ABC  Vol.3 No.2 , April 2013
Importance of integrin receptors in the field of pharmaceutical & medical science
Author(s) Sumit Goswami*
Integrin receptors have remained as a key subject of interest in the pharmaceutical industry for the last few years. There are a total of 24 different types of integrin heterodimers. Each of these heterodimers plays important role in various biological processes that are inherent to different pathological conditions. As a result, integrin receptors have been extensively evaluated for their role in therapeutic targeting. There are different classes of inhibitors against integrin receptors and this review provides an overview on different classes of integrin inhibitors that are currently available. A number of review articles have been written on the possible application of integrin receptors in therapeutic targeting. Many of these articles have heavily emphasized on the importance of αvβ3 & αvβ5 receptors as major pharmaceutical target in cancer but little emphasis has been given on the importance of other integrin receptors, such as α5β1, αIIbβ3, α4β7, αvβ6 etc. While this review gives due importance to both αvβ3 & αvβ5 receptors and provides an historical perspective on how these two receptors have evolved as a potential target for cancer, significant emphasis has also been given on the other integrin receptors that have started enjoying the status of important drug target over the course of last few years. Effort has been maintained to discuss briefly on the key physiological basis of their importance as drug target. For example, involvement of αvβ3 in angiogenesis has made it a therapeutic target for the treatment of cancer. At the same time expression of this receptor on the surface of osteoclast has made it a target for the treatment of osteoporosis. Thus, emphasis has been given on discussing the role of the integrin receptors in different disease conditions followed by specific examples of drug molecules that have been trialed against these receptors. While hundreds of candidate molecules have been developed against different integrin receptors only a handful of them has been subject to phase-III clinical trial. That necessitates careful consideration of certain concerns that are associated with direct targeting of integrins and thus has also been an important goal of this review. In the last few years application of integrin receptors have extended beyond mere therapeutic targeting. Several integrin receptors are currently are studied for their potential of aiding at diagnostic imaging and drug delivery. In this review a brief overview has also been provided on how integrin are being targeted for diagnostic imaging and drug delivery with relevant examples. Thus the primary aim of this review has been to provide an comprehensive overview on the broad scope of application that integrin receptors have in the field of medical science.

Cite this paper
Goswami, S. (2013) Importance of integrin receptors in the field of pharmaceutical & medical science. Advances in Biological Chemistry, 3, 224-252. doi: 10.4236/abc.2013.32028.
[1]   Hynes, R.O. (2004) The emergence of integrins: A personal and historical perspective. Matrix Biology, 23, 333-340. doi:10.1016/j.matbio.2004.08.001

[2]   Tamkun, J.W., et al. (1986) Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin. Cell, 46, 271-282. doi:10.1016/0092-8674(86)90744-0

[3]   Stupack, D.G. (2007) The biology of integrins. Oncology, 21, 6-12.

[4]   Barczyk, M., Carracedo, S. and Gullberg, D. (2010). Integrins. Cell and Tissue Research, 339, 269-280. doi:10.1007/s00441-009-0834-6

[5]   Humphries, M.J., Symonds, E.J. and Mould, A.P. (2003) Mapping functional residues onto integrin crystal structures. Current Opinion in Structural Biology, 13, 236-243. doi:10.1016/S0959-440X(03)00035-6

[6]   Curley, G.P., Blum, H. and Humphries, M.J. (1999). Integrin antagonists. Cellular and Molecular Life Sciences, 56, 427-441. doi:10.1007/s000180050443

[7]   Larson, R.S., et al. (1989) Primary structure of the leukocyte function-associated molecule-1 alpha subunit: An integrin with an embedded domain defining a protein superfamily. The Journal of Cell Biology, 108, 703-712. doi:10.1083/jcb.108.2.703

[8]   Askari, J.A., et al. (2009) Linking integrin conformation to function. Journal of Cell Science, 122,165-170. doi:10.1242/jcs.018556

[9]   Calvete, J.J. (2004) Structures of integrin domains and concerted conformational changes in the bidirectional signaling mechanism of alphaIIbbeta3. Experimental Biology and Medicine, 229, 732-744.

[10]   Gahmberg, C.G., et al. (2009) Regulation of integrin activity and signalling. Biochimica et Biophysica Acta, 1790, 431-444. doi:10.1016/j.bbagen.2009.03.007

[11]   Honda, S., et al. (2009) Integrin-linked kinase associated with integrin activation. Blood, 113, 5304-5313. doi:10.1182/blood-2008-07-169136

[12]   Giancotti, F.G. and Ruoslahti, E. (1999) Integrin signaling. Science, 285, 1028-1032. doi:10.1126/science.285.5430.1028

[13]   Brooks, P.C., Clark, R.A. and Cheresh, D.A. (1994) Requirement of vascular integrin alphavbeta3 for angiogenesis. Science, 264, 569-571. doi:10.1126/science.7512751

[14]   Storgard, C.M., et al. (1999) Decreased angiogenesis and arthritic disease in rabbits treated with an alphavbeta3 antagonist. Journal of Clinical Investigation, 103, 47-54. doi:10.1172/JCI3756

[15]   Horton, M.A., et al. (1991) Arg-Gly-Asp (RGD) peptides and the anti-vitronectin receptor antibody 23C6 inhibit dentine resorption and cell spreading by osteoclasts. Experimental Cell Research, 195, 368-375. doi:10.1016/0014-4827(91)90386-9

[16]   Davenport, R.J. and J.R. Munday, (2007) Alpha4-integrin antagonism—An effective approach for the treatment of inflammatory diseases? Drug Discovery Today, 12, 569576. doi:10.1016/j.drudis.2007.05.001

[17]   Kim, S., et al. (2000) Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. American Journal of Pathology, 156, 1345-1362. doi:10.1016/S0002-9440(10)65005-5

[18]   Goodman, S.L. and Picard, M. (2012) Integrins as therapeutic targets. Trends in Pharmacological Sciences, 33, 405-412. doi:10.1016/

[19]   Byron, A., et al. (2009) Anti-integrin monoclonal antibodies. Journal of Cell Science, 122, 4009-4011. doi:10.1242/jcs.056770

[20]   Mould, A.P., Akiyama, S.K. and Humphries, M.J. (1996) The inhibitory anti-beta1 integrin monoclonal antibody 13 recognizes an epitope that is attenuated by ligand occupancy. Evidence for allosteric inhibition of integrin function. The Journal of Biological Chemistry, 271, 20365-20374. doi:10.1074/jbc.271.34.20365

[21]   Artoni, A., et al. (2004) Integrin beta3 regions controlling binding of murine mAb 7E3: implications for the mechanism of integrin alphaIIbbeta3 activation. Proceedings of the National Academy of Sciences of the United States of America, 101, 13114-13120. doi:10.1073/pnas.0404201101

[22]   Weinreb, P.H., et al. (2004) Function-blocking integrin alphavbeta6 monoclonal antibodies: Distinct ligand-mimetic and nonligand-mimetic classes. The Journal of Biological Chemistry, 279, 17875-17887. doi:10.1074/jbc.M312103200

[23]   Deckmyn, H., et al. (1994) An echistatin-like Arg-GlyAsp (RGD)-containing sequence in the heavy chain CDR3 of a murine monoclonal antibody that inhibits human platelet glycoprotein IIb/IIIa function. British Journal of Haematology, 87, 562-571. doi:10.1111/j.1365-2141.1994.tb08313.x

[24]   Hynes, R.O., (2002) Integrins: Bidirectional, allosteric signaling machines. Cell, 110, 673-687. doi:10.1016/S0092-8674(02)00971-6

[25]   Nagarajan, S.R., et al. (2007) R-isomers of Arg-Gly-Asp (RGD) mimics as potent alphavbeta3 inhibitors. Bioorganic & Medicinal Chemistry, 15, 3783-3800. doi:10.1016/j.bmc.2007.03.034

[26]   Xiong, J.P., et al. (2002) Crystal structure of the extracellular segment of integrin alphavbeta3 in complex with an Arg-Gly-Asp ligand. Science, 296, 151-155. doi:10.1126/science.1069040

[27]   Liu, Z., Wang, F. and Chen, X. (2008) Integrin avb3Targeted Cancer Therapy. Drug Development Research, 69, 329-339. doi:10.1002/ddr.20265

[28]   Eble, J.A. and Haier, J. (2006) Integrins in cancer treatment. Current Cancer Drug Targets, 6, 89-105. doi:10.2174/156800906776056518

[29]   Tucker, G.C. (2003) Alpha v integrin inhibitors and cancer therapy. Current Opinion in Investigational Drugs, 4, 722-731.

[30]   Tucker, G.C. (2006) Integrins: Molecular targets in cancer therapy. Current Oncology Reports, 8, 96-103. doi:10.1007/s11912-006-0043-3

[31]   Kimura, R.H., et al. (2009) Engineered cystine knot peptides that bind alphavbeta3, alphavbeta5, and alpha5beta1 integrins with low-nanomolar affinity. Proteins, 77, 359369. doi:10.1002/prot.22441

[32]   Huang, T.F. (1998) What have snakes taught us about integrins? Cellular and Molecular Life Sciences, 54, 527-540. doi:10.1007/s000180050181

[33]   Yeh, C.H., et al. (2001) Rhodostomin, a snake venom disintegrin, inhibits angiogenesis elicited by basic fibroblast growth factor and suppresses tumor growth by a selective alphavbeta3 blockade of endothelial cells. Molecular Pharmacology, 59, 1333-1342.

[34]   Swenson, S., et al. (2004) Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression. Molecular Cancer Therapeutics, 3, 499-511.

[35]   Aota, S., Nomizu, M. and Yamada, K.M. (1994) The short amino acid sequence Pro-His-Ser-Arg-Asn in human fibronectin enhances cell-adhesive function. The Journal of Biological Chemistry, 269, 24756-24761.

[36]   Maeshima, Y., Colorado, P.C. and Kalluri, R. (2000) Two RGD-independent alphavbeta3 integrin binding sites on tumstatin regulate distinct anti-tumor properties. The Journal of Biological Chemistry, 275, 23745-23750. doi:10.1074/jbc.C000186200

[37]   Thevenard, J., et al. (2010) The YSNSG cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down-regulating endothelial cell migration. International Journal of Cancer, 126, 1055-1066.

[38]   Castel, S., et al. (2001) RGD peptides and monoclonal antibodies, antagonists of alpha v-integrin, enter the cells by independent endocytic pathways. Laboratory Investigation, 81, 1615-1626. doi:10.1038/labinvest.3780375

[39]   Paolillo, M., et al. (2009) Small molecule integrin antagonists in cancer therapy. Mini-Reviews in Medicinal Chemistry, 9, 1439-1446. doi:10.2174/138955709789957404

[40]   Heckmann, D., et al. (2009) Breaking the dogma of the metal-coordinating carboxylate group in integrin ligands: Introducing hydroxamic acids to the MIDAS to tune potency and selectivity. Angewandte Chemie International Edition, 48, 4436-4440. doi:10.1002/anie.200900206

[41]   Duggan, M.E. and Hutchinson, J.H. (2000) Ligands to the integrin receptor αvβ3. Expert opinion in therapeutic patents. 10, 1367-1383. doi:10.1517/13543776.10.9.1367

[42]   Hutchinson, J.H., et al. (2003) Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis. Journal of Medicinal Chemistry, 46, 4790-4798. doi:10.1021/jm030306r

[43]   Murphy, M.G., et al. (2005) Effect of L-000845704, an alphavbeta3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. The Journal of Clinical Endocrinology & Metabolism, 90, 2022-2028. doi:10.1210/jc.2004-2126

[44]   Komoriya, A., et al. (1991) The minimal essential sequence for a major cell type-specific adhesion site (CS1) within the alternatively spliced type III connecting segment domain of fibronectin is leucine-aspartic acid-valine. The Journal of Biological Chemistry, 266, 15075-15079.

[45]   Newham, P., et al. ((1997)).Alpha4 integrin binding interfaces on VCAM-1 and MAdCAM-1. Integrin binding footprints identify accessory binding sites that play a role in integrin specificity. The Journal of Biological Chemistry, 272, 19429-19440. doi:10.1074/jbc.272.31.19429

[46]   Lin, K., et al. (1999) Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses. Journal of Medicinal Chemistry, 42, 920-934. doi:10.1021/jm980673g

[47]   Hijazi, Y., et al. (2004) Pharmacokinetics, safety, and tolerability of R411, a dual alpha4beta1-alpha4beta7 integrin antagonist after oral administration at single and multiple once-daily ascending doses in healthy volunteers. The Journal of Clinical Pharmacology, 44, 1368-78. doi:10.1177/0091270004270147

[48]   Kumar, C.C. (2003) Integrin alphavbeta3 as a therapeutic target for blocking tumor-induced angiogenesis. Current Drug Targets, 4, 123-131. doi:10.2174/1389450033346830

[49]   Mousa, S.A. (2002) Anti-integrin as novel drug-discovery targets: Potential therapeutic and diagnostic implications. Current Opinion in Chemical Biology, 6, 534-541. doi:10.1016/S1367-5931(02)00350-2

[50]   Mousa, S.A. (2003) Alphav vitronectin receptors in vascular-mediated disorders. Medicinal Research Reviews, 23,190-199. doi:10.1002/med.10031

[51]   Goldring, S.R. and Gravallese, E.M. (2000) Pathogenesis of bone erosions in rheumatoid arthritis. Current Opinion in Rheumatology, 12,195-199. doi:10.1097/00002281-200005000-00006

[52]   Albelda, S.M., et al. (1990) Integrin distribution in malignant melanoma: Association of the beta3 subunit with tumor progression. Cancer Research, 50, 6757-6764.

[53]   Gladson, C.L. and Cheresh, D.A. (1991) Glioblastoma expression of vitronectin and the alphavbeta3 integrin. Adhesion mechanism for transformed glial cells. Journal of Clinical Investigation, 88, 1924-1932. doi:10.1172/JCI115516

[54]   Hanahan, D. and Folkman, J. (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86, 353-364. doi:10.1016/S0092-8674(00)80108-7

[55]   Ruegg, C., Dormond, O. and Foletti, A. (2002) Suppression of tumor angiogenesis through the inhibition of integrin function and signaling in endothelial cells: Which side to target? Endothelium, 9, 151-160. doi:10.1080/10623320213635

[56]   Weidner, N., et al. (1991) Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. The New England Journal of Medicine, 324, 1-8. doi:10.1056/NEJM199101033240101

[57]   Mizejewski, G.J. (1999) Role of integrins in cancer: Survey of expression patterns. Proceedings of the Society for Experimental Biology and Medicine, 222, 124-138. doi:10.1046/j.1525-1373.1999.d01-122.x

[58]   Tucker, G.C. (2002) Inhibitors of integrins. Current Opinion in Pharmacology, 2, 394-402. doi:10.1016/S1471-4892(02)00175-3

[59]   Friedlander, M., et al. (1995) Definition of two angiogenic pathways by distinct alpha v integrins. Science, 270, 1500-1502. doi:10.1126/science.270.5241.1500

[60]   MacDonald, T.J., et al. (2001) Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha v integrin antagonist. Neurosurgery, 48, 151-157.

[61]   Taga, T., et al. (2002) Alphav-integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. International Journal of Cancer, 98, 690-697. doi:10.1002/ijc.10265

[62]   Colevas, A.D., Scharf, O. and Schoenfeldt, M. (2004) Clinical trials referral resource. Current clinical trials of cilengitide, an alphav antagonist in clinical development as an anticancer agent. Oncology, 18, 1778, 1781-1782, 1784.

[63]   Reardon, D.A., et al. (2008) Cilengitide: An integrintargeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opinion on Investigational Drugs, 17, 1225-1235. doi:10.1517/13543784.17.8.1225

[64]   Weller, M., et al. (2009) Will integrin inhibitors have proangiogenic effects in the clinic? Nature Medicine, 15, 726. doi:10.1517/13543784.17.8.1225

[65]   Kurozumi, K., et al. (2012) Cilengitide treatment for malignant glioma: Current status and future direction. Neurologia Medico-Chirurgica, 52, 539-547. doi:10.2176/nmc.52.539

[66]   Manegold, C., et al. (2012) Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer. Investigational New Drugs, 31, 175-182.

[67]   Wu, H., et al. (1998) Stepwise in vitro affinity maturation of Vitaxin, an alphavbeta3-specific humanized mAb. Proceedings of the National Academy of Sciences of the United States of America, 95, 6037-6042. doi:10.1073/pnas.95.11.6037

[68]   Trikha, M., et al. (2004) CNTO 95, a fully human monoclonal antibody that inhibits alphav integrins, has antitumor and antiangiogenic activity in vivo. International Journal of Cancer, 110, 326-335. doi:10.1002/ijc.20116

[69]   Goel, H.L., et al. (2008) Integrins in prostate cancer progression. Endocrine-Related Cancer, 15, 657-664. doi:10.1677/ERC-08-0019

[70]   Liaw, L., et al. (1995) The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alphavbeta3 in smooth muscle cell migration to osteopontin in vitro. Journal of Clinical Investigation, 95, 713-724. doi:10.1172/JCI117718

[71]   Choi, E.T., et al. (1994) Inhibition of neointimal hyperplasia by blocking alphavbeta3 integrin with a small peptide antagonist GpenGRGDSPCA. Journal of Vascular Surgery, 19, 125-134. doi:10.1016/S0741-5214(94)70127-X

[72]   Bishop, G.G., et al. (2001) Selective alphavbeta3-receptor blockade reduces macrophage infiltration and restenosis after balloon angioplasty in the atherosclerotic rabbit. Circulation, 103, 1906-1911. doi:10.1161/01.CIR.103.14.1906

[73]   Coleman, K.R., et al. (1999). Vitaxin, a humanized monoclonal antibody to the vitronectin receptor (alphavbeta3), reduces neointimal hyperplasia and total vessel area after balloon injury in hypercholesterolemic rabbits. Circulation Research, 84, 1268-1276. doi:10.1161/01.RES.84.11.1268

[74]   Teitelbaum, S.L. (2000) Bone resorption by osteoclasts. Science, 289, 1504-1508. doi:10.1126/science.289.5484.1504

[75]   Parfitt, A.M. (1994) Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. Journal of Cellular Biochemistry, 55, 273-286. doi:10.1002/jcb.240550303

[76]   Teitelbaum, S.L. (2000) Osteoclasts, integrins, and osteoporosis. Journal of Bone and Mineral Metabolism, 18, 344-349. doi:10.1007/s007740070007

[77]   McHugh, K.P., et al. (2000) Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. Journal of Clinical Investigation, 105, 433-440. doi:10.1172/JCI8905

[78]   Ross, F.P., et al. (1993) Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alphavbeta3 potentiate bone resorption. The Journal of Biological Chemistry, 268, 99019907.

[79]   Engleman, V.W., et al. (1997) A peptidomimetic antagonist of the alphavbeta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. Journal of Clinical Investigation, 99, 2284-2292. doi:10.1172/JCI119404

[80]   McCabe, C.J. and Akehurst, R.L. (1997) Health economics in rheumatology. Baillière’s Clinical Rheumatology, 11, 145-156. doi:10.1016/S0950-3579(97)80038-6

[81]   Stupack, D.G., Storgard, C.M. and Cheresh, D.A. (1999) A role for angiogenesis in rheumatoid arthritis. Brazilian Journal of Medical and Biological Research, 32, 573581. doi:10.1590/S0100-879X1999000500011

[82]   Kimball, E.S. and Gross, J.L. (1991) Angiogenesis in pannus formation. Agents Actions, 34, 329-331. doi:10.1007/BF01988724

[83]   Ainola, M.M., et al. (2005) Pannus invasion and cartilage degradation in rheumatoid arthritis: Involvement of MM P-3 and interleukin-1beta. Clinical and Experimental Rheumatology, 23, 644-650.

[84]   Koch, A.E. (1998) Review: Angiogenesis: Implications for rheumatoid arthritis. Arthritis & Rheumatism, 41, 951-962. doi:10.1002/1529-0131(199806)41:6<951::AID-ART2>3.0.CO;2-D

[85]   Colville-Nash, P.R. and Scott, D.L. (1992) Angiogenesis and rheumatoid arthritis: Pathogenic and therapeutic implications. Annals of the Rheumatic Diseases, 51, 919925.

[86]   Wilder, R.L., (2002) Integrin alphavbeta3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases. Annals of the Rheumatic Diseases, 61, ii96-99. doi:10.1136/ard.51.7.919

[87]   Paleolog, E., (1997) Target effector role of vascular endothelium in the inflammatory response: Insights from the clinical trial of anti-TNF alpha antibody in rheumatoid arthritis. Molecular Pathology, 50, 225-233. doi:10.1136/mp.50.5.225

[88]   Badger, A.M., et al. (2001) Disease-modifying activity of SB 273005, an orally active, nonpeptide alphavbeta3 (vitronectin receptor) antagonist, in rat adjuvant-induced arthritis. Arthritis & Rheumatism, 44, 128-137. doi:10.1002/1529-0131(200101)44:1<128::AID-ANR17>3.0.CO;2-M

[89]   Luna, J., et al. (1996) Antagonists of integrin alphavbeta3 inhibit retinal neovascularization in a murine model. Laboratory Investigation, 75, 563-573.

[90]   Hammes, H.P., et al. (1996) Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nature Medicine, 2, 529-533. doi:10.1038/nm0596-529

[91]   Yasukawa, T., et al. (2004) Inhibition of experimental choroidal neovascularization in rats by an alphav-integrin antagonist. Current Eye Research, 28, 359-366. doi:10.1076/ceyr.28.5.359.28678

[92]   Santulli, R.J., et al. (2008) Studies with an orally bioavailable alpha v integrin antagonist in animal models of ocular vasculopathy: retinal neovascularization in mice and retinal vascular permeability in diabetic rats. Journal of Pharmacology and Experimental Therapeutics, 324, 894-901. doi:10.1124/jpet.107.131656

[93]   Coutre, S. and Leung, L. (1995) Novel antithrombotic therapeutics targeted against platelet glycoprotein IIb/IIIa. Annual Review of Medicine, 46, 257-265. doi:10.1146/

[94]   Jordan, R.E., Wagner, C.L., Mascelli, M., Treacy, G., Nedelman, M.A. and Woody, J.N. (1996) Preclinical development of c7E3 Fab; a mouse/human chimeric monoclonal antibody fragment that inhibits platelet function by blocking of GPIIb/IIIa receptors with the observations on the immunogenicity of c7E3 Fab in humans. In: H. M. A., Ed., Adhesion Receptors as Therapeutic Targets, CRC Press, Boca Raton.

[95]   Breuss, J.M., et al. (1993) Restricted distribution of integrin beta6 mRNA in primate epithelial tissues. Journal of Histochemistry & Cytochemistry, 41, 1521-1527. doi:10.1177/41.10.8245410

[96]   Breuss, J.M., et al. (1995) Expression of the beta6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. Journal of Cell Science, 108, 2241-2251.

[97]   Thomas, G.J., Nystrom, M.L. and Marshall, J.F. (2006) Alphavbeta6 integrin in wound healing and cancer of the oral cavity. Journal of Oral Pathology & Medicine, 35, 1-10. doi:10.1111/j.1600-0714.2005.00374.x

[98]   Busk, M., Pytela, R. and Sheppard, D. (1992) Characterization of the integrin alphavbeta6 as a fibronectinbinding protein. The Journal of Biological Chemistry, 267, 5790-5796.

[99]   Thomas, G.J., et al. (2001) Alphavbeta6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes. Journal of Investigative Dermatology, 116, 898-904. doi:10.1046/j.1523-1747.2001.01352.x

[100]   Clark, R.A., et al. (1996) Re-epithelialization of normal human excisional wounds is associated with a switch from alphavbeta5 to alphavbeta6 integrins. British Journal of Dermatology, 135, 46-51. doi:10.1111/j.1365-2133.1996.tb03606.x

[101]   Haapasalmi, K., et al. (1996) Keratinocytes in human wounds express alphavbeta6 integrin. Journal of Investigative Dermatology, 106, 42-48. doi:10.1111/1523-1747.ep12327199

[102]   Verrecchia, F. and Mauviel, A. (2002) Transforming growth factor-beta signaling through the Smad pathway: Role in extracellular matrix gene expression and regulation. Journal of Investigative Dermatology, 118, 211-215. doi:10.1046/j.1523-1747.2002.01641.x

[103]   Hsiao, J.R., et al. (2009) Cyclic alphavbeta6-targeting peptide selected from biopanning with clinical potential for head and neck squamous cell carcinoma. Head & Neck, 32, 160-172.

[104]   Thomas, G.J., et al. (2001) Expression of the alphav beta6 integrin promotes migration and invasion in squamous carcinoma cells. Journal of Investigative Dermatology, 117, 67-73. doi:10.1046/j.0022-202x.2001.01379.x

[105]   Ramos, D.M., et al. (2002) Expression of integrin beta 6 enhances invasive behavior in oral squamous cell carcinoma. Matrix Biology, 21, 297-307. doi:10.1016/S0945-053X(02)00002-1

[106]   Xue, H., et al. (2001) Role of the alpha v beta6 integrin in human oral squamous cell carcinoma growth in vivo and in vitro. Biochemical and Biophysical Research Communications, 288, 610-618. doi:10.1006/bbrc.2001.5813

[107]   Gleizes, P.E., et al. (1997) TGF-beta latency: Biological significance and mechanisms of activation. Stem Cells, 15, 190-197. doi:10.1002/stem.150190

[108]   Miyazono, K., et al. (1988) Latent high molecular weight complex of transforming growth factor beta1. Purification from human platelets and structural characterization. The Journal of Biological Chemistry, 263, 6407-6415.

[109]   Lawrence, D.A., (2001) Latent-TGF-beta: An overview. Molecular and Cellular Biochemistry, 219, 163-170. doi:10.1023/A:1010819716023

[110]   Sheppard, D. (2008) The role of integrins in pulmonary fibrosis. European Rspiratory Review, 17, 157-162. doi:10.1183/09059180.00010909

[111]   Munger, J.S., et al. (1999) The integrin alphavbeta6 binds and activates latent TGF beta 1: A mechanism for regulating pulmonary inflammation and fibrosis. Cell, 96, 319-328. doi:10.1016/S0092-8674(00)80545-0

[112]   Annes, J.P., Rifkin, D.B. and Munger, J.S. (2002) The integrin alphavbeta6 binds and activates latent TGFbeta3. FEBS Letters, 511, 65-68. doi:10.1016/S0014-5793(01)03280-X

[113]   Horan, G.S., et al. (2008) Partial inhibition of integrin alphavbeta6 prevents pulmonary fibrosis without exacerbating inflammation. American Journal of Respiratory and Critical Care Medicine, 177, 56-65. doi:10.1164/rccm.200706-805OC

[114]   Wang, B., et al. (2007) Role of alphavbeta6 integrin in acute biliary fibrosis. Hepatology, 46, 1404-1412. doi:10.1002/hep.21849

[115]   Huang, X.Z., et al. (1996) Inactivation of the integrin beta6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. The Journal of Cell Biology, 133, 921-928. doi:10.1083/jcb.133.4.921

[116]   Puthawala, K., et al. (2008) Inhibition of integrin alphav beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. American Journal of Respiratory and Critical Care Medicine, 177, 82-90. doi:10.1164/rccm.200706-806OC

[117]   Davenpeck, K.L., Sterbinsky, S.A. and Bochner, B.S. (1998) Rat neutrophils express alpha4 and beta1 integrins and bind to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Blood, 91, 2341-2346.

[118]   Jackson, D.Y. (2002) Alpha 4 integrin antagonists. Current Pharmaceutical Design, 8, 1229-1253.

[119]   Hyun, Y.M., Lefort, C.T. and Kim, M. (2009) Leukocyte integrins and their ligand interactions. Immunologic Research, 45,195-208. doi:10.1007/s12026-009-8101-1

[120]   Jackson, D.Y., et al. (1997) Potent alpha4beta 1 peptide antagonists as potential anti-inflammatory agents. Journal of Medicinal Chemistry, 40, 3359-3368. doi:10.1021/jm970175s

[121]   Yacyshyn, B.R. (2008) Adhesion molecule therapeutics in IBD. Inflammatory Bowel Diseases, 14, S279-280.

[122]   Gorfu, G., Rivera-Nieves, J. and Ley, K. (2009) Role of beta7 integrins in intestinal lymphocyte homing and retention. Current Molecular Medicine, 9, 836-850. doi:10.2174/156652409789105525

[123]   von Andrian, U.H. and Mempel, T.R. (2003) Homing and cellular traffic in lymph nodes. Nature Reviews Immunology, 3, 867-878. doi:10.1038/nri1222

[124]   Luster, A.D., Alon, R. and von Andrian, U.H. (2005) Immune cell migration in inflammation: Present and future therapeutic targets. Nature Immunology, 6, 11821190. doi:10.1038/ni1275

[125]   Ley, K., et al. (2007) Getting to the site of inflammation: The leukocyte adhesion cascade updated. Nature Reviews Immunology, 7, 678-689. doi:10.1038/nri2156

[126]   Lanzarotto, F., et al. (2006) Novel treatment options for inflammatory bowel disease: Targeting alpha 4 integrin. Drugs, 66, 1179-1189. doi:10.2165/00003495-200666090-00002

[127]   Sheremata, W.A., et al. (2005) The role of alpha-4 integrin in the aetiology of multiple sclerosis: Current knowledge and therapeutic implications. CNS Drugs, 19, 909-922. doi:10.2165/00023210-200519110-00002

[128]   Yednock, T.A., et al. (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha4beta 1 integrin. Nature, 356, 63-66. doi:10.1038/356063a0

[129]   Kingsley, G., Pitzalis, C. and Panayi, G.S. (1990) Immunogenetic and cellular immune mechanisms in rheumatoid arthritis: Relevance to new therapeutic strategies. British Journal of Rheumatology, 29, 58-64. doi:10.1093/rheumatology/29.1.58

[130]   Barbadillo, C., et al. (1995) Anti-integrin immunotherapy in rheumatoid arthritis: Protective effect of anti-alpha4 antibody in adjuvant arthritis. Springer Seminars in Immunopathology, 16, 427-436. doi:10.1007/BF00196098

[131]   Postigo, A.A., et al. (1992) Increased binding of synovial T lymphocytes from rheumatoid arthritis to endothelial-leukocyte adhesion molecule-1 (ELAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Journal of Clinical Investigation, 89, 1445-1452. doi:10.1172/JCI115734

[132]   Stoolman, L.M., (1989) Adhesion molecules controlling lymphocyte migration. Cell, 56, 907-910. doi:10.1016/0092-8674(89)90620-X

[133]   Metzger, W.J. (1995) Therapeutic approaches to asthma based on VLA-4 integrin and its counter receptors. Seminars in Immunopathology, 16, 467-478. doi:10.1007/BF00196101

[134]   Naclerio, R.M., et al. (1985) Inflammatory mediators in late antigen-induced rhinitis. The New England Journal of Medicine, 313, 65-70. doi:10.1056/NEJM198507113130201

[135]   Humphries, M.J., et al. (1986) Identification of an alternatively spliced site in human plasma fibronectin that mediates cell type-specific adhesion. The Journal of Cell Biology, 103, 2637-2647. doi:10.1083/jcb.103.6.2637

[136]   Guan, J.L. and Hynes, R.O. (1990) Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha4beta1. Cell, 60, 53-61. doi:10.1016/0092-8674(90)90715-Q

[137]   Stuve, O., et al. (2008) Alpha4-integrin antagonism with natalizumab: Effects and adverse effects. Journal of Neurology, 255, 58-65. doi:10.1007/s00415-008-6011-0

[138]   Langer-Gould, A., et al. (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. The New England Journal of Medicine, 353, 375381. doi:10.1056/NEJMoa051847

[139]   Kleinschmidt-DeMasters, B.K. and Tyler, K.L. (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. The New England Journal of Medicine, 353, 369-374. doi:10.1056/NEJMoa051782

[140]   Van Assche, G., et al. (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. The New England Journal of Medicine, 353, 362368. doi:10.1056/NEJMoa051586

[141]   Hauser, S.L. and Johnston, S.C. (2009) Balancing risk and reward: The question of natalizumab. Annals of Neurology, 66, A7-8. doi:10.1002/ana.21873

[142]   Schowinsky, J., et al. Natalizumab-associated complication? First case of peripheral T cell lymphoma. Acta Neuropathologica, 123, 751-752. doi:10.1007/s00401-012-0967-7

[143]   Schweikert, A., et al. (2009) Primary central nervous system lymphoma in a patient treated with natalizumab. Annals of Neurology, 66, 403-406. doi:10.1002/ana.21782

[144]   Soler, D., et al. (2009) The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflamematory bowel diseases. Journal of Pharmacology and Experimental Therapeutics, 330, 864-875. doi:10.1124/jpet.109.153973

[145]   Singh, J., et al. (2004) Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma. Current Topics in Medicinal Chemistry, 4, 1497-1507. doi:10.2174/1568026043387520

[146]   Ravensberg, A.J., et al. (2006) The effect of a single inhaled dose of a VLA-4 antagonist on allergen-induced airway responses and airway inflammation in patients with asthma. Allergy, 61, 1097-1103. doi:10.1111/j.1398-9995.2006.01146.x

[147]   Humphries, J.D., Byron, A. and Humphries, M.J. (2006) Integrin ligands at a glance. Journal of Cell Science, 119, 3901-3903. doi:10.1242/jcs.03098

[148]   Magnussen, A., et al. (2005) Rapid access of antibodies to alpha5beta1 integrin overexpressed on the luminal surface of tumor blood vessels. Cancer Research, 65, 27122721. doi:10.1158/0008-5472.CAN-04-2691

[149]   Parsons-Wingerter, P., et al. (2005) Uniform overexpression and rapid accessibility of alpha5beta1 integrin on blood vessels in tumors. American Journal of Pathology, 167, 193-211. doi:10.1016/S0002-9440(10)62965-3

[150]   Kita, D., et al. (2001) Expression of dominant-negative form of Ets-1 suppresses fibronectin-stimulated cell adhesion and migration through down-regulation of integrin alpha5 expression in U251 glioma cell line. Cancer Research, 61, 7985-7991.

[151]   Gong, J., et al. (1997) Role of alpha5beta1 integrin in determining malignant properties of colon carcinoma cells. Cellular differentiation, 8, 83-90.

[152]   Smallheer, J.M., et al. (2004) Synthesis and biological evaluation of nonpeptide integrin antagonists containing spirocyclic scaffolds. Bioorganic & Medicinal Chemistry Letters, 14, 383-387. doi:10.1016/j.bmcl.2003.10.057

[153]   Maglott, A., et al. (2006) The small alpha5beta1 integrin antagonist, SJ749, reduces proliferation and clonogenicity of human astrocytoma cells. Cancer Research, 66, 60026007. doi:10.1158/0008-5472.CAN-05-4105

[154]   Umeda, N., et al. (2006) Suppression and regression of choroidal neovascularization by systemic administration of an alpha5beta1 integrin antagonist. Molecular Pharmacology, 69, 1820-1828. doi:10.1124/mol.105.020941

[155]   Pastor, J.C., de la Rua, E.R. and Martin, F. (2002) Proliferative vitreoretinopathy: Risk factors and pathobiology. Progress in Retinal and Eye Research, 21, 127-144. doi:10.1016/S1350-9462(01)00023-4

[156]   Casaroli-Marano, R.P., Pagan, R. and Vilaro, S. (1999) Epithelial-mesenchymal transition in proliferative vitreoretinopathy: Intermediate filament protein expression in retinal pigment epithelial cells. Investigative Ophthalmology & Visual Science, 40, 2062-2072.

[157]   Jin, M., et al. (2000) Promotion of adhesion and migration of RPE cells to provisional extracellular matrices by TNF-alpha. Investigative Ophthalmology & Visual Science, 41, 4324-4332.

[158]   Okazaki, T., et al. (2009) Alpha5beta1 Integrin blockade inhibits lymphangiogenesis in airway inflammation. American Journal of Pathology, 174, 2378-2387. doi:10.2353/ajpath.2009.080942

[159]   Witte, M.H., et al. (2006) Structure function relationships in the lymphatic system and implications for cancer biology. Cancer and Metastasis Reviews, 25, 159-184. doi:10.1007/s10555-006-8496-2

[160]   Randolph, G.J., Angeli, V. and Swartz, M.A. (2005) Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nature Reviews Immunology, 5, 617-628. doi:10.1038/nri1670

[161]   Zhang, X., Groopman, J.E. and Wang, J.F. (2005). Extracellular matrix regulates endothelial functions through interaction of VEGFR-3 and integrin alpha5beta1. Jour-nal of Cellular Physiology, 202, 205-214. doi:10.1002/jcp.20106

[162]   Dietrich, T., et al. (2007) Inhibition of inflammatory lymphangiogenesis by integrin alpha5 blockade. American Journal of Pathology, 171, 361-372. doi:10.2353/ajpath.2007.060896

[163]   Ricart, A.D., et al. (2008) Volociximab, a chimeric monoclonal antibody that specifically binds alpha5beta1 integrin: A phase I, pharmacokinetic, and biological correlative study. Clinical Cancer Research, 14, 7924-7929. doi:10.1158/1078-0432.CCR-08-0378

[164]   Livant, D.L., et al. (2000) Anti-invasive, antitumorigenic, and antimetastatic activities of the PHSCN sequence in prostate carcinoma. Cancer Research, 60, 309-320.

[165]   Bouvard, D., et al. (2001) Functional consequences of integrin gene mutations in mice. Circulation Research, 89, 211-223. doi:10.1161/hh1501.094874

[166]   Varner, J.A. and Cheresh, D.A. (1996) Integrins and cancer. Current Opinion in Cell Biology, 8, 724-730. doi:10.1016/S0955-0674(96)80115-3

[167]   Reynolds, L.E., et al. (2002) Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nature Medicine, 8, 27-34. doi:10.1038/nm0102-27

[168]   Senger, D.R., et al. (2002) The alpha1beta1 and alpha2beta1 integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. American Journal of Pathology, 160, 195-204. doi:10.1016/S0002-9440(10)64363-5

[169]   Goh, K.L., Yang, J.T. and Hynes, R.O. (1997) Mesodermal defects and cranial neural crest apoptosis in alpha5 integrin-null embryos. Development, 124, 4309-4319.

[170]   Bader, B.L., et al. (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell, 95, 507-519. doi:10.1016/S0092-8674(00)81618-9

[171]   Legler, D.F., et al. (2001) Superactivation of integrin alphavbeta3 by low antagonist concentrations. Journal of Cell Science, 114, 1545-1553.

[172]   Reynolds, A.R., et al. (2009) Stimulation of tumor growth and angiogenesis by low concentrations of RGDmimetic integrin inhibitors. Nature Medicine, 15, 392400. doi:10.1038/nm.1941

[173]   Carmeliet, P., (2002) Integrin indecision. Nature Medicine, 8, 14-16. doi:10.1038/nm0102-14

[174]   Smith, J.J., Sorensen, A.G. and Thrall, J.H. (2003) Biomarkers in imaging: Realizing radiology’s future. Radiology, 227, 633-638. doi:10.1148/radiol.2273020518

[175]   Beer, A.J. and Schwaiger, M. (2008) Imaging of integrin alphavbeta3 expression. Cancer and Metastasis Reviews, 27, 631-644. doi:10.1007/s10555-008-9158-3

[176]   McDonald, D.M. and Choyke, P.L. (2003) Imaging of angiogenesis: From microscope to clinic. Nature Medicine, 9, 713-725. doi:10.1038/nm0603-713

[177]   Rudin, M. and Weissleder, R. (2003) Molecular imaging in drug discovery and development. Nature Reviews Drug Discovery, 2, 123-131. doi:10.1038/nrd1007

[178]   Wadas, T.J., et al. (2009) Targeting the alphavbeta3 integrin for small-animal PET/CT of osteolytic bone metastases. Journal of Nuclear Medicine, 50, 1873-1880. doi:10.2967/jnumed.109.067140

[179]   Friedlander, M., et al. (1996) Involvement of integrins alphavbeta3 and alphavbeta5 in ocular neovascular diseases. Proceedings of the National Academy of Sciences of the United States of America, 93, 9764-9769. doi:10.1073/pnas.93.18.9764

[180]   Kotys, M.S., et al. (2009) Profile order and time-dependent artifacts in contrast-enhanced coronary MR angiography at 3T: Origin and prevention. Magnetic Resonance in Medicine, 62, 292-299. doi:10.1002/mrm.21997

[181]   Chen, X., et al. (2004) Pegylated Arg-Gly-Asp peptide: 64Cu labeling and PET imaging of brain tumor alphavbeta3-integrin expression. Journal of Nuclear Medicine, 45, 1776-1783.

[182]   Wu, Y., et al. (2005) MicroPET imaging of glioma integrin alphavbeta3 expression using (64)Cu-labeled tetrameric RGD peptide. Journal of Nuclear Medicine, 46, 1707-1718.

[183]   Cai, W., et al. (2006) In vitro and in vivo characterization of 64Cu-labeled Abegrin, a humanized monoclonal antibody against integrin alphavbeta3. Cancer Research, 66, 9673-9681. doi:10.1158/0008-5472.CAN-06-1480

[184]   Kimura, R.H., et al. (2009) Engineered knottin peptides: A new class of agents for imaging integrin expression in living subjects. Cancer Research, 69, 2435-2442. doi:10.1158/0008-5472.CAN-08-2495

[185]   Hamidi, S., et al. (2000) Expression of alphavbeta6 integrin in oral leukoplakia. British Journal of Cancer, 82, 1433-1440. doi:10.1054/bjoc.1999.1130

[186]   Hausner, S.H., et al. (2009) Targeted in vivo imaging of integrin alpha v beta6 with an improved radiotracer and its relevance in a pancreatic tumor model. Cancer Research, 69, 5843-5850. doi:10.1158/0008-5472.CAN-08-4410

[187]   Liu, Z., et al. (2007) In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nature Nanotechnology, 2, 47-52. doi:10.1038/nnano.2006.170

[188]   Schmieder, A.H., et al. (2008) Three-dimensional MR mapping of angiogenesis with alpha5beta1(alphavbeta3)targeted theranostic nanoparticles in the MDA-MB-435 xenograft mouse model. The FASEB Journal, 22, 41794189. doi:10.1096/fj.08-112060

[189]   Daldrup-Link, H.E., Simon, G.H. and Brasch, R.C. (2006) Imaging of tumor angiogenesis: Current approaches and future prospects. Current Pharmaceutical Design, 12, 2661-2672. doi:10.2174/138161206777698774

[190]   Kaufmann, B.A. and Lindner, J.R. (2007) Molecular imaging with targeted contrast ultrasound. Current Opinion in Biotechnology, 18, 11-16. doi:10.1016/j.copbio.2007.01.004

[191]   Willmann, J.K., et al. (2010) Targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with contrast microbubbles conjugated to integrin-binding knottin peptides. Journal of Nuclear Medicine, 51, 433-440. doi:10.2967/jnumed.109.068007

[192]   Chen, X., Conti, P.S. and Moats, R.A. (2004) In vivo near-infrared fluorescence imaging of integrin alphav beta3 in brain tumor xenografts. Cancer Research, 64, 8009-8014. doi:10.1158/0008-5472.CAN-04-1956

[193]   von Wallbrunn, A., et al. (2007) In vivo imaging of integrin alphavbeta3 expression using fluorescence-mediated tomography. European Journal of Nuclear Medicine and Molecular, 34, 745-754. doi:10.1007/s00259-006-0269-1

[194]   Cai, W. Hsu, A. R., Li, Z.-B. and Chen, X.Y. (2007) Are quantum dots ready for in vivo imaging in human subjects? Nanoscale Research Letters, 2, 265-281. doi:10.1007/s11671-007-9061-9

[195]   Wang, Z., Chui, W.K and Ho, P.C. (2010) Integrin targeted drug and gene delivery. Expert Opinion on Drug Delivery, 7, 159-171. doi:10.1517/17425240903468696

[196]   Arap, W., Pasqualini, R. and Ruoslahti, E. (1998) Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science, 279, 377-380.

[197]   Burkhart, D.J., et al. (2004) Doxorubicin-formaldehyde conjugates targeting alphavbeta3 integrin. Molecular Cancer Therapeutics, 3, 1593-1604.

[198]   Chen, X., et al. (2005) Synthesis and biological evaluation of dimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drug delivery. Journal of Medicinal Chemistry, 48, 1098-1106. doi:10.1021/jm049165z

[199]   Pilkington-Miksa, M., et al. (2012) Design, synthesis, and biological evaluation of novel cRGD-paclitaxel conjugates for integrin-assisted drug delivery. Bioconjugate Chemistry, 23, 1610-1622. doi:10.1021/bc300164t

[200]   Curnis, F., et al. (2004) Coupling tumor necrosis factor-alpha with alphav integrin ligands improves its antineoplastic activity. Cancer Research, 64, 565-571. doi:10.1158/0008-5472.CAN-03-1753

[201]   Danhier, F., et al. (2009) Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles loaded with paclitaxel. Journal of Controlled Release, 140, 166-173. doi:10.1016/j.jconrel.2009.08.011

[202]   Zhou, H.F., et al. (2009) Alphavbeta3-targeted nanotherapy suppresses inflammatory arthritis in mice. The FASEB Journal, 23, 2978-2985. doi:10.1096/fj.09-129874

[203]   Hood, J.D., et al. (2002) Tumor regression by targeted gene delivery to the neovasculature. Science, 296, 24042407. doi:10.1126/science.1070200

[204]   Bhattacharyya, J., et al. (2009) Single subcutaneous administration of RGDK-lipopeptide: rhPDGF-B gene complex heals wounds in streptozotocin-induced diabetic rats. Molecular Pharmaceutics, 6, 918-927. doi:10.1021/mp800231z

[205]   Peer, D. and Shimaoka, M. (2009) Systemic siRNA delivery to leukocyte-implicated diseases. Cell Cycle, 8, 853-859. doi:10.4161/cc.8.6.7936

[206]   Waite, C.L. and Roth, C.M. (2009) Pamam-Rgd conjugates enhance siRNA delivery through a multicellular spheroid model of malignant glioma. Bioconjugate Chemistry, 20, 1908-1916. doi:10.1021/bc900228m

[207]   Lemieux, J.M., Horowitz, M.C. and Kacena, M.A. (2010) Involvement of integrins alpha3beta1 and alpha5beta1 and glycoprotein IIb in megakaryocyte-induced osteoblast proliferation. Journal of Cellular Biochemistry, 109, 927-932.

[208]   Cordes, N. and Park, C.C. (2007) Beta1 integrin as a molecular therapeutic target. International Journal of Radiation Biology, 83, 753-760. doi:10.1080/09553000701639694

[209]   Haubner, R., et al. (2005) Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLOS Medicine, 2, e70.