Targeting receptor-mediated endocytotic pathways with nanoparticles: Rationale and advances

Sutherland, 1981, Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin, Proc. Natl. Acad. Sci. U. S. A., 78, 4515, 10.1073/pnas.78.7.4515 Widera, 2003, Mechanisms of TfR-mediated transcytosis and sorting in epithelial cells and applications toward drug delivery, Adv. Drug Deliv. Rev., 55, 1439, 10.1016/j.addr.2003.07.004 Vidal, 1985, LDL-mediated targeting of liposomes to leukemic lymphocytes in vitro, EMBO J., 4, 2461, 10.1002/j.1460-2075.1985.tb03957.x Rajendran, 2010, Subcellular targeting strategies for drug design and delivery, Nat. Rev. Drug Discov., 9, 29, 10.1038/nrd2897 Sahay, 2010, Endocytosis of nanomedicines, J. Control. Release, 145, 182, 10.1016/j.jconrel.2010.01.036 Pearse, 1987, Structure and assembly of coated vesicles, Annu. Rev. Biophys. Biophys. Chem., 16, 49, 10.1146/annurev.bb.16.060187.000405 Goldstein, 1985, Receptor-mediated endocytosis: concepts emerging from the LDL receptor system, Annu. Rev. Cell Biol., 1, 1, 10.1146/annurev.cb.01.110185.000245 Doherty, 2009, Mechanisms of endocytosis, Annu. Rev. Biochem., 78, 857, 10.1146/annurev.biochem.78.081307.110540 McMahon, 2011, Molecular mechanism and physiological functions of clathrin-mediated endocytosis, Nat. Rev. Mol. Cell Biol., 12, 517, 10.1038/nrm3151 Traub, 2009, Tickets to ride: selecting cargo for clathrin-regulated internalization, Nat. Rev. Mol. Cell Biol., 10, 583, 10.1038/nrm2751 Grant, 2009, Pathways and mechanisms of endocytic recycling, Nat. Rev. Mol. Cell Biol., 10, 597, 10.1038/nrm2755 Reider, 2011, Endocytic adaptors—social networking at the plasma membrane, J. Cell Sci., 124, 1613, 10.1242/jcs.073395 Brodsky, 2012, Diversity of clathrin function: new tricks for an old protein, Annu. Rev. Cell Dev. Biol., 28, 17.1, 10.1146/annurev-cellbio-101011-155716 Bonazzi, 2011, Clathrin phosphorylation is required for actin recruitment at sites of bacterial adhesion and internalization, J. Cell Biol., 195, 525, 10.1083/jcb.201105152 Yoo, 2010, Polymer particles that switch shape in response to a stimulus, Proc. Natl. Acad. Sci. U. S. A., 107, 11205, 10.1073/pnas.1000346107 Khormaee, 2010, The influence of aromatic side-chains on the aqueous properties of pH-sensitive poly(l-lysine iso-phthalamide) derivatives, J. Biomater. Sci. Polym. Ed., 21, 1573, 10.1163/092050609X12519805626194 Kyriakides, 2002, pH-sensitive polymers that enhance intracellular drug delivery in vivo, J. Control. Release, 78, 295, 10.1016/S0168-3659(01)00504-1 Wu, 2011, A novel vaccine delivery system: biodegradable nanoparticles in thermosensitive hydrogel, Growth Factors, 29, 290, 10.3109/08977194.2011.624517 Zhan, 2011, Acid-activatable prodrug nanogels for efficient intracellular doxorubicin release, Biomacromolecules, 12, 3612, 10.1021/bm200876x Cross, 2009, Composition and functions of the influenza fusion peptide, Protein Pept. Lett., 16, 766, 10.2174/092986609788681715 Bavdek, 2012, pH dependence of listeriolysin O aggregation and pore-forming ability, FEBS J., 279, 126, 10.1111/j.1742-4658.2011.08405.x Terra, 2007, Structural and functional behavior of biologically active monomeric melittin, J. Mol. Graph. Model., 25, 767, 10.1016/j.jmgm.2006.06.006 Donaldson, 2011, ARF family G proteins and their regulators: roles in membrane transport, development and disease, Nat. Rev. Mol. Cell Biol., 12, 362, 10.1038/nrm3117 Wernick, 2010, Cholera toxin: an intracellular journey into the cytosol by way of the endoplasmic reticulum, Toxins (Basel), 2, 310, 10.3390/toxins2030310 Sandvig, 2010, Endocytosis and retrograde transport of Shiga toxin, Toxicon, 56, 1181, 10.1016/j.toxicon.2009.11.021 Bitler, 2010, MUC1 regulates nuclear localization and function of the epidermal growth factor receptor, J. Cell Sci., 123, 1716, 10.1242/jcs.062661 Polishchuk, 2004, Delivery of raft-associated, GPI-anchored proteins to the apical surface of polarized MDCK cells by a transcytotic pathway, Nat. Cell Biol., 6, 297, 10.1038/ncb1109 Rojas, 2002, Immunoglobulin transport across polarized epithelial cells, Nat. Rev. Mol. Cell Biol., 3, 944, 10.1038/nrm972 Tesar, 2008, The chicken yolk sac IgY receptor, a mammalian mannose receptor family member, transcytoses IgY across polarized epithelial cells, Mol. Biol. Cell, 19, 1587, 10.1091/mbc.E07-09-0972 He, 2008, FcRn-mediated antibody transport across epithelial cells revealed by electron tomography, Nature, 455, 542, 10.1038/nature07255 Predescu, 2007, Molecular determinants of endothelial transcytosis and their role in endothelial permeability, Am. J. Physiol. Lung Cell. Mol. Physiol., 293, L823, 10.1152/ajplung.00436.2006 Roopenian, 2007, FcRn: the neonatal Fc receptor comes of age, Nat. Rev. Immunol., 7, 715, 10.1038/nri2155 Johansen, 2011, Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity, Mucosal Immunol., 4, 598, 10.1038/mi.2011.37 Herve, 2008, CNS delivery via adsorptive transcytosis, AAPS J., 10, 455, 10.1208/s12248-008-9055-2 Fuchs, 2004, Endocytic and transcytotic processes in villous syncytiotrophoblast: role in nutrient transport to the human fetus, Traffic, 5, 725, 10.1111/j.1600-0854.2004.00221.x Altschuler, 2003, The apical compartment: trafficking pathways, regulators and scaffolding proteins, Curr. Opin. Cell Biol., 15, 423, 10.1016/S0955-0674(03)00084-X Tuma, 2003, Transcytosis: crossing cellular barriers, Physiol. Rev., 83, 871, 10.1152/physrev.00001.2003 Mostov, 2003, Polarized epithelial membrane traffic: conservation and plasticity, Nat. Cell Biol., 5, 287, 10.1038/ncb0403-287 Jones, 1972, The mechanism of intestinal uptake and transcellular transport of IgG in the neonatal rat, J. Clin. Invest., 51, 2916, 10.1172/JCI107116 Rodewald, 1976, pH-dependent binding of immunoglobulins to intestinal cells of the neonatal rat, J. Cell Biol., 71, 666, 10.1083/jcb.71.2.666 Simister, 1996, An IgG-transporting Fc receptor expressed in the syncytiotrophoblast of human placenta, Eur. J. Immunol., 26, 1527, 10.1002/eji.1830260718 Leach, 1996, Isolation from human placenta of the IgG transporter, FcRn, and localization to the syncytiotrophoblast: implications for maternal-fetal antibody transport, J. Immunol., 157, 3317, 10.4049/jimmunol.157.8.3317 Jerdeva, 2010, Comparison of FcRn- and pIgR-mediated transport in MDCK cells by fluorescence confocal microscopy, Traffic, 11, 1205, 10.1111/j.1600-0854.2010.01083.x Tzaban, 2009, The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity, J. Cell Biol., 185, 673, 10.1083/jcb.200809122 Dickinson, 1999, Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line, J. Clin. Invest., 104, 903, 10.1172/JCI6968 Yoshida, 2004, Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells, Immunity, 20, 769, 10.1016/j.immuni.2004.05.007 Li, 2011, Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection, Proc. Natl. Acad. Sci. U. S. A., 108, 4388, 10.1073/pnas.1012861108 Ben Suleiman, 2012, Neonatal Fc receptor for IgG (FcRn) expressed in the gastric epithelium regulates bacterial infection in mice, Mucosal Immunol., 5, 87, 10.1038/mi.2011.53 Bitonti, 2004, Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway, Proc. Natl. Acad. Sci. U. S. A., 101, 9763, 10.1073/pnas.0403235101 Dumont, 2005, Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway, J. Aerosol Med., 18, 294, 10.1089/jam.2005.18.294 Zhang, 2001, Mediated efflux of IgG molecules from brain to blood across the blood–brain barrier, J. Neuroimmunol., 114, 168, 10.1016/S0165-5728(01)00242-9 Deane, 2005, IgG-assisted age-dependent clearance of Alzheimer's amyloid beta peptide by the blood–brain barrier neonatal Fc receptor, J. Neurosci., 25, 11495, 10.1523/JNEUROSCI.3697-05.2005 Roopenian, 2003, The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG–Fc-coupled drugs, J. Immunol., 170, 3528, 10.4049/jimmunol.170.7.3528 Chaudhury, 2003, The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan, J. Exp. Med., 197, 315, 10.1084/jem.20021829 von Kleist, 2011, Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition, Cell, 146, 471, 10.1016/j.cell.2011.06.025 Polo, 2006, Endocytosis conducts the cell signaling orchestra, Cell, 124, 897, 10.1016/j.cell.2006.02.025 Lakadamyali, 2006, Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes, Cell, 124, 997, 10.1016/j.cell.2005.12.038 Gkouvatsos, 2012, Regulation of iron transport and the role of transferrin, Biochim. Biophys. Acta, 1820, 188, 10.1016/j.bbagen.2011.10.013 Gao, 2009, Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression, Cell Metab., 9, 217, 10.1016/j.cmet.2009.01.010 Schmidt, 2008, The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression, Cell Metab., 7, 205, 10.1016/j.cmet.2007.11.016 Tosoni, 2005, TTP specifically regulates the internalization of the transferrin receptor, Cell, 123, 875, 10.1016/j.cell.2005.10.021 Chen, 2009, Transferrin-directed internalization and cycling of transferrin receptor 2, Traffic, 10, 1488, 10.1111/j.1600-0854.2009.00961.x Norouziyan, 2008, Tyrphostin A8 stimulates a novel trafficking pathway of apically endocytosed transferrin through Rab11-enriched compartments in Caco-2 cells, Am. J. Physiol. Cell Physiol., 294, C7, 10.1152/ajpcell.00372.2006 Descamps, 1996, Receptor-mediated transcytosis of transferrin through blood–brain barrier endothelial cells, Am. J. Physiol., 270, H1149 Christensen, 2002, Megalin and cubilin: multifunctional endocytic receptors, Nat. Rev. Mol. Cell Biol., 3, 256, 10.1038/nrm778 Maurer, 2005, Endocytosis of megalin by visceral endoderm cells requires the Dab2 adaptor protein, J. Cell Sci., 118, 5345, 10.1242/jcs.02650 Mishra, 2008, Internalization of LDL-receptor superfamily yolk-protein receptors during mosquito oogenesis involves transcriptional regulation of PTB-domain adaptors, J. Cell Sci., 121, 1264, 10.1242/jcs.025833 Morris, 2001, Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2, Traffic, 2, 111, 10.1034/j.1600-0854.2001.020206.x Mishra, 2002, Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor, EMBO J., 21, 4915, 10.1093/emboj/cdf487 He, 2002, ARH is a modular adaptor protein that interacts with the LDL receptor, clathrin, and AP-2, J. Biol. Chem., 277, 44044, 10.1074/jbc.M208539200 Sigismund, 2005, Clathrin-independent endocytosis of ubiquitinated cargos, Proc. Natl. Acad. Sci. U. S. A., 102, 2760, 10.1073/pnas.0409817102 Kazazic, 2009, Epsin 1 is involved in recruitment of ubiquitinated EGF receptors into clathrin-coated pits, Traffic, 10, 235, 10.1111/j.1600-0854.2008.00858.x Sorkin, 2009, Endocytosis and intracellular trafficking of ErbBs, Exp. Cell Res., 315, 683, 10.1016/j.yexcr.2008.07.029 Madshus, 2009, Internalization and intracellular sorting of the EGF receptor: a model for understanding the mechanisms of receptor trafficking, J. Cell Sci., 122, 3433, 10.1242/jcs.050260 McNiven, 2006, Big gulps: specialized membrane domains for rapid receptor-mediated endocytosis, Trends Cell Biol., 16, 487, 10.1016/j.tcb.2006.08.007 Swanson, 2008, Shaping cups into phagosomes and macropinosomes, Nat. Rev. Mol. Cell Biol., 9, 639, 10.1038/nrm2447 Kerr, 2009, Defining macropinocytosis, Traffic, 10, 364, 10.1111/j.1600-0854.2009.00878.x Lim, 2011, Macropinocytosis: an endocytic pathway for internalising large gulps, Immunol. Cell Biol., 89, 836, 10.1038/icb.2011.20 Jones, 2007, Macropinocytosis: searching for an endocytic identity and role in the uptake of cell penetrating peptides, J. Cell. Mol. Med., 11, 670, 10.1111/j.1582-4934.2007.00062.x Kaplan, 2005, Cationic TAT peptide transduction domain enters cells by macropinocytosis, J. Control. Release, 102, 247, 10.1016/j.jconrel.2004.10.018 Nakase, 2004, Cellular uptake of arginine-rich peptides: roles for macropinocytosis and actin rearrangement, Mol. Ther., 10, 1011, 10.1016/j.ymthe.2004.08.010 Zaro, 2006, Membrane transduction of oligoarginine in HeLa cells is not mediated by macropinocytosis, Mol. Pharm., 3, 181, 10.1021/mp0500869 Nishimura, 2008, Combinatorial targeting of the macropinocytotic pathway in leukemia and lymphoma cells, J. Biol. Chem., 283, 11752, 10.1074/jbc.M708849200 McNiven, 2006, Vesicle formation at the plasma membrane and trans-Golgi network: the same but different, Science, 313, 1591, 10.1126/science.1118133 McNiven, 2006, Focus on membrane dynamics, Trends Cell Biol., 16, 485, 10.1016/j.tcb.2006.08.010 Lipardi, 1998, Caveolin transfection results in caveolae formation but not apical sorting of glycosylphosphatidylinositol (GPI)-anchored proteins in epithelial cells, J. Cell Biol., 140, 617, 10.1083/jcb.140.3.617 Hansen, 2010, Exploring the caves: cavins, caveolins and caveolae, Trends Cell Biol., 20, 177, 10.1016/j.tcb.2010.01.005 Hill, 2008, PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function, Cell, 132, 113, 10.1016/j.cell.2007.11.042 Liu, 2008, Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance, Cell Metab., 8, 310, 10.1016/j.cmet.2008.07.008 Bastiani, 2010, Caveolae at a glance, J. Cell Sci., 123, 3831, 10.1242/jcs.070102 Nichols, 2002, A distinct class of endosome mediates clathrin-independent endocytosis to the Golgi complex, Nat. Cell Biol., 4, 374, 10.1038/ncb787 Parton, 2003, Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms, Traffic, 4, 724, 10.1034/j.1600-0854.2003.00128.x Sprenger, 2006, Spatial segregation of transport and signalling functions between human endothelial caveolae and lipid raft proteomes, Biochem. J., 400, 401, 10.1042/BJ20060355 Pelkmans, 2004, Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic, Cell, 118, 767, 10.1016/j.cell.2004.09.003 Hayer, 2010, Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation, J. Cell Biol., 191, 615, 10.1083/jcb.201003086 Predescu, 2002, Transport of nitrated albumin across continuous vascular endothelium, Proc. Natl. Acad. Sci. U. S. A., 99, 13932, 10.1073/pnas.212253499 Tiruppathi, 2004, Albumin mediates the transcytosis of myeloperoxidase by means of caveolae in endothelial cells, Proc. Natl. Acad. Sci. U. S. A., 101, 7699, 10.1073/pnas.0401712101 Mehta, 2004, Integrated control of lung fluid balance, Am. J. Physiol. Lung Cell. Mol. Physiol., 287, L1081, 10.1152/ajplung.00268.2004 Oh, 2007, Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung, Nat. Biotechnol., 25, 327, 10.1038/nbt1292 Hansen, 2009, Molecular mechanisms of clathrin-independent endocytosis, J. Cell Sci., 122, 1713, 10.1242/jcs.033951 Howes, 2010, Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells, J. Cell Biol., 190, 675, 10.1083/jcb.201002119 Howes, 2010, Molecules, mechanisms, and cellular roles of clathrin-independent endocytosis, Curr. Opin. Cell Biol., 22, 519, 10.1016/j.ceb.2010.04.001 Mayor, 1994, Sequestration of GPI-anchored proteins in caveolae triggered by cross-linking, Science, 264, 1948, 10.1126/science.7516582 Sabharanjak, 2004, Folate receptor endocytosis and trafficking, Adv. Drug Deliv. Rev., 56, 1099, 10.1016/j.addr.2004.01.010 Kalia, 2006, Arf6-independent GPI-anchored protein-enriched early endosomal compartments fuse with sorting endosomes via a Rab5/phosphatidylinositol-3′-kinase-dependent machinery, Mol. Biol. Cell, 17, 3689, 10.1091/mbc.E05-10-0980 Sabharanjak, 2002, GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway, Dev. Cell, 2, 411, 10.1016/S1534-5807(02)00145-4 Naslavsky, 2004, Characterization of a nonclathrin endocytic pathway: membrane cargo and lipid requirements, Mol. Biol. Cell, 15, 3542, 10.1091/mbc.E04-02-0151 Eyster, 2009, Discovery of new cargo proteins that enter cells through clathrin-independent endocytosis, Traffic, 10, 590, 10.1111/j.1600-0854.2009.00894.x Slimane, 2003, Raft-mediated trafficking of apical resident proteins occurs in both direct and transcytotic pathways in polarized hepatic cells: role of distinct lipid microdomains, Mol. Biol. Cell, 14, 611, 10.1091/mbc.E02-08-0528 Hughes, 2009, Pertuzumab increases epidermal growth factor receptor down-regulation by counteracting epidermal growth factor receptor-ErbB2 heterodimerization, Mol. Cancer Ther., 8, 1885, 10.1158/1535-7163.MCT-09-0291 Kumari, 2008, Nicotinic acetylcholine receptor is internalized via a Rac-dependent, dynamin-independent endocytic pathway, J. Cell Biol., 181, 1179, 10.1083/jcb.200709086 Tesar, 2006, Ligand valency affects transcytosis, recycling and intracellular trafficking mediated by the neonatal Fc receptor, Traffic, 7, 1127, 10.1111/j.1600-0854.2006.00457.x Maeda, 2009, Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect, Eur. J. Pharm. Biopharm., 71, 409, 10.1016/j.ejpb.2008.11.010 Kirpotin, 2006, Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models, Cancer Res., 66, 6732, 10.1158/0008-5472.CAN-05-4199 Bartlett, 2007, Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging, Proc. Natl. Acad. Sci. U. S. A., 104, 15549, 10.1073/pnas.0707461104 Choi, 2010, Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles, Proc. Natl. Acad. Sci. U. S. A., 107, 1235, 10.1073/pnas.0914140107 Faraji, 2009, Nanoparticles in cellular drug delivery, Bioorg. Med. Chem., 17, 2950, 10.1016/j.bmc.2009.02.043 Drummond, 1999, Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors, Pharmacol. Rev., 51, 691 Lai, 2009, Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues, Adv. Drug Deliv. Rev., 61, 158, 10.1016/j.addr.2008.11.002 De Jong, 2008, Drug delivery and nanoparticles:applications and hazards, Int. J. Nanomedicine, 3, 133, 10.2147/IJN.S596 Yadav, 2011, Effect of size on the biodistribution and blood clearance of etoposide-loaded PLGA Nanoparticles, PDA J. Pharm. Sci. Technol., 65, 131 Gaumet, 2008, Nanoparticles for drug delivery: the need for precision in reporting particle size parameters, Eur. J. Pharm. Biopharm., 69, 1, 10.1016/j.ejpb.2007.08.001 Cho, 2008, Therapeutic nanoparticles for drug delivery in cancer, Clin. Cancer Res., 14, 1310, 10.1158/1078-0432.CCR-07-1441 Leikina, 2002, Reversible stages of the low-pH-triggered conformational change in influenza virus hemagglutinin, EMBO J., 21, 5701, 10.1093/emboj/cdf559 Simoes, 2004, On the formulation of pH-sensitive liposomes with long circulation times, Adv. Drug Deliv. Rev., 56, 947, 10.1016/j.addr.2003.10.038 Chen, 2011, Effects of receptor binding on plasma half-life of bifunctional transferrin fusion proteins, Mol. Pharm., 8, 457, 10.1021/mp1003064 Vecchione, 2011, EGFR-targeted therapy, Exp. Cell Res., 317, 2765, 10.1016/j.yexcr.2011.08.021 Tseng, 2009, The use of biotinylated-EGF-modified gelatin nanoparticle carrier to enhance cisplatin accumulation in cancerous lungs via inhalation, Biomaterials, 30, 3476, 10.1016/j.biomaterials.2009.03.010 Hadjipanayis, 2010, EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma, Cancer Res., 70, 6303, 10.1158/0008-5472.CAN-10-1022 Austin, 2004, Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin, Mol. Biol. Cell, 15, 5268, 10.1091/mbc.E04-07-0591 Leonard, 2008, Sorting of EGF and transferrin at the plasma membrane and by cargo-specific signaling to EEA1-enriched endosomes, J. Cell Sci., 121, 3445, 10.1242/jcs.031484 Leslie, 2005, EGF is internalized and degraded, J. Cell Biol., 1, 3 Liu, 2011, Tumor specific delivery and therapy by double-targeted nanostructured lipid carriers with anti-VEGFR-2 antibody, Mol. Pharm., 8, 2291, 10.1021/mp200402e Overington, 2006, How many drug targets are there?, Nat. Rev. Drug Discov., 5, 993, 10.1038/nrd2199 Kroeze, 2003, G-protein-coupled receptors at a glance, J. Cell Sci., 116, 4867, 10.1242/jcs.00902 Hild, 2010, G protein-coupled receptors function as logic gates for nanoparticle binding and cell uptake, Proc. Natl. Acad. Sci. U. S. A., 107, 10667, 10.1073/pnas.0912782107 Hanyaloglu, 2008, Regulation of GPCRs by endocytic membrane trafficking and its potential implications, Annu. Rev. Pharmacol. Toxicol., 48, 537, 10.1146/annurev.pharmtox.48.113006.094830 Insel, 2007, Impact of GPCRs in clinical medicine: monogenic diseases, genetic variants and drug targets, Biochim. Biophys. Acta, 1768, 994, 10.1016/j.bbamem.2006.09.029 Zhou, 2007, Peptide-labeled quantum dots for imaging GPCRs in whole cells and as single molecules, Bioconjug. Chem., 18, 323, 10.1021/bc0601929 Hartmann, 2007, Folate receptor overexpression is associated with poor outcome in breast cancer, Int. J. Cancer, 121, 938, 10.1002/ijc.22811 Iwakiri, 2008, Expression status of folate receptor alpha is significantly correlated with prognosis in non-small-cell lung cancers, Ann. Surg. Oncol., 15, 889, 10.1245/s10434-007-9755-3 Chen, 2009, Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide, Mol. Cancer Ther., 8, 1955, 10.1158/1535-7163.MCT-09-0045 Zhao, 2008, Targeted drug delivery via folate receptors, Expert Opin. Drug Deliv., 5, 309, 10.1517/17425247.5.3.309 Gabizon, 2010, Improved therapeutic activity of folate-targeted liposomal doxorubicin in folate receptor-expressing tumor models, Cancer Chemother. Pharmacol., 66, 43, 10.1007/s00280-009-1132-4 Nichols, 2009, Endocytosis of lipid-anchored proteins: excluding GEECs from the crowd, J. Cell Biol., 186, 457, 10.1083/jcb.200907119 Lakhan, 2009, Endocytosis of glycosylphosphatidylinositol-anchored proteins, J. Biomed. Sci., 16, 93, 10.1186/1423-0127-16-93 Saeed, 2011, Modular construction of multifunctional bioresponsive cell-targeted nanoparticles for gene delivery, Bioconjug. Chem., 22, 156, 10.1021/bc100149g Liu, 2012, Modular synthesis of folate conjugated ternary copolymers: polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol)-folate for targeted gene delivery, Bioconjugate Chem., 23, 1211, 10.1021/bc300025d Werner, 2011, Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis, Biomaterials, 32, 8548, 10.1016/j.biomaterials.2011.07.067 Lu, 2011, Multifunctional hollow nanoparticles based on graft-diblock copolymers for doxorubicin delivery, Biomaterials, 32, 2213, 10.1016/j.biomaterials.2010.11.051 Dohmen, 2012, Nanosized multifunctional polyplexes for receptor-mediated SiRNA delivery, ACS Nano, 6, 5198, 10.1021/nn300960m Li, 2010, Targeting human clonogenic acute myelogenous leukemia cells via folate conjugated liposomes combined with receptor modulation by all-trans retinoic acid, Int. J. Pharm., 402, 57, 10.1016/j.ijpharm.2010.09.019 Hynes, 2002, Integrins: bidirectional, allosteric signaling machines, Cell, 110, 673, 10.1016/S0092-8674(02)00971-6 Aplin, 1998, Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins, Pharmacol. Rev., 50, 197 Gottschalk, 2002, The structures of Integrins and integrin-ligand complexes: implications for drug design and signal transduction, Angew. Chem. Int. Ed., 41, 3767, 10.1002/1521-3773(20021018)41:20<3767::AID-ANIE3767>3.0.CO;2-T Nishimura, 2007, Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3, Dev. Cell, 13, 15, 10.1016/j.devcel.2007.05.003 Ezratty, 2009, Clathrin mediates integrin endocytosis for focal adhesion disassembly in migrating cells, J. Cell Biol., 187, 733, 10.1083/jcb.200904054 Shi, 2008, Caveolin-1-dependent beta1 integrin endocytosis is a critical regulator of fibronectin turnover, J. Cell Sci., 121, 2360, 10.1242/jcs.014977 Desgrosellier, 2010, Integrins in cancer: biological implications and therapeutic opportunities, Nat. Rev. Cancer, 10, 9, 10.1038/nrc2748 Senger, 1997, Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha(1)beta(1) and alpha(2)beta(1) integrins, Proc. Natl. Acad. Sci. U. S. A., 94, 13612, 10.1073/pnas.94.25.13612 Senger, 2002, The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis, Am. J. Pathol., 160, 195, 10.1016/S0002-9440(10)64363-5 Whelan, 2003, Collagen I initiates endothelial cell morphogenesis by inducing actin polymerization through suppression of cyclic AMP and protein kinase A, J. Biol. Chem., 278, 327, 10.1074/jbc.M207554200 Garmy-Susini, 2005, Integrin alpha(4)beta(1)-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation, J. Clin. Invest., 115, 1542, 10.1172/JCI23445 Yang, 1993, Embryonic mesodermal defects in alpha(5) integrin-deficient mice, Development, 119, 1093, 10.1242/dev.119.4.1093 Goh, 1997, Mesodermal defects and cranial neural crest apoptosis in alpha 5 integrin-null embryos, Development, 124, 4309, 10.1242/dev.124.21.4309 Francis, 2002, Central roles of alpha(5)beta(1) integrin and fibronectin in vascular development in mouse embryos and embryoid bodies, Arterioscler. Thromb. Vasc. Biol., 22, 927, 10.1161/01.ATV.0000016045.93313.F2 Kim, 2000, Regulation of angiogenesis in vivo by ligation of integrin alpha 5 beta 1 with the central cell-binding domain of fibronectin, Am. J. Pathol., 156, 1345, 10.1016/S0002-9440(10)65005-5 Rehn, 2001, Interaction of endostatin with integrins implicated in angiogenesis, Proc. Natl. Acad. Sci. U. S. A., 98, 1024, 10.1073/pnas.98.3.1024 Byzova, 2000, A mechanism for modulation of cellular responses to VEGF: activation of the integrins, Mol. Cell, 6, 851 Stupack, 2004, Integrins and angiogenesis, vol. 64, 207 Bader, 1998, Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins, Cell, 95, 507, 10.1016/S0092-8674(00)81618-9 Hodivala-Dilke, 1999, beta 3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival, J. Clin. Invest., 103, 229, 10.1172/JCI5487 Reynolds, 2002, Enhanced pathological angiogenesis in mice lacking beta(3) integrin or beta(3) and beta(5) integrins, Nat. Med., 8, 27, 10.1038/nm0102-27 Robinson, 2004, beta 3-integrin regulates vascular endothelial growth factor-A-dependent permeability, Arterioscler. Thromb. Vasc. Biol., 24, 2108, 10.1161/01.ATV.0000143857.27408.de Reynolds, 2004, Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta(3)-integrin-deficient mice, Cancer Res., 64, 8643, 10.1158/0008-5472.CAN-04-2760 McCarty, 2002, Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alpha v integrins, Mol. Cell. Biol., 22, 7667, 10.1128/MCB.22.21.7667-7677.2002 Zhu, 2002, beta 8 integrins are required for vascular morphogenesis in mouse embryos, Development, 129, 2891, 10.1242/dev.129.12.2891 McCarty, 2005, Selective ablation of alpha v integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death, Development, 132, 165, 10.1242/dev.01551 Hiran, 2003, Endothelial expression of the alpha 6 beta 4 integrin is negatively regulated during angiogenesis, J. Cell Sci., 116, 3771, 10.1242/jcs.00681 Nikolopoulos, 2004, Integrin beta 4 signaling promotes tumor angiogenesis, Cancer Cell, 6, 471, 10.1016/j.ccr.2004.09.029 Eliceiri, 1999, The role of alpha v integrins during angiogenesis: insights into potential mechanisms of action and clinical development, J. Clin. Invest., 103, 1227, 10.1172/JCI6869 Brooks, 1996, Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3, Cell, 85, 683, 10.1016/S0092-8674(00)81235-0 Gale, 1999, Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development, Genes Dev., 13, 1055, 10.1101/gad.13.9.1055 Koivunen, 1995, Phage libraries displaying cyclic-peptides with different ring sizes — ligand specificities of the Rgd-directed integrins, Biotechnology, 13, 265, 10.1038/nbt0395-265 Pasqualini, 1997, alpha v Integrins as receptors for tumor targeting by circulating ligands, Nat. Biotechnol., 15, 542, 10.1038/nbt0697-542 Boger, 2001, Identification of a novel class of small-molecule antiangiogenic agents through the screening of combinatorial libraries which function by inhibiting the binding and localization of proteinase MMP2 to integrin alpha(v)beta(3), J. Am. Chem. Soc., 123, 1280, 10.1021/ja003579+ Arap, 1998, Chemotherapy targeted to tumor vasculature, Curr. Opin. Oncol., 10, 560, 10.1097/00001622-199811000-00014 Vuori, 1994, Association of insulin-receptor substrate-1 with integrins, Science, 266, 1576, 10.1126/science.7527156 Schneller, 1997, alpha v beta 3 integrin associates with activated insulin and PDGF beta receptors and potentiates the biological activity of PDGF, EMBO J., 16, 5600, 10.1093/emboj/16.18.5600 Furundzija, 2010, IGF-1 increases macrophage motility via PKC/p38-dependent alpha v beta 3-integrin inside-out signaling, Biochem. Biophys. Res. Commun., 394, 786, 10.1016/j.bbrc.2010.03.072 Kabir-Salmani, 2003, alpha(v)beta(3) integrin signaling pathway is involved in insulin-like growth factor I-stimulated human extravillous trophoblast cell migration, Endocrinology, 144, 1620, 10.1210/en.2002-220886 Wagner, 2010, Enhanced drug targeting by attachment of an anti alphav integrin antibody to doxorubicin loaded human serum albumin nanoparticles, Biomaterials, 31, 2388, 10.1016/j.biomaterials.2009.11.093 Humphries, 2006, Integrin ligands at a glance, J. Cell Sci., 119, 3901, 10.1242/jcs.03098 Chen, 2009, Triblock copolymer coated iron oxide nanoparticle conjugate for tumor integrin targeting, Biomaterials, 30, 6912, 10.1016/j.biomaterials.2009.08.045 Kluza, 2010, Synergistic targeting of alphavbeta3 integrin and galectin-1 with heteromultivalent paramagnetic liposomes for combined MR imaging and treatment of angiogenesis, Nano Lett., 10, 52, 10.1021/nl902659g Han, 2010, Targeted gene silencing using RGD-labeled chitosan nanoparticles, Clin. Cancer Res., 16, 3910, 10.1158/1078-0432.CCR-10-0005 Kim, 2012, A phase I clinical trial of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in patients with recurrent gynecologic cancer, Clin. Cancer Res., 18, 3440, 10.1158/1078-0432.CCR-11-2852 Byrne, 2008, Active targeting schemes for nanoparticle systems in cancer therapeutics, Adv. Drug Deliv. Rev., 60, 1615, 10.1016/j.addr.2008.08.005 Hong, 2009, Efficient tumor targeting of hydroxycamptothecin loaded PEGylated niosomes modified with transferrin, J. Control. Release, 133, 96, 10.1016/j.jconrel.2008.09.005 Li, 2009, Targeted delivery of doxorubicin using stealth liposomes modified with transferrin, Int. J. Pharm., 373, 116, 10.1016/j.ijpharm.2009.01.023 Daniels, 2012, The transferrin receptor and the targeted delivery of therapeutic agents against cancer, Biochim. Biophys. Acta, 1820, 291, 10.1016/j.bbagen.2011.07.016 Davis, 2010, Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles, Nature, 464, 1067, 10.1038/nature08956 Shao, 2011, Target drug delivery system as a new scarring modulation after glaucoma filtration surgery, Diagn. Pathol., 6, 64, 10.1186/1746-1596-6-64 Corbin, 2007, Mimicking nature's nanocarrier: synthetic low-density lipoprotein-like nanoparticles for cancer-drug delivery, Nanomedicine (Lond.), 2, 375, 10.2217/17435889.2.3.375 Jin, 2012, Mechanistic insights into LDL nanoparticle-mediated siRNA delivery, Bioconjug. Chem., 23, 33, 10.1021/bc200233n Corbin, 2007, Functionalizing low-density lipoprotein nanoparticles for in vivo near-infrared optical imaging of cancer, Proc. SPIE, 6626, 1 Roy, 1998, Effect of shape, size, and valency of multivalent mannosides on their binding properties to phytohemagglutinins, Glycoconj. J., 15, 251, 10.1023/A:1006945028547 Kiessling, 2006, Synthetic multivalent ligands as probes of signal transduction, Angew. Chem. Int. Ed Engl., 45, 2348, 10.1002/anie.200502794 Kiessling, 2000, Principles for multivalent ligand design, Annu. Rep. Med. Chem., 35, 321, 10.1016/S0065-7743(00)35030-8 Kitov, 2011, Impact of the nature and size of the polymeric backbone on the ability of heterobifunctional ligands to mediate shiga toxin and serum amyloid p component ternary complex formation, Toxins (Basel), 3, 1065, 10.3390/toxins3091065 Carrithers, 1996, Synthesis and characterization of bivalent peptide ligands targeted to G-protein-coupled receptors, Chem. Biol., 3, 537, 10.1016/S1074-5521(96)90144-1 Graef, 1997, Proximity and orientation underlie signaling by the non-receptor tyrosine kinase ZAP70, EMBO J., 16, 5618, 10.1093/emboj/16.18.5618 Nishizumi, 1998, A double-edged kinase Lyn: a positive and negative regulator for antigen receptor-mediated signals, J. Exp. Med., 187, 1343, 10.1084/jem.187.8.1343 Torigoe, 1998, An unusual mechanism for ligand antagonism, Science, 281, 568, 10.1126/science.281.5376.568 Lundquist, 2002, The cluster glycoside effect, Chem. Rev., 102, 555, 10.1021/cr000418f Mammen, 1998, Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors, Angew. Chem. Int. Ed., 37, 2755, 10.1002/(SICI)1521-3773(19981102)37:20<2754::AID-ANIE2754>3.0.CO;2-3 Barkey, 2011, Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand, J. Med. Chem., 54, 8078, 10.1021/jm201226w Kiessling, 1996, Strength in numbers: non-natural polyvalent carbohydrate derivatives, Chem. Biol., 3, 71, 10.1016/S1074-5521(96)90280-X Kitov, 2000, Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands, Nature, 403, 669, 10.1038/35001095 Fan, 2000, High-affinity pentavalent ligands of Escherichia coli heat-labile enterotoxin by modular structure-based design, J. Am. Chem. Soc., 122, 2663, 10.1021/ja993388a Zhang, 2002, Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-binding of cholera toxin, J. Am. Chem. Soc., 124, 12991, 10.1021/ja027584k Jencks, 1981, On the attribution and additivity of binding energies, Proc. Natl. Acad. Sci. U. S. A., 78, 4046, 10.1073/pnas.78.7.4046 Howorka, 2004, Stochastic detection of monovalent and bivalent protein–ligand interactions, Angew. Chem. Int. Ed Engl., 43, 842, 10.1002/anie.200352614 Mammen, 1995, Effective inhibitors of hemagglutination by influenza virus synthesized from polymers having active ester groups. Insight into mechanism of inhibition, J. Med. Chem., 38, 4179, 10.1021/jm00021a007 Hood, 2003, Tumor regression by targeted gene delivery, Cancer Gene Ther., 10, 49 Hood, 2002, Tumor regression by targeted gene delivery to the neovasculature, Science, 296, 2404, 10.1126/science.1070200 Miyamoto, 1995, Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function, Science, 267, 883, 10.1126/science.7846531 Hlavacek, 2002, Retention of antigen on follicular dendritic cells and B lymphocytes through complement-mediated multivalent ligand–receptor interactions: theory and application to HIV treatment, Math. Biosci., 176, 185, 10.1016/S0025-5564(02)00091-3 Kessler, 1989 Vagner, 2004, Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: homooligomers of alpha-MSH, Bioorg. Med. Chem. Lett., 14, 211, 10.1016/j.bmcl.2003.09.079 Hong, 2007, The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform, Chem. Biol., 14, 107, 10.1016/j.chembiol.2006.11.015 Li, 2012, Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting, Eur. J. Med. Chem., 47, 560, 10.1016/j.ejmech.2011.11.027 Martinez-Veracoechea, 2011, Designing super selectivity in multivalent nano-particle binding, Proc. Natl. Acad. Sci. U. S. A., 108, 10963, 10.1073/pnas.1105351108 Josan, 2011, Cell-specific targeting by heterobivalent ligands, Bioconjug. Chem., 22, 1270, 10.1021/bc1004284 Xu, 2009, Enhanced targeting with heterobivalent ligands, Mol. Cancer Ther., 8, 2356, 10.1158/1535-7163.MCT-08-1183 Lee, 2010, Design and synthesis of trivalent ligands targeting opioid, cholecystokinin, and melanocortin receptors for the treatment of pain, Bioorg. Med. Chem. Lett., 20, 4080, 10.1016/j.bmcl.2010.05.078 Quan, 2009, Dual targeting of a thermosensitive nanogel conjugated with transferrin and RGD-containing peptide for effective cell uptake and drug release, Nanotechnology, 20, 335101, 10.1088/0957-4484/20/33/335101 Ko, 2011, A multimodal nanoparticle-based cancer imaging probe simultaneously targeting nucleolin, integrin alphavbeta3 and tenascin-C proteins, Biomaterials, 32, 1130, 10.1016/j.biomaterials.2010.10.034 Singh, 2009, Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV, Gene Ther., 16, 645, 10.1038/gt.2008.185 Kluza, 2010, Synergistic targeting of alpha(v)beta(3) integrin and galectin-1 with heteromultivalent paramagnetic liposomes for combined MR imaging and treatment of angiogenesis, Nano Lett., 10, 52, 10.1021/nl902659g