahti E (2004) Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells. Proc Natl Acad Sci 101(25):9381–9386
Le Joncour V, Laakkonen P (2018) Seek & destroy, use of targeting peptides for cancer detection and drug delivery. Bioorg Med Chem 26(10):2797–2806
Lu Y, Yang J, Sega E (2006) Issues related to targeted delivery of proteins and peptides. AAPS J 8(3):E446–E478
Mäkelä AR, Matilainen H, White DJ, Ruoslahti E, Oker-Blom C (2006) Enhanced baculovirus-mediated transduction of human cancer cells by tumor-homing peptides. J Virol 80(13): 6603–6611
Mäkelä AR, Enbäck J, Laakkonen JP, Vihinen-Ranta M, Laakkonen P, Oker-Blom C (2008) Tumor targeting of baculovirus displaying a lymphatic homing peptide. J Gene Med 10:1019–1031
Mann AP, Scodeller P, Hussain S, Joo J, Kwon E, Braun GB, Mölder T, She ZG, Kotamraju VR, Ranscht B, Krajewski S, Teesalu T, Bhatia S, Sailor MJ, Ruoslahti E (2016) A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries. Nat Commun 7
Mann AP, Scodeller P, Hussain S, Braun GB, Mölder T, Toome K, Ambasudhan R, Teesalu T, Lipton SA, Ruoslahti E (2017) Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer’s disease. Nat Commun 8(1):1403
McGregor DP (2008) Discovering and improving novel peptide therapeutics. Curr Opin Pharmacol 8:616–619
Meyer-Losic F, Quinonero J, Dubois V, Alluis B, Dechambre M, Michel M, Cailler F, Fernandez AM, Trouet A, Kearsey J (2006) Improved therapeutic efficacy of doxorubicin through conjugation with a novel peptide drug delivery technology (Vectocell). J Med Chem 49(23):6908–6916
Montet X, Funovics M, Montet-Abou K, Weissleder R, Josephson L (2006) Multivalent effects of RGD peptides obtained by nanoparticle display. J Med Chem 49(20):6087–6093
Na DH, Lee KC, DeLuca PP (2005) PEGylation of octreotide: II. Effect of N-terminal mono PEGylation on biological activity and pharmacokinetics. Pharm Res 22(5):743–749
Nahar K, Absar S, Patel B, Ahsan F (2014) Starch-coated magnetic liposomes as an inhalable carrier for accumulation of fasudil in the pulmonary vasculature. Int J Pharm 464(1–2):185–195
Nestor J (2007) Peptide and protein drugs: issues and solutions. In: Taylor J, Triggle D (eds) Comprehensive medicinal chemistry II, 1st edn. Elsevier, Oxford, pp 573–601
Neumeister P, Eibl M, Zinke-Cerwenka W, Scarpatetti M, Sill H, Linkesch W (2001) Hepatic veno-occlusive disease in two patients with relapsed acute myeloid leukemia treated with anti-CD33 calicheamicin (CMA-676) immunoconjugate. Ann Hematol 80(2):119–120
Oh P, Li Y, Yu J, Durr E, Krasinska KM, Carver LA, Testa JE, Schintzer JE (2004) Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature 429(6992):629–635
Okarvi SM (2008) Peptide-based radiopharmaceuticals and cytotoxic conjugates: potential tools against cancer. Cancer Treat Rev 34:13–26
Paasonen L, Sharm S, Braun GB, Kotamraju VR, Chung TDY, Zhi-Gang S, Sugahara KN, Yliperttula M, Wu B, Pellecchia M, Ruoslahti E, Teesalu T (2016) New p32/gC1qR ligands for targeted tumor drug delivery. Chembiochem 17(7):570–575
Pang HB, Braun GB, Friman T, Aza-Blanc Ruidiaz ME, Sugahara KN, Teesalu T, Ruoslahti E (2014) An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability. Nat Commun 5:4904
Pasqualini R, Ruoslahti E (1996) Organ targeting in vivo using phage display peptide libraries. Nature 380(6572):364–366
Peng X, Leal J, Mohanty R, Soto M, Ghosh D (2018) Quantitative PCR of T7 bacteriophage from biopanning. J Vis Exp (139):58165
Pierce MC, Javier DJ, Richards-Kortum R (2008) Optical contrast agents and imaging systems for detection and diagnosis of cancer. Int J Cancer 123(9):1979–1990
Pilch J, Brown DM, Komatsu M, Järvinen TA, Yang M, Peters D, Hoffman RM, Ruoslahti E (2006) Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds. Proc Natl Acad Sci 103(8):2800–2804
Porkka K, Laakkonen P, Hoffman JA, Bernasconi M, Ruoslahti E (2002) A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo. Proc Natl Acad Sci 99(11):7444–7449
Rajotte D, Ruoslahti E (1999) Membrane dipeptidase is the receptor for a lung-targeting peptide identified by in vivo phage display. J Biol Chem 274(17):11593–11598
Reubi JC, Maecke HR (2008) Peptide-based probes for cancer imaging. J Nucl Med 49(11): 1735–1738
Reulen SW, Dankers PY, Bomans PH, Meijer EW, Merkx M (2009) Collagen targeting using protein-functionalized micelles: the strength of multiple weak interactions. J Am Chem Soc 131(21):7304–7312
Roth L, Agemy L, Kotamraju VR, Braun G, Teesalu T, Sugahara KN, Hamzah J, Ruoslahti E (2012) Transtumoral targeting enabled by a novel neuropilin-binding peptide. Oncogene 31:3754–3763
Ruoslahti E (2017) Tumor penetrating peptides for improved drug delivery. Adv Drug Deliv Rev 110–111:3–12
Ruoslahti E, Rajotte D (2000) An address system in the vasculature of normal tissues and tumors. Annu Rev Immunol 18:813–827
Ruoslahti E, Bhatia SN, Sailor MJ (2010) Targeting of drugs and nanoparticles to tumors. J Cell Biol 188(6):759–768
Samoylova T, Smith BF (1999) Elucidation of muscle-binding peptides by phage display screening. Muscle Nerve 22:460–466
Sellers DL, Bergen JM, Johnson RN, Back H, Ravits JM, Horner PJ, Pun SH (2016) Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration. Proc Natl Acad Sci 112(9):2514–2519
Sheu TJ, Schwarz EM, O’Keefe RJ, Rosier RN, Puzas JE (2002) Use of a phage display technique to identify potential osteoblast binding sites within osteoclast lacunae. J Bone Miner Res 17(5):915–922
Shi Q, Zhang Y, Liu S, Liu G, Xu J, Zhao X, Anderson GJ, Nie G, Li S (2018) Specific tissue factor delivery using a tumor-homing peptide for inducing tumor infarction. Biochem Pharmacol 156:501–510
Simberg D, Duza T, Park JH, Essler M, Pilch J, Zhang L, Derfus AM, Yang M, Hoffman RM, Bhatia S, Sailor MJ, Ruoslahti E (2007) Biomimetic amplification of nanoparticle foming to tumors. Proc Natl Acad Sci 104(3):932–936
Smith GP (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228(2705):1315–1317
Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM, Hanahan D, Mattrey RF, Ruoslahti E (2009) Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16(6):510–520
Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, Ruoslahti E (2010) Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328(5981):1031–1035
Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E (2009) C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci 106(38): 16157–16162
Teesalu T, Sugahara KN, Ruoslahti E (2012) Mapping of vascular ZIP codes by phage display. Methods Enzymol 503:35–56
Toba M, Alzoubi A, O’Neill K, Abe K, Urakami T, Komatsu M, Alvarez D, Järvinen TA, Mann D, Ruoslahti E, McMurtry IF, Oka M (2014) A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension. Am J Pathol 184(2):369–375
Tonnesen MG, Feng X, Clark RAF (2000) Angiogenesis in wound healing. J Investig Dermatol Symp Proc 5(1):40–46
Urakami T, Järvinen TA, Toba M, Sawada J, Ambalavanan N, Mann D, McMurtry I, Oka M, Ruoslahti E, Komatsu M (2011) Peptide-directed highly selective targeting of pulmonary arterial hypertension. Am J Pathol 178(6):2489–2495
Vanharanta S, Massagué J (2013) Origins of metastatic traits. Cancer Cell 24(4):410–421
Wang Y, Newman M, Ackun-Farmmer M, Baranello MP, Scheu TJ, Puzas JE, Benoit DSW (2017) Fracture-targeted delivery of β-catenin agonists via peptide-functionalized nanoparticles augments fracture healing. ACS Nano 11(9):9445–9458
Whitney MA, Crisp JL, Nguyen LT, Friedman B, Gross LA, Steinbach P, Tsien RY, Nguyen QT (2011) Fluorescent peptides highlight peripheral nerves during surgery in mice. Nat Biotechnol 29(4):352–356
Ye F, Jeong EK, Zhanjun J, Yang T, Parker D, Lu ZR (2008) A peptide targeted contrast agent specific to fibrin-fibronectin complexes for cancer molecular imaging with MRI. Bioconjug Chem 19(12):2300–2303
Yin H, Moulton HM, Betts C, Seow Y, Boutilier J, Iverson PL, Wood MJA (2009) A fusion peptide directs enhanced systemic dystrophin exon skipping and functional restoration in dystrophin-deficient mdx mice. Hum Mol Genet 18(22):4405–4414
Zhang L, Hoffman JA, Ruoslahti E (2005) Molecular profiling of heart endothelial cells. Circulation 112:1601–1611
Acknowledgments
TP wants to thank MD Antti Pemmari for his insightful comments. This work was supported by the Academy of Finland and Emil Aaltonen foundation.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Switzerland AG
About this entry
Cite this entry
Pemmari, T., Koho, T., Järvinen, T.A.H. (2021). Probing Vasculature by In Vivo Phage Display for Target Organ-Specific Delivery in Regenerative Medicine. In: Holnthoner, W., Banfi, A., Kirkpatrick, J., Redl, H. (eds) Vascularization for Tissue Engineering and Regenerative Medicine. Reference Series in Biomedical Engineering(). Springer, Cham. https://doi.org/10.1007/978-3-319-54586-8_21
Download citation
DOI: https://doi.org/10.1007/978-3-319-54586-8_21
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-54584-4
Online ISBN: 978-3-319-54586-8
eBook Packages: EngineeringReference Module Computer Science and Engineering