_:b428211660 . _:b7259961 "RGD peptides and antibodies to \u03B1v\u03B23 integrin have also been successfully used in targeted delivery of diagnostic probes to tumors (Sipkins et al., 1998; Stollman et al., 2009; Sugahara et al., >>2009<<), and imaging probes based on this approach are in clinical trials." . _:b428211504 . . _:b428211391 . . . . . _:b428211142 . . . _:b428211282 . _:b428211509 . _:b428211194 . . _:b428211747 . _:b428211171 . . _:b428211673 . . _:b428211160 . _:b428211292 . _:b7259899 . _:b428211325 . _:b428211793 . _:b428211527 . _:b428211659 . . _:b7260017 "and a high resolution mapping that can be visualized during surgery to identify surgical margins (by fluorescence imaging of quantum dots; Wang et al., 2004; Kim et al., 2005; Sathe et al., 2006; Kim and Taton, 2007; Song et al., >>2007<<; Park et al., 2008; Ye et al., 2008). Recently, we have also designed iron oxide nanoparticles (nanoworms; Park et al., 2009b) with improved properties and nontoxic silicon-based quantum dots (Park et al., 2009a) for such purposes." . _:b7259873 "(the so-called enhanced permeability and retention [EPR] effect), but EPR is not very effective, and its size dependency and variability from tumor to tumor limit its usefulness (Maeda et al., 2000; Iyer et al., 2006; Sugahara et al., >>2009<<). Interstitial fibrosis can further retard the diffusion of compounds through tumors (Olive et al., 2009)." . _:b7259978 "F3 (Porkka et al., >>2002<<), LyP-1 (Laakkonen et al., 2002), and CRGRRST (Joyce et al., 2003) each contain a potential CendR sequence." . . _:b428211697 . . . . . . . . . . . _:b428211483 . _:b428211519 . _:b428211354 . . . _:b7260009 . _:b428211717 "2"^^ . _:b428211239 . _:b428211716 "2"^^ . . _:b428211719 "2"^^ . . _:b428211718 "2"^^ . _:b428211157 . _:b428211713 "2"^^ . _:b428211834 . . _:b428211537 . _:b428211712 "2"^^ . . _:b428211715 "2"^^ . _:b428211714 "2"^^ . _:b7259920 "ReceptorReferencesRGD-directed integrins (\u03B1v\u03B23 and \u03B1v\u03B25)Ruoslahti, 2002; Desgrosellier and Cheresh, >>2010< . _:b7259959 "RGD peptides and antibodies to \u03B1v\u03B23 integrin have also been successfully used in targeted delivery of diagnostic probes to tumors (Sipkins et al., >>1998<<; Stollman et al., 2009; Sugahara et al., 2009), and imaging probes based on this approach are in clinical trials." . _:b428211725 "2"^^ . _:b428211724 "2"^^ . _:b428211727 "2"^^ . _:b428211726 "2"^^ . _:b7260008 "The approach is similar to clotting induced in tumor vessels by tumor-targeted tissue factor (Huang et al., 1997; Bieker et al., >>2009<<) with the exception that the CREKA system is based on self-amplified nanoparticle homing." . _:b7259895 "The in vivo screening of phage libraries has also produced several potent tumor-homing peptides, the target molecules of which remain to be identified (Hoffman et al., 2003; Joyce et al., 2003; J\u00E4rvinen and Ruoslahti, >>2007<<; Chang et al., 2009)." . _:b428211721 "2"^^ . _:b428211720 "2"^^ . _:b428211263 . _:b428211203 . _:b428211821 . _:b428211723 "2"^^ . _:b428211802 . _:b428211722 "2"^^ . _:b428211573 . _:b428211733 "2"^^ . _:b428211371 . . . _:b428211732 "2"^^ . _:b428211106 . _:b428211520 . _:b428211707 . _:b428211735 "2"^^ . . _:b428211229 . _:b428211734 "2"^^ . _:b428211298 . _:b428211729 "2"^^ . . . _:b428211728 "2"^^ . _:b428211731 "2"^^ . _:b7259880 . _:b7259991 "Once the receptors of the homing peptide have been saturated, the specificity of the targeting declines (adapted from experimental data in Kranenborg et al., >>1998<<). au, arbitrary units." . _:b428211730 "2"^^ . . . . . _:b428211741 "2"^^ . _:b428211796 . _:b428211740 "2"^^ . _:b428211191 . _:b428211743 "2"^^ . _:b428211699 . _:b7259996 "Reulen et al. (>>2009<<) converted a nonbinding variant of a collagen-binding protein into an active targeting probe by inserting multiple copies of the protein into a micelle, artificially producing a multivalent ensemble." . _:b428211742 "2"^^ . . _:b428211521 . _:b428211737 "2"^^ . _:b7260010 "These materials are metallic structures that efficiently convert optical radiation into heat by coupling into one or more plasmon modes (Hirsch et al., 2003; Hu et al., >>2006<<). We have recently shown that photothermal heating mediated by tumor-targeted gold nanorods can increase binding sites for targeted delivery with thermosensitive drug carriers (Fig. 3; von Maltzahn et al., 2009; Park et al., 2010). Other" . _:b428211736 "2"^^ . . _:b428211739 "2"^^ . . _:b428211569 . . . _:b428211738 "2"^^ . _:b7259940 "The idea that this level of specificity can be achieved with tumor vessels has been demonstrated with tumor type\u2013specific peptides (Hoffman et al., 2003; Joyce et al., 2003; Laakkonen et al., >>2004<<). Peptides like this should make diagnostic and therapeutic applications possible that are more selective than angiogenesis-based targeting. The use of peptides (or other types of probes) with this kind of focused specificity would likely" . _:b428211471 . . _:b428211749 "2"^^ . _:b428211748 "2"^^ . _:b428211751 "2"^^ . . . _:b7259997 . _:b7259907 "NG2, a membrane-spanning chondroitin sulfate proteoglycan, is a cell surface marker of pericytes (and smooth muscle cells) in angiogenic vessels not expressed in the pericytes of normal vessels (Stallcup and Huang, >>2008<<). One of the PDFG receptors is another marker that is expressed at high levels in pericytes (Song et al., 2005)." . _:b428211750 "2"^^ . _:b428211745 "2"^^ . _:b428211744 "2"^^ . _:b428211747 "2"^^ . _:b7259987 "Jiang et al. (>>2004<<) have described a peptide design in which a negatively charged sequence tethered to a cationic cell-penetrating peptide blocks the cell-penetrating activity until a tumor protease cleaves the tether." . _:b428211507 . _:b428211583 . _:b428211746 "2"^^ . _:b428211242 . _:b428211757 "2"^^ . _:b428211756 "2"^^ . _:b428211759 "2"^^ . _:b428211758 "2"^^ . _:b428211686 . _:b7259937 . _:b428211662 . _:b7259975 "efficacy is not dominated by changes in overall drug uptake by the tumor (i.e., increased volumetric concentration) but rather changes in cellular internalization of the drug or how long it is retained in the tumor (Bartlett et al., >>2007<<). Thus, there is little or no specific accumulation of probes targeted solely to tumor cells (Fig." . _:b428211753 "2"^^ . _:b428211752 "2"^^ . _:b428211755 "2"^^ . . _:b428211745 . _:b428211754 "2"^^ . _:b428211726 . _:b428211765 "2"^^ . _:b428211764 "2"^^ . _:b428211767 "2"^^ . _:b428211766 "2"^^ . _:b428211761 "2"^^ . _:b428211760 "2"^^ . _:b428211763 "2"^^ . _:b428211328 . _:b428211664 . _:b428211762 "2"^^ . . _:b7259969 . _:b428211224 . _:b428211773 "2"^^ . . _:b428211772 "2"^^ . _:b7259992 . _:b428211775 "2"^^ . . _:b428211774 "2"^^ . . _:b428211769 "2"^^ . . _:b7259923 . . _:b428211768 "2"^^ . _:b428211771 "2"^^ . _:b428211770 "2"^^ . _:b428211781 "2"^^ . _:b428211780 "2"^^ . _:b428211783 "2"^^ . _:b428211782 "2"^^ . _:b428211777 "2"^^ . _:b428211347 . . . _:b428211578 . _:b428211776 "2"^^ . _:b428211232 . _:b7259980 . _:b7259953 "reported with RGD and NGR peptides; the targeted cytokine was effective in doses as much as 1,000-fold lower than the usual dose and effectively mitigating side effects as a result of the high toxicity of this cytokine (Curnis et al., >>2004<<). These same peptides have also been used to deliver tissue factor to induce blood clotting specifically in tumor blood vessels, with resulting occlusion of the vessels and tumor necrosis (Bieker et al., 2009)." . _:b428211201 . _:b428211779 "2"^^ . _:b428211778 "2"^^ . _:b428211789 "2"^^ . _:b7259988 "The greater tumor-homing selectivity of peptides derived from in vivo phage display such as iRGD (12-fold) is likely because of the presence of a homing sequence (RGD in iRGD) in these peptides (Sugahara et al., >>2009<<)." . . _:b428211255 . _:b428211788 "2"^^ . _:b428211791 "2"^^ . _:b428211790 "2"^^ . . _:b428211311 . _:b428211785 "2"^^ . _:b428211741 . _:b428211784 "2"^^ . _:b428211787 "2"^^ . _:b428211739 . _:b428211786 "2"^^ . . _:b428211797 "2"^^ . "PMC0" . _:b428211575 . . . _:b428211796 "2"^^ . _:b7259995 . . _:b428211799 "2"^^ . _:b428211798 "2"^^ . _:b428211623 . . _:b428211793 "2"^^ . _:b428211218 . _:b7259919 "ReceptorReferencesRGD-directed integrins (\u03B1v\u03B23 and \u03B1v\u03B25)Ruoslahti, >>2002<<; Desgrosellier and Cheresh, 2010Aminopeptidase NPasqualini et al., 2000TEMsCarson-Walter et al., 2001EndosialinChristian et al., 2001Cell surface nucleolinChristian et al., 2003Cell surface annexin-1Oh et al., 2004Cell surface p32/gC1q" . _:b428211197 . _:b428211792 "2"^^ . _:b428211795 "2"^^ . . _:b428211703 . _:b428211794 "2"^^ . _:b428211461 . _:b7259898 "In addition to aforementioned nucleolin, the cytoplasmic proteins annexin1 (Oh et al., 2004) and plectin-1 (Kelly et al., >>2008<<) have been found to be present at the cell surface of endothelial cells in tumors but not in normal tissues." . _:b428211805 "2"^^ . . _:b428211460 . . _:b428211804 "2"^^ . _:b428211463 . _:b7259943 "site of integrins (Koivunen et al., 1994), but this motif was later identified as the binding motif in tumor-homing peptides that were more potent than could be expected on the basis of the weak integrin binding (Arap et al., >>1998<<). It was subsequently shown that the NGR peptides recognize aminopeptidase N (Pasqualini et al., 2000) and potentially, after a chemical alteration, \u03B1v integrins (Curnis et al., 2008)." . _:b428211807 "2"^^ . _:b428211462 . _:b428211777 . _:b428211806 "2"^^ . _:b428211457 . . _:b428211801 "2"^^ . . _:b7259878 . _:b428211456 . _:b428211800 "2"^^ . _:b428211459 . . _:b428211433 . _:b428211803 "2"^^ . _:b7259958 "Moreover, targeting the same proapoptotic peptide to the blood vessels of the normal prostate caused partial destruction of the prostate and delayed the development of cancers in transgenic prostate cancer mice (Arap et al., >>2002<<). The potential of synaphic targeting is very well illustrated; the combination of homing peptides with nonselectively toxic compounds, such as proapoptotic peptides and TNF, can profoundly alter the in vivo activity of the toxins. RGD" . _:b428211458 . _:b428211805 . _:b428211404 . _:b428211802 "2"^^ . _:b428211469 . _:b428211625 . _:b428211813 "2"^^ . _:b428211122 . _:b428211468 . _:b428211812 "2"^^ . _:b428211471 . _:b7259936 . . _:b428211815 "2"^^ . _:b428211470 . _:b7259939 . _:b428211814 "2"^^ . _:b7259938 . _:b428211465 . _:b428211809 "2"^^ . _:b428211464 . _:b428211808 "2"^^ . _:b428211467 . _:b428211811 "2"^^ . _:b428211466 . _:b428211789 . _:b428211564 . _:b428211217 . _:b428211810 "2"^^ . _:b428211477 . . . _:b428211821 "2"^^ . _:b428211476 . _:b7259962 . _:b428211246 . _:b428211820 "2"^^ . _:b428211479 . _:b428211823 "2"^^ . _:b7260007 "The approach is similar to clotting induced in tumor vessels by tumor-targeted tissue factor (Huang et al., >>1997<<; Bieker et al., 2009) with the exception that the CREKA system is based on self-amplified nanoparticle homing." . _:b428211478 . . . _:b428211822 "2"^^ . _:b428211473 . _:b428211539 . _:b428211817 "2"^^ . _:b428211641 . _:b428211472 . . _:b428211816 "2"^^ . _:b428211475 . _:b428211392 . _:b428211819 "2"^^ . _:b7259991 . _:b428211474 . _:b7259899 "This protein is primarily a mitochondrial protein, but it is also expressed at the cell surface of lymphatic, myeloid, and cancer cells in tumors but not in normal tissues (Fogal et al., >>2008<<). This protein is the receptor for the tumor-homing peptide LyP-1, originally discovered using in vivo phage display (Laakkonen et al., 2002)." . _:b7259970 "receptors other than integrins have also been successfully used in preclinical studies to target gene therapy vectors, drugs, and biologicals into tumors (M\u00FCller et al., 2003; Hamzah et al., 2008; Chang et al., 2009; Karmali et al., >>2009<<)." . _:b7260020 "Recently, we have also designed iron oxide nanoparticles (nanoworms; Park et al., 2009b) with improved properties and nontoxic silicon-based quantum dots (Park et al., 2009a) for such purposes." . . _:b428211818 "2"^^ . . . . _:b428211485 . _:b7259992 "Phage display with cells in vitro or tissues in vivo as the target (Hoffman et al., >>2003<<) is a prime example of a system that probes this moderate affinity, multivalent landscape." . _:b428211829 "2"^^ . _:b428211484 . . _:b428211828 "2"^^ . _:b428211487 . _:b428211513 . _:b428211831 "2"^^ . _:b428211326 . . _:b428211486 . _:b428211830 "2"^^ . _:b428211481 . . . _:b428211825 "2"^^ . _:b428211480 . _:b428211824 "2"^^ . _:b428211483 . _:b7260015 "procedure (by magnetic resonance imaging) and a high resolution mapping that can be visualized during surgery to identify surgical margins (by fluorescence imaging of quantum dots; Wang et al., 2004; Kim et al., 2005; Sathe et al., >>2006<<; Kim and Taton, 2007; Song et al., 2007; Park et al., 2008; Ye et al., 2008)." . _:b428211827 "2"^^ . _:b428211482 . _:b428211826 "2"^^ . _:b428211516 . _:b428211493 . _:b7259935 . _:b428211492 . _:b7259956 . _:b428211495 . _:b428211459 . . _:b428211494 . . _:b428211695 . _:b7259918 "Perhaps the most interesting among the TEMs is TEM 8, which is one of the two receptors for the anthrax toxin (Nanda et al., >>2004<<). An effort is under way to develop anthrax toxin variants that bind only to TEM 8 and that could be used to target tumor vasculature for destruction. Table I provides a list of the principal cell surface markers available in tumor" . _:b428211489 . _:b428211833 "2"^^ . . _:b428211700 . _:b428211488 . _:b428211832 "2"^^ . . . _:b428211491 . _:b428211379 . _:b428211490 . _:b428211834 "2"^^ . . _:b428211501 . . _:b428211386 . _:b428211500 . _:b428211192 . . _:b428211278 . _:b428211503 . _:b428211772 . . . _:b428211502 . . . _:b428211497 . _:b428211496 . _:b428211382 . _:b428211422 . _:b428211499 . . _:b428211498 . . . . . _:b428211509 . _:b428211607 . . _:b428211508 . _:b428211340 . . _:b428211511 . _:b428211812 . _:b428211510 . . _:b428211505 . . _:b7259974 . _:b428211504 . _:b428211610 . _:b428211507 . . _:b428211506 . _:b428211517 . _:b428211829 . _:b428211516 . . _:b428211519 . _:b428211522 . _:b428211153 . _:b428211518 . . . _:b428211513 . _:b428211512 . . _:b7259908 . _:b428211515 . _:b7259909 . _:b428211514 . _:b7259910 . _:b428211525 . _:b7259966 . _:b7259911 . _:b428211524 . _:b428211441 . _:b7259904 . _:b428211527 . _:b7259905 . _:b428211526 . _:b7259906 . . . _:b428211817 . _:b428211521 . _:b428211455 . _:b7259907 . _:b428211520 . _:b7259916 . _:b428211548 . . _:b428211523 . . _:b428211645 . _:b7259917 . _:b428211522 . . _:b7259918 . _:b428211135 . _:b428211533 . _:b428211120 . _:b7259919 . _:b428211532 . _:b7259912 . _:b428211535 . . _:b7259913 . . _:b428211411 . _:b428211534 . _:b7259906 "Proteolytically processed type IV collagen is another matrix component that can be detected with antibodies or peptides (Roth et al., 2006; Mueller et al., >>2009<<). The support cells (mural cells) in the vascular wall also contain markers that are specific for tumor vessels and that can be potentially useful in tumor targeting. NG2, a membrane-spanning chondroitin sulfate proteoglycan, is a cell" . _:b7259914 . . _:b428211529 . _:b428211310 . . _:b7260009 "These materials are metallic structures that efficiently convert optical radiation into heat by coupling into one or more plasmon modes (Hirsch et al., >>2003<<; Hu et al., 2006)." . _:b7259915 . _:b428211668 . _:b428211528 . _:b428211228 . . _:b7259924 . . _:b428211531 . _:b7259925 . _:b428211702 . _:b428211530 . _:b7259926 . _:b428211541 . _:b7259927 . _:b428211661 . _:b428211540 . _:b428211604 . _:b7259920 . _:b428211543 . _:b7259921 . _:b428211542 . _:b7259922 . _:b7259932 . . _:b7259886 "In vitro, all cells seem to be positive for cell surface nucleolin (Borer et al., >>1989<<; Bonnet et al., 1996) presumably because cultured cells resemble cells that have been activated in vivo." . _:b428211537 . _:b7259923 . _:b428211536 . . _:b7259979 . _:b7259932 . _:b428211482 . . . _:b428211539 . _:b7259933 . _:b428211363 . _:b428211538 . _:b428211655 . _:b7259934 . _:b428211223 . _:b428211549 . _:b7259935 . _:b428211548 . _:b7259928 . _:b428211551 . _:b428211334 . _:b7259929 . _:b428211550 . _:b7259921 "ReceptorReferencesRGD-directed integrins (\u03B1v\u03B23 and \u03B1v\u03B25)Ruoslahti, 2002; Desgrosellier and Cheresh, 2010Aminopeptidase NPasqualini et al., >>2000< . _:b7259930 . . _:b428211545 . _:b7259931 . . _:b428211544 . _:b7259940 . _:b428211225 . _:b428211547 . _:b7259941 . _:b428211546 . . _:b7259942 . _:b428211333 . . _:b428211557 . _:b428211266 . _:b428211450 . _:b7259943 . . _:b428211768 . _:b428211556 . _:b428211293 . _:b7259936 . _:b428211559 . _:b7259937 . _:b428211558 . _:b7259938 . . _:b428211553 . _:b428211437 . _:b7259939 . _:b428211552 . _:b428211103 "11"^^ . _:b7259948 . _:b428211163 . . _:b428211555 . _:b428211402 . _:b7259949 . _:b428211102 "12"^^ . _:b428211554 . _:b7259950 . _:b428211101 "12"^^ . _:b428211099 "20"^^ . _:b428211565 . . _:b7259951 . . _:b428211564 . _:b7259944 . _:b428211100 "16"^^ . _:b428211567 . . _:b7259945 . _:b428211566 . . _:b7259946 . . _:b428211561 . _:b428211630 . _:b7259947 . _:b428211560 . _:b428211110 "7"^^ . _:b7259956 . _:b428211563 . _:b428211111 "7"^^ . _:b7259957 . . _:b428211562 . _:b7259958 . _:b428211108 "8"^^ . _:b428211573 . _:b7259959 . _:b428211109 "8"^^ . _:b428211572 . _:b7259952 . _:b428211106 "9"^^ . _:b428211575 . _:b7259953 . _:b428211107 "8"^^ . _:b7259874 . _:b428211574 . _:b7259954 . _:b428211449 . _:b428211669 . _:b428211569 . _:b428211104 "10"^^ . _:b428211586 . _:b7259955 . _:b428211193 . . _:b428211254 . _:b428211568 . _:b428211105 "9"^^ . _:b428211118 "6"^^ . _:b7259964 . . _:b428211757 . _:b428211571 . _:b428211119 "6"^^ . _:b7259965 . _:b428211342 . _:b428211570 . _:b428211116 "6"^^ . _:b428211294 . _:b7259966 . _:b428211581 . _:b428211117 "6"^^ . _:b7259967 . . _:b428211580 . _:b428211114 "6"^^ . . _:b7259960 . _:b428211131 . _:b428211583 . _:b428211115 "6"^^ . _:b7259961 . _:b428211639 . . _:b428211582 . _:b428211112 "7"^^ . _:b7259962 . . _:b428211577 . _:b428211113 "6"^^ . _:b7259906 . _:b7259963 . _:b428211576 . _:b428211585 . _:b428211531 . _:b7259972 . _:b428211125 "5"^^ . _:b428211579 . _:b428211308 . _:b7259973 . _:b428211578 . _:b428211124 "6"^^ . _:b7259974 . _:b428211127 "5"^^ . _:b428211589 . _:b428211511 . . _:b428211721 . _:b7259975 . . . _:b428211126 "5"^^ . _:b428211588 . _:b428211122 "6"^^ . . _:b7259968 . _:b428211591 . _:b428211123 "6"^^ . . _:b7259969 . . _:b428211590 . _:b428211566 . _:b428211120 "6"^^ . . _:b7259970 . _:b428211585 . _:b7259936 "Peptide probes that distinguish between the blood vessels of premalignant and fully malignant lesions of some de novo cancers in mice have been reported (Hoffman et al., 2003; Joyce et al., >>2003<<). The vascular molecules recognized by these peptides remain to be identified. It may also be possible to develop targeting probes that distinguish between physiological and tumor angiogenesis (Seaman et al., 2007)." . _:b428211121 "6"^^ . _:b428211571 . _:b7259971 . . _:b428211584 . _:b7259980 . _:b428211133 "5"^^ . _:b428211587 . _:b7259981 . _:b428211492 . _:b428211132 "5"^^ . _:b428211586 . _:b7259982 . . _:b428211135 "5"^^ . _:b428211597 . _:b428211523 . _:b428211205 . . _:b7259983 . _:b428211296 . _:b428211134 "5"^^ . _:b428211596 . . . _:b7259976 . _:b428211129 "5"^^ . _:b428211599 . . _:b7259977 . _:b428211128 "5"^^ . _:b428211598 . . _:b7259978 . . _:b428211593 . . _:b428211131 "5"^^ . . _:b7259979 . _:b428211473 . _:b428211130 "5"^^ . _:b428211592 . . _:b7259988 . . _:b428211141 "5"^^ . _:b428211595 . . . _:b7259989 . _:b428211140 "5"^^ . _:b428211594 . . _:b7259933 . _:b7259910 "Leaked fibrinogen is converted to a fibrin meshwork by tissue-procoagulant proteins such as tissue factor (Dvorak et al., 1985; Abe et al., >>1999<<; Pilch et al., 2006)." . . _:b7259990 . _:b428211810 . _:b428211143 "5"^^ . _:b428211605 . _:b428211663 . _:b7259991 . _:b428211142 "5"^^ . _:b428211604 . _:b7259984 . _:b7259997 "enhancement in dendrimer binding to a surface (dendrimers are branched synthetic polymers that can form nanoparticles and present ligands in a multivalent fashion in which the valency can be readily controlled; Montet et al., >>2006<<; Hong et al., 2007). At the same time, multivalent peptide presentation can increase recognition of nanoparticles by the reticuloendothelial system (RES; also known as the mononuclear phagocyte system [MPS])." . _:b428211137 "5"^^ . _:b428211607 . _:b7259985 . _:b428211136 "5"^^ . _:b428211606 . . _:b7259986 . _:b428211176 . _:b428211601 . _:b428211139 "5"^^ . _:b7259987 . _:b428211138 "5"^^ . _:b428211600 . _:b7259996 . _:b428211149 "4"^^ . _:b428211495 . _:b428211603 . _:b7259909 . _:b7259869 . _:b7259997 . . _:b7259934 . _:b428211148 "4"^^ . _:b428211602 . _:b7259868 . _:b7259998 . _:b428211151 "4"^^ . _:b428211613 . _:b7259999 . _:b428211150 "4"^^ . . _:b428211612 . _:b428211312 . _:b7259992 . . _:b428211145 "5"^^ . _:b428211615 . _:b7259993 . _:b428211151 . _:b428211614 . . . _:b428211144 "5"^^ . _:b7259994 . _:b428211147 "4"^^ . . _:b428211609 . . . _:b7259995 . _:b428211146 "5"^^ . _:b428211608 . _:b7260004 . . _:b428211157 "4"^^ . . _:b428211611 . . . _:b7260005 . _:b428211156 "4"^^ . . _:b428211610 . . _:b7260006 . _:b428211159 "4"^^ . _:b428211621 . _:b428211725 . _:b428211344 . _:b7260007 . _:b428211158 "4"^^ . _:b428211620 . _:b7260000 . _:b428211153 "4"^^ . . _:b7259993 "Thus, phage display complements other target discovery methods such as those based on antibodies (Jacobson et al., >>1996<<; Oh et al., 2004) or cloning methods (Seaman et al., 2007)." . _:b428211640 . _:b428211623 . _:b7260001 . _:b428211152 "4"^^ . _:b428211622 . _:b7260002 . _:b428211155 "4"^^ . _:b428211819 . _:b428211617 . _:b428211711 . _:b428211406 . _:b7260003 . _:b428211154 "4"^^ . _:b428211616 . _:b7260012 . _:b428211165 "4"^^ . _:b428211619 . _:b428211389 . _:b7260013 . _:b428211164 "4"^^ . . _:b428211618 . . _:b428211712 . _:b7260014 . _:b428211167 "4"^^ . _:b428211629 . _:b7260015 . _:b428211166 "4"^^ . _:b428211628 . . _:b428211167 . _:b7260008 . . _:b428211400 . _:b428211161 "4"^^ . _:b428211631 . . _:b7260009 . _:b428211160 "4"^^ . _:b428211630 . _:b7260010 . _:b428211163 "4"^^ . _:b428211625 . . _:b7259877 "The expression of many of these proteins in tumor vessels is associated with angiogenesis, and they are often functionally important in that process (Hanahan and Folkman, 1996; Alitalo and Carmeliet, >>2002<<). Tumors also contain lymphatic vessels, and many tumors produce growth factors that stimulate lymphangiogenesis (Karpanen and Alitalo, 2008). Lymphatics are not necessary for tumor growth but are important conduits of metastasis. Like" . _:b7260011 . _:b428211162 "4"^^ . _:b428211624 . _:b7260020 . _:b428211173 "4"^^ . . _:b428211627 . _:b428211172 "4"^^ . _:b428211626 . _:b428211175 "3"^^ . _:b428211637 . . . _:b428211174 "4"^^ . _:b428211636 . _:b7260016 . _:b428211169 "4"^^ . _:b428211639 . . _:b7260017 . . _:b428211168 "4"^^ . _:b428211638 . _:b7260018 . _:b428211171 "4"^^ . _:b428211633 . _:b428211591 . _:b7259964 . _:b7260019 . _:b428211170 "4"^^ . . _:b428211632 . _:b428211181 "3"^^ . _:b428211635 . _:b428211180 "3"^^ . _:b428211634 . _:b7259961 . _:b428211183 "3"^^ . _:b428211645 . . _:b428211627 . _:b428211182 "3"^^ . . _:b428211644 . _:b428211177 "3"^^ . . _:b428211647 . _:b428211631 . _:b428211176 "3"^^ . _:b428211762 . _:b428211646 . _:b428211179 "3"^^ . _:b428211641 . . _:b428211178 "3"^^ . _:b428211640 . . _:b428211189 "3"^^ . . _:b428211643 . _:b428211188 "3"^^ . _:b428211642 . _:b428211191 "3"^^ . _:b428211275 . _:b428211653 . _:b7259922 "ReceptorReferencesRGD-directed integrins (\u03B1v\u03B23 and \u03B1v\u03B25)Ruoslahti, 2002; Desgrosellier and Cheresh, 2010Aminopeptidase NPasqualini et al., 2000TEMsCarson-Walter et al., >>2001< "3"^^ . _:b428211801 . _:b428211414 . _:b428211652 . . _:b428211185 "3"^^ . _:b428211655 . _:b428211722 . _:b428211184 "3"^^ . _:b428211654 . _:b428211187 "3"^^ . . _:b428211649 . _:b428211792 . _:b428211186 "3"^^ . _:b428211648 . _:b428211197 "3"^^ . _:b428211651 . . _:b428211196 "3"^^ . . _:b428211650 . _:b428211199 "3"^^ . _:b7259881 "Other unbiased methods, such as antibody-based screens (Jacobson et al., 1996), cloning strategies (Carson-Walter et al., >>2001<<), and in vivo biotinylation (Borgia et al., 2010), have also been used successfully in analyzing tumor vasculature." . _:b428211280 . _:b428211574 . _:b428211661 . _:b428211198 "3"^^ . _:b428211660 . _:b428211193 "3"^^ . _:b428211693 . _:b428211663 . _:b428211192 "3"^^ . _:b428211662 . _:b428211195 "3"^^ . _:b428211657 . . _:b428211194 "3"^^ . _:b7259893 "The in vivo screening of phage libraries has also produced several potent tumor-homing peptides, the target molecules of which remain to be identified (Hoffman et al., >>2003<<; Joyce et al., 2003; J\u00E4rvinen and Ruoslahti, 2007; Chang et al., 2009)." . _:b428211656 . _:b428211814 . _:b428211659 . . _:b428211658 . _:b428211735 . . _:b428211669 . _:b428211196 . _:b428211489 . _:b428211668 . _:b7259867 "The apparent reason is the difficulty in delivering drugs into these tumors; drugs only penetrate a few cell diameters into the extravascular tumor tissue from blood vessels (Hambley and Hait, >>2009<<). This low penetration appears to arise from two main factors: first, tumor vessels are poorly perfused with blood and are dysfunctional, which limits the delivery of blood-borne compounds to tumors (Jain, 1999). Second, tumors have a" . . _:b428211671 . _:b7259959 . _:b428211132 . _:b428211670 . _:b428211815 . _:b428211665 . . _:b428211664 . . . _:b428211667 . _:b428211666 . . _:b428211654 . _:b428211332 . _:b428211677 . . _:b428211258 . _:b428211676 . . _:b428211679 . _:b428211678 . _:b428211421 . _:b428211673 . . _:b428211672 . . _:b7259930 "al., 2003Cell surface annexin-1Oh et al., 2004Cell surface p32/gC1q receptorFogal et al., 2008Cell surface plectin-1Kelly et al., 2008Fibronectin ED-BNilsson et al., 2001Fibrin\u2013fibronectin complexesPilch et al., 2006; Simberg et al., >>2007< . _:b428211497 . _:b428211675 . _:b428211100 . _:b428211782 . _:b428211551 . _:b428211674 . _:b7260001 . _:b428211685 . . _:b428211684 . _:b428211141 . _:b428211740 . . _:b428211674 . _:b428211494 . _:b428211687 . . _:b428211686 . _:b428211524 . _:b7259879 "Screening of phage-displayed peptide libraries, particularly when performed in vivo, has provided a very useful discovery tool for vascular markers in tumor vessels and elsewhere (Pasqualini and Ruoslahti, >>1996<<). A major advantage of the in vivo phage screening is that it is unbiased in revealing what works in vivo." . _:b7259891 "Cell surface nucleolin is an angiogenesis marker that is both a suitable target for drug delivery (Christian et al., 2001; Reddy et al., 2006; Henke et al., 2008; Drecoll et al., >>2009<<) and involved in the angiogenesis process (Fogal et al., 2009)." . . _:b428211681 . _:b428211616 . _:b428211680 . . _:b428211572 . _:b428211316 . _:b428211683 . . _:b7259957 . _:b428211682 . _:b428211693 . _:b428211592 . _:b7259955 "A targeted TNF is currently in clinical trials (Paoloni et al. >>2009<<; Gregorc et al., 2010)." . . _:b428211593 . _:b428211102 . _:b428211692 . _:b428211305 . _:b428211695 . _:b428211629 . . _:b428211694 . _:b428211689 . _:b428211576 . _:b428211647 . _:b428211646 . _:b428211688 . _:b428211691 . _:b428211287 . _:b7259981 "Moreover, F3 and LyP-1 have been shown to cause extravasation of their cargo, which can be as large as a nanoparticle, with subsequent uptake into tumor endothelial cells and tumor cells (Porkka et al., >>2002<<; Laakkonen et al., 2004; Karmali et al., 2009)." . _:b428211690 . _:b428211807 . _:b428211701 . _:b428211439 . _:b428211550 . _:b428211700 . . _:b428211703 . . _:b428211702 . _:b428211126 . . _:b428211697 . _:b428211696 . _:b428211547 . _:b428211699 . _:b428211698 . _:b428211395 . _:b428211709 . _:b428211708 . . _:b428211148 . . . . _:b428211711 . _:b428211444 . _:b428211710 . _:b428211705 . _:b7259975 . . . _:b428211704 . . . _:b428211707 . _:b428211706 . _:b7260005 . _:b428211205 . . _:b428211803 . _:b428211204 . _:b428211677 . _:b428211207 . _:b7259888 . _:b428211244 . . _:b428211206 . . . _:b7260013 . . _:b428211201 . . . _:b428211200 . . _:b428211203 . _:b7259956 "A targeted TNF is currently in clinical trials (Paoloni et al. 2009; Gregorc et al., >>2010<<)." . . _:b428211202 . . . _:b428211166 . _:b428211213 . . . _:b428211212 . _:b428211727 . _:b428211214 . _:b428211215 . _:b428211214 . _:b7259947 . . _:b428211656 . _:b428211209 . _:b428211208 . _:b7259972 . _:b428211211 . _:b428211210 . _:b428211764 . _:b428211200 . . _:b428211221 . _:b7260000 . _:b428211220 . _:b428211223 . _:b428211222 . _:b428211601 . _:b428211144 . _:b428211217 . _:b428211500 . _:b428211376 . _:b428211216 . . _:b428211219 . _:b428211218 . _:b428211657 . _:b428211229 . _:b428211690 . _:b7259964 "Drug-loaded nanoparticles have also been targeted with RGD peptides to suppress tumor growth or metastasis (Hood et al., 2002; Murphy et al., 2008; Sugahara et al., >>2009<<). Finally, RGD and other tumor-homing peptides have been used to alter the host range of viral gene therapy vectors (Wickham, 2000; Haviv et al., 2002). Several homing peptides that bind to receptors other than integrins have also been" . _:b428211788 . _:b428211228 . _:b428211231 . _:b428211528 . . _:b428211230 . _:b428211225 . . _:b7259988 . _:b428211307 . _:b428211224 . _:b428211227 . _:b428211226 . _:b7259985 . _:b7260011 . . _:b428211253 . _:b428211237 . _:b428211744 . _:b428211236 . _:b428211463 . _:b428211239 . _:b428211710 . _:b428211238 . _:b7259927 "2000TEMsCarson-Walter et al., 2001EndosialinChristian et al., 2001Cell surface nucleolinChristian et al., 2003Cell surface annexin-1Oh et al., 2004Cell surface p32/gC1q receptorFogal et al., 2008Cell surface plectin-1Kelly et al., >>2008< . _:b428211233 . . . _:b428211232 . _:b428211235 . _:b428211487 . . _:b428211234 . . _:b7259977 . . _:b428211245 . . _:b428211244 . . _:b428211247 . . _:b428211635 . _:b428211246 . _:b428211241 . . _:b428211240 . _:b428211243 . _:b428211215 . . _:b428211242 . . _:b428211245 . _:b428211253 . . _:b428211749 . _:b428211825 . _:b428211252 . . _:b428211243 . _:b428211255 . . _:b7259969 "peptides that bind to receptors other than integrins have also been successfully used in preclinical studies to target gene therapy vectors, drugs, and biologicals into tumors (M\u00FCller et al., 2003; Hamzah et al., 2008; Chang et al., >>2009<<; Karmali et al., 2009)." . . _:b428211254 . _:b428211760 . . _:b428211249 . _:b428211248 . _:b428211248 . _:b428211698 . _:b428211831 . _:b428211251 . _:b428211636 . _:b7259893 . _:b428211250 . _:b7259945 . _:b428211261 . _:b7259894 . . _:b428211260 . _:b7259892 "nucleolin is an angiogenesis marker that is both a suitable target for drug delivery (Christian et al., 2001; Reddy et al., 2006; Henke et al., 2008; Drecoll et al., 2009) and involved in the angiogenesis process (Fogal et al., >>2009<<). The in vivo screening of phage libraries has also produced several potent tumor-homing peptides, the target molecules of which remain to be identified (Hoffman et al., 2003; Joyce et al., 2003; J\u00E4rvinen and Ruoslahti, 2007; Chang et al." . _:b428211263 . _:b428211553 . . _:b428211262 . . _:b428211715 . _:b7259986 "Unlike the cell-penetrating peptides related to the human immunodeficiency virus Tat protein, which do not display any cell type specificity (Gump and Dowdy, >>2007<<), the CendR tumor-homing peptides are tumor specific." . . _:b428211257 . . _:b428211256 . _:b428211733 . _:b428211776 . . _:b428211393 . _:b428211259 . _:b428211109 . _:b428211258 . _:b428211833 . _:b7259884 "F3 is an example of a novel tumor-homing peptide identified by in vivo phage screening (Porkka et al., >>2002<<). F3 binds to nucleolin, which is ubiquitous as an intracellular protein but is expressed at the cell surface of endothelial cells and tumor cells in vivo (Christian et al., 2003). In vitro, all cells seem to be positive for cell surface" . _:b428211750 . . _:b428211269 . . _:b428211227 . _:b428211268 . . _:b428211388 . _:b428211271 . . _:b428211398 . . _:b428211270 . _:b428211265 . . _:b428211264 . _:b7259916 "by the serial analysis of gene expression technique has revealed a large number of striking differences between endothelial cells isolated from human colon cancers and those from adjacent normal tissue (Carson-Walter et al., >>2001<<). Among these TEMs are collagens, some of which are expressed at strikingly high levels in tumor endothelial cells, at least at the mRNA level." . _:b428211154 . _:b7259870 . _:b428211251 . _:b7260015 . _:b428211267 . _:b428211417 . _:b428211266 . . _:b428211291 . _:b428211277 . _:b428211123 . _:b428211477 . _:b428211276 . _:b428211169 . _:b428211771 . _:b428211279 . . . _:b428211278 . . _:b428211273 . . _:b428211272 . _:b428211506 . _:b428211275 . _:b428211274 . _:b428211285 . _:b7259998 "in dendrimer binding to a surface (dendrimers are branched synthetic polymers that can form nanoparticles and present ligands in a multivalent fashion in which the valency can be readily controlled; Montet et al., 2006; Hong et al., >>2007<<). At the same time, multivalent peptide presentation can increase recognition of nanoparticles by the reticuloendothelial system (RES; also known as the mononuclear phagocyte system [MPS])." . . _:b428211164 . _:b428211420 . . _:b428211284 . . _:b428211287 . . _:b428211286 . _:b428211281 . . . _:b428211280 . . _:b428211271 . . _:b428211283 . _:b428211282 . _:b428211317 . _:b7259917 "The high collagen expression may relate to the extensive fibrosis found in many tumors and recently shown to contribute to the poor penetration of drugs into tumors (Olive et al., >>2009<<). Perhaps the most interesting among the TEMs is TEM 8, which is one of the two receptors for the anthrax toxin (Nanda et al., 2004). An effort is under way to develop anthrax toxin variants that bind only to TEM 8 and that could be used" . _:b428211293 . _:b428211701 . . _:b428211292 . _:b428211295 . . _:b428211114 . _:b428211294 . _:b428211276 . _:b428211289 . _:b428211288 . . _:b428211291 . . _:b428211290 . . _:b7259913 . _:b428211818 . _:b428211301 . . _:b428211300 . _:b7259888 "Cell surface nucleolin is an angiogenesis marker that is both a suitable target for drug delivery (Christian et al., >>2001<<; Reddy et al., 2006; Henke et al., 2008; Drecoll et al., 2009) and involved in the angiogenesis process (Fogal et al., 2009)." . _:b428211622 . _:b7259986 . _:b428211303 . . . _:b428211302 . . . _:b428211297 . _:b428211207 . . _:b7259998 . _:b428211296 . _:b428211708 . . _:b428211299 . . _:b428211813 . _:b428211298 . _:b428211517 . _:b7259904 "An alternatively spliced form of fibronectin containing an additional type III domain, ED-B, is selectively expressed in tumor (and other) angiogenic vessels (Nilsson et al., >>2001<<). Antibodies to ED-B have been used to construct immunotoxins and other compounds for tumor targeting. Proteolytically processed type IV collagen is another matrix component that can be detected with antibodies or peptides (Roth et al.," . _:b428211179 . _:b428211309 . . _:b428211808 . _:b428211375 . . _:b428211308 . . _:b428211611 . . _:b428211311 . _:b7259926 . _:b428211310 . . . _:b428211305 . _:b428211304 . . _:b428211307 . _:b428211165 . _:b428211554 . _:b428211306 . . _:b428211317 . . . _:b428211316 . _:b428211514 . _:b7259985 "of paclitaxel and albumin, with the LyP-1 or iRGD peptide made the drug capable of penetrating into tumor tissue, resulting in several-fold higher activity than that of the original drug (Karmali et al., 2009; Sugahara et al., >>2009<<). The tissue-penetrating properties of these peptides and their internalization into cells makes them particularly efficient in achieving a high concentration of the peptide and any payload attached to it in tumor tissue." . _:b428211319 . _:b7259911 "Leaked fibrinogen is converted to a fibrin meshwork by tissue-procoagulant proteins such as tissue factor (Dvorak et al., 1985; Abe et al., 1999; Pilch et al., >>2006<<). Other plasma proteins, plasma fibronectin in particular, become covalently linked or otherwise bound to the fibrin meshwork. These fibrin\u2013fibronectin complexes in the walls of tumor vessels and in the tumor interstitial stroma can be" . _:b7260000 "Long circulation times are especially important when the target is outside the vasculature, although tumor-penetrating peptides offer a potential solution to this problem (Sugahara et al., >>2009<<). The half-life primarily depends on the rate of elimination into the urine (small molecules) and uptake by the RES in the liver and spleen (particles). Coupling a small molecular mass drug or probe to polyethylene glycol is commonly used" . _:b428211236 . _:b428211318 . _:b7259999 "Multivalency may partially explain the remarkable 1,000-fold increase in the antitumor activity of TNF observed when homing peptides recognizing tumor vessels were added to the protein (Curnis et al., >>2004<<). TNF is a trimeric protein, which would render the homing peptide multivalent." . _:b428211289 . . _:b7259895 . _:b428211313 . _:b428211312 . _:b428211315 . _:b428211314 . . _:b428211325 . _:b428211324 . . _:b428211327 . _:b428211525 . _:b428211178 . . . . . _:b428211326 . _:b428211321 . . _:b428211372 . _:b428211588 . _:b428211320 . _:b428211323 . _:b428211502 . _:b7259968 "Several homing peptides that bind to receptors other than integrins have also been successfully used in preclinical studies to target gene therapy vectors, drugs, and biologicals into tumors (M\u00FCller et al., 2003; Hamzah et al., >>2008<<; Chang et al., 2009; Karmali et al., 2009)." . _:b428211322 . _:b428211333 . . _:b428211688 . _:b428211332 . _:b428211490 . _:b428211335 . . _:b428211334 . _:b7260012 . . . _:b428211329 . _:b428211608 . _:b428211118 . _:b428211328 . _:b428211560 . _:b7259885 "F3 binds to nucleolin, which is ubiquitous as an intracellular protein but is expressed at the cell surface of endothelial cells and tumor cells in vivo (Christian et al., >>2003<<). In vitro, all cells seem to be positive for cell surface nucleolin (Borer et al., 1989; Bonnet et al., 1996) presumably because cultured cells resemble cells that have been activated in vivo. Cell surface nucleolin is an angiogenesis" . _:b428211331 . _:b428211330 . . . _:b428211341 . _:b428211718 . . _:b428211340 . . . . _:b428211343 . _:b7260019 . _:b428211756 . _:b428211342 . . _:b428211337 . . _:b7260020 . _:b428211336 . . _:b7259971 "This problem is particularly prominent with solid tumors, which have a high interstitial pressure, presumably because their blood vessels tend to be leaky and their lymphatic vessels poorly functional (Jain, >>1999<<). Drugs generally do not penetrate further than three to five cell diameters from blood vessels, which leaves more distantly located tumor cells without any drug or exposes them to low drug concentrations that are likely to facilitate the" . _:b428211403 . _:b428211339 . _:b7259867 . _:b428211667 . _:b428211338 . _:b428211159 . _:b428211277 . _:b428211349 . _:b428211348 . _:b7259978 . _:b428211351 . . . _:b7259981 . _:b428211350 . . . . _:b428211345 . _:b428211475 . _:b428211344 . . . _:b7259918 . _:b428211241 . _:b428211347 . _:b428211671 . _:b7259926 "2010Aminopeptidase NPasqualini et al., 2000TEMsCarson-Walter et al., 2001EndosialinChristian et al., 2001Cell surface nucleolinChristian et al., 2003Cell surface annexin-1Oh et al., 2004Cell surface p32/gC1q receptorFogal et al., >>2008< . _:b428211752 . _:b428211765 . _:b428211357 . . _:b428211356 . . _:b428211129 . . _:b428211359 . . _:b428211358 . _:b428211435 . . . _:b428211353 . _:b428211427 . _:b428211352 . . _:b428211355 . . . _:b428211354 . _:b428211355 . . . _:b428211322 . . _:b428211365 . _:b428211172 . . _:b428211666 . _:b428211281 . _:b428211364 . . _:b428211367 . _:b428211779 . _:b428211689 . _:b428211474 . _:b428211366 . . _:b428211357 . _:b428211361 . _:b7259900 . _:b428211360 . _:b428211558 . _:b428211363 . . _:b428211362 . . . _:b428211373 . _:b428211205 "3"^^ . _:b428211372 . _:b428211365 . _:b428211204 "3"^^ . _:b428211375 . _:b428211637 . _:b428211781 . _:b428211207 "3"^^ . _:b7259990 "potential solution to this problem is to use higher affinity ligands for the targeting, but this strong binding can lead to reduced tumor penetration through the so-called binding site barrier (van Osdol et al., 1991; Thurber et al., >>2008<<). Other potential solutions include using anticancer agents with higher potency than most current drugs, using nanoparticle delivery vehicles that deliver more drug per receptor occupied than one to one conjugates, or inducing more" . _:b428211374 . . _:b428211206 "3"^^ . _:b428211369 . _:b428211201 "3"^^ . _:b428211139 . _:b428211368 . _:b428211380 . _:b428211174 . _:b428211200 "3"^^ . _:b428211371 . _:b428211541 . _:b428211203 "3"^^ . _:b428211370 . _:b428211602 . _:b428211202 "3"^^ . _:b428211381 . _:b7260005 "Other results suggest that the RES uptake may have little to do with plasma protein\u2013mediated opsonization (Simberg et al., >>2009<<). The likely explanation for why this has been such an intractable problem is that the Kupffer cell receptors use multiple low affinity interactions to capture nano (and micro)-particles, rendering conventional receptor identification" . _:b7259890 "Cell surface nucleolin is an angiogenesis marker that is both a suitable target for drug delivery (Christian et al., 2001; Reddy et al., 2006; Henke et al., >>2008<<; Drecoll et al., 2009) and involved in the angiogenesis process (Fogal et al., 2009)." . _:b428211213 "3"^^ . _:b428211380 . _:b7260002 . _:b428211212 "3"^^ . _:b428211383 . . . _:b428211215 "3"^^ . _:b428211382 . _:b428211214 "3"^^ . _:b428211377 . . . . _:b428211209 "3"^^ . _:b428211376 . _:b428211208 "3"^^ . _:b428211379 . . . _:b428211518 . _:b428211177 . _:b428211211 "3"^^ . _:b428211378 . _:b428211210 "3"^^ . _:b428211389 . . . _:b428211221 "3"^^ . _:b428211388 . _:b428211220 "3"^^ . _:b428211391 . _:b428211223 "3"^^ . _:b428211390 . _:b7260016 . _:b428211222 "3"^^ . _:b428211385 . _:b428211217 "3"^^ . _:b428211384 . _:b428211206 . _:b428211216 "3"^^ . _:b428211387 . _:b428211714 . _:b428211219 "3"^^ . _:b428211386 . _:b428211218 "3"^^ . _:b428211397 . _:b428211229 "3"^^ . _:b428211396 . . . _:b428211228 "3"^^ . _:b428211399 . _:b7260004 "It has been empirically shown that particle charge (anionic or neutral), size (<100 nm), and ability to prevent complement binding can reduce rates of RES uptake and extend circulation time in mice (for review see Peer et al., >>2007<<). Other results suggest that the RES uptake may have little to do with plasma protein\u2013mediated opsonization (Simberg et al., 2009). The likely explanation for why this has been such an intractable problem is that the Kupffer cell" . _:b428211231 "3"^^ . _:b428211398 . . _:b428211230 "3"^^ . _:b428211432 . _:b428211393 . . _:b428211225 "3"^^ . _:b428211392 . _:b7259976 . _:b428211270 . _:b428211224 "3"^^ . _:b428211395 . _:b428211227 "3"^^ . _:b428211394 . . _:b428211226 "3"^^ . _:b428211405 . _:b428211268 . _:b428211346 . _:b428211237 "3"^^ . _:b428211404 . _:b428211119 . _:b428211236 "3"^^ . _:b428211407 . _:b428211239 "3"^^ . _:b428211406 . _:b428211238 "3"^^ . _:b428211401 . . . . _:b428211233 "3"^^ . _:b428211400 . . _:b428211232 "3"^^ . _:b428211403 . _:b428211658 . _:b428211651 . _:b428211235 "3"^^ . _:b428211402 . . . . _:b428211220 . _:b428211234 "3"^^ . _:b428211413 . _:b428211245 "3"^^ . _:b428211412 . . _:b428211244 "3"^^ . _:b428211415 . _:b7259889 "Cell surface nucleolin is an angiogenesis marker that is both a suitable target for drug delivery (Christian et al., 2001; Reddy et al., >>2006<<; Henke et al., 2008; Drecoll et al., 2009) and involved in the angiogenesis process (Fogal et al., 2009)." . . _:b428211247 "3"^^ . _:b428211414 . _:b428211353 . _:b428211246 "3"^^ . _:b428211409 . . _:b428211241 "3"^^ . . _:b428211408 . _:b428211108 . _:b428211240 "3"^^ . _:b428211411 . _:b428211243 "3"^^ . . _:b428211213 . _:b428211410 . . _:b428211242 "3"^^ . _:b428211421 . _:b428211253 "3"^^ . _:b428211420 . _:b428211424 . _:b428211252 "3"^^ . _:b428211423 . _:b428211822 . _:b428211255 "3"^^ . _:b428211422 . _:b428211418 . . _:b428211254 "3"^^ . _:b7259976 "The peptides contain a tissue penetration motif, R/KXXR/K, which has to be exposed at the C terminus of a peptide (or protein) to be active (the C-end rule [CendR]; Teesalu et al., >>2009<<). A tumor-homing CendR peptide contains both a tumor-specific homing sequence and a cryptic (not C terminal) CendR sequence. The homing sequence takes the peptide to the vascular endothelium in the target tissue, where the peptide is" . _:b428211417 . _:b428211249 "3"^^ . _:b428211416 . . _:b428211248 "3"^^ . _:b7259963 "Drug-loaded nanoparticles have also been targeted with RGD peptides to suppress tumor growth or metastasis (Hood et al., 2002; Murphy et al., >>2008<<; Sugahara et al., 2009)." . _:b428211419 . _:b428211251 "3"^^ . _:b428211491 . _:b428211370 . _:b428211418 . _:b428211250 "3"^^ . . _:b428211429 . _:b428211390 . _:b428211161 . _:b428211261 "3"^^ . _:b428211428 . _:b428211260 "3"^^ . _:b428211431 . _:b428211263 "3"^^ . _:b428211430 . _:b428211262 "3"^^ . _:b428211425 . _:b428211632 . . . _:b428211826 . _:b428211257 "3"^^ . _:b428211424 . . . _:b428211256 "3"^^ . _:b428211427 . . . _:b428211259 "3"^^ . _:b428211426 . . _:b428211258 "3"^^ . _:b428211416 . _:b428211437 . . _:b428211269 "3"^^ . _:b428211323 . _:b428211436 . _:b428211268 "3"^^ . _:b428211439 . _:b428211271 "2"^^ . . _:b428211377 . _:b428211438 . _:b428211270 "2"^^ . . _:b428211728 . _:b428211433 . . _:b428211265 "3"^^ . _:b7259928 "et al., 2001Cell surface nucleolinChristian et al., 2003Cell surface annexin-1Oh et al., 2004Cell surface p32/gC1q receptorFogal et al., 2008Cell surface plectin-1Kelly et al., 2008Fibronectin ED-BNilsson et al., >>2001< . _:b428211432 . _:b428211264 "3"^^ . _:b428211830 . _:b428211679 . _:b428211146 . . _:b428211435 . . _:b428211546 . . _:b428211267 "3"^^ . _:b428211434 . _:b428211266 "3"^^ . _:b428211445 . . _:b428211277 "2"^^ . _:b428211444 . . . _:b428211276 "2"^^ . _:b428211633 . _:b428211401 . . _:b428211447 . _:b7259875 "being tortuous, uneven in diameter, and leaky, tumor vessels express various cell surface and extracellular matrix proteins that normal vessels do not express or do so at much lower levels than tumor vessels (for review see Ruoslahti, >>2002<<). The expression of many of these proteins in tumor vessels is associated with angiogenesis, and they are often functionally important in that process (Hanahan and Folkman, 1996; Alitalo and Carmeliet, 2002)." . _:b428211279 "2"^^ . _:b428211446 . _:b428211348 . _:b428211278 "2"^^ . _:b428211441 . _:b428211273 "2"^^ . _:b428211440 . _:b428211272 "2"^^ . _:b428211443 . . _:b428211275 "2"^^ . . _:b428211256 . _:b428211442 . . _:b428211526 . _:b428211274 "2"^^ . _:b428211453 . . _:b428211285 "2"^^ . _:b428211452 . _:b428211284 "2"^^ . _:b428211455 . . _:b428211287 "2"^^ . _:b428211809 . _:b428211454 . _:b428211286 "2"^^ . . _:b428211449 . _:b428211281 "2"^^ . _:b7259971 . . . _:b428211448 . _:b428211280 "2"^^ . _:b428211451 . _:b428211283 "2"^^ . _:b428211450 . _:b428211282 "2"^^ . . _:b428211785 . _:b428211293 "2"^^ . . . _:b428211292 "2"^^ . _:b428211295 "2"^^ . . . . . _:b428211133 . _:b428211294 "2"^^ . _:b428211387 . _:b7259934 "Initiation of angiogenesis (the angiogenic switch) occurs already in premalignant lesions (Hanahan and Folkman, >>1996<<). Peptide probes that distinguish between the blood vessels of premalignant and fully malignant lesions of some de novo cancers in mice have been reported (Hoffman et al., 2003; Joyce et al., 2003). The vascular molecules recognized by" . _:b428211505 . _:b428211289 "2"^^ . _:b7259982 "Moreover, F3 and LyP-1 have been shown to cause extravasation of their cargo, which can be as large as a nanoparticle, with subsequent uptake into tumor endothelial cells and tumor cells (Porkka et al., 2002; Laakkonen et al., >>2004<<; Karmali et al., 2009)." . _:b428211288 "2"^^ . . _:b428211579 . _:b428211291 "2"^^ . . _:b428211468 . _:b428211290 "2"^^ . _:b428211301 "2"^^ . . _:b428211300 "2"^^ . . _:b428211682 . _:b428211303 "2"^^ . _:b428211302 "2"^^ . . _:b7259942 "Peptides containing an NGR sequence motif had previously been shown to bind weakly to the RGD-binding site of integrins (Koivunen et al., >>1994<<), but this motif was later identified as the binding motif in tumor-homing peptides that were more potent than could be expected on the basis of the weak integrin binding (Arap et al., 1998)." . _:b428211297 "2"^^ . _:b7259955 . . _:b428211743 . _:b428211296 "2"^^ . _:b428211359 . _:b428211299 "2"^^ . . _:b7259915 "The CREKA peptide has been used to confer a new function to nanoparticles: self-amplification of tumor homing (see Amplified tumor homing; Simberg et al., >>2007<<)." . _:b428211298 "2"^^ . _:b428211309 "2"^^ . _:b7259863 . _:b428211308 "2"^^ . _:b428211624 . _:b428211311 "2"^^ . _:b428211310 "2"^^ . _:b428211606 . _:b428211138 . _:b428211305 "2"^^ . _:b7259880 "Other unbiased methods, such as antibody-based screens (Jacobson et al., >>1996<<), cloning strategies (Carson-Walter et al., 2001), and in vivo biotinylation (Borgia et al., 2010), have also been used successfully in analyzing tumor vasculature." . _:b428211304 "2"^^ . _:b7259868 . . _:b7259994 "Thus, phage display complements other target discovery methods such as those based on antibodies (Jacobson et al., 1996; Oh et al., >>2004<<) or cloning methods (Seaman et al., 2007)." . _:b428211773 . _:b7259990 . _:b428211820 . _:b428211307 "2"^^ . _:b7259869 . _:b7259924 "integrins (\u03B1v\u03B23 and \u03B1v\u03B25)Ruoslahti, 2002; Desgrosellier and Cheresh, 2010Aminopeptidase NPasqualini et al., 2000TEMsCarson-Walter et al., 2001EndosialinChristian et al., 2001Cell surface nucleolinChristian et al., >>2003< "2"^^ . _:b7259870 . . _:b428211317 "2"^^ . _:b7259871 . _:b428211316 "2"^^ . _:b7259864 . . . _:b428211755 . _:b428211319 "2"^^ . _:b7259865 . _:b428211318 "2"^^ . _:b7259866 . . _:b428211313 "2"^^ . _:b7259867 . _:b428211312 "2"^^ . _:b7259876 . . . _:b428211315 "2"^^ . _:b7259877 . _:b428211314 . . _:b428211436 . . _:b7259878 . _:b428211314 "2"^^ . _:b428211325 "2"^^ . _:b7259902 "A prime example is the overexpression of \u03B1v\u03B23 and \u03B1v\u03B25 integrins in angiogenic vessels (Brooks et al., 1994; Erdreich-Epstein et al., >>2000<<; Desgrosellier and Cheresh, 2010)." . _:b7259879 . _:b7259989 "One potential solution to this problem is to use higher affinity ligands for the targeting, but this strong binding can lead to reduced tumor penetration through the so-called binding site barrier (van Osdol et al., >>1991<<; Thurber et al., 2008)." . . . _:b428211324 "2"^^ . _:b7259872 . . _:b428211327 "2"^^ . _:b7259873 . _:b428211326 "2"^^ . _:b7259874 . _:b428211321 "2"^^ . _:b7259875 . _:b428211705 . _:b428211598 . _:b428211320 "2"^^ . _:b7259884 . _:b428211323 "2"^^ . _:b7259885 . _:b428211322 "2"^^ . _:b7259886 . _:b428211333 "2"^^ . _:b7259887 . _:b428211332 "2"^^ . _:b7259880 . _:b428211335 "2"^^ . _:b7259881 . . _:b428211334 "2"^^ . _:b7259882 . . . _:b428211329 "2"^^ . _:b7259883 . _:b428211328 "2"^^ . _:b7259892 . _:b428211456 . . _:b428211331 "2"^^ . _:b7259893 . _:b428211613 . _:b428211330 "2"^^ . _:b7259894 . _:b428211341 "2"^^ . _:b7259895 . _:b428211101 . _:b7259984 "a nanoparticle drug composed of paclitaxel and albumin, with the LyP-1 or iRGD peptide made the drug capable of penetrating into tumor tissue, resulting in several-fold higher activity than that of the original drug (Karmali et al., >>2009<<; Sugahara et al., 2009)." . _:b428211340 "2"^^ . _:b7259888 . _:b428211208 . _:b428211510 . . _:b428211343 "2"^^ . _:b7259889 . . _:b428211342 "2"^^ . _:b7259890 . . . _:b428211337 "2"^^ . _:b7259891 . . _:b428211336 "2"^^ . _:b7259900 . . . _:b428211339 "2"^^ . _:b7259901 . _:b428211338 "2"^^ . _:b7259902 . . . _:b428211335 . _:b428211306 . _:b428211349 "2"^^ . _:b7259903 . _:b7259928 . _:b428211384 . _:b428211348 "2"^^ . _:b7259896 . _:b428211351 "2"^^ . _:b7259897 . . _:b428211350 "2"^^ . _:b7259898 . _:b428211345 "2"^^ . _:b7259899 . _:b428211344 "2"^^ . _:b428211485 . . _:b428211347 "2"^^ . _:b428211734 . . _:b428211346 "2"^^ . . . _:b428211357 "2"^^ . _:b428211362 . _:b428211356 "2"^^ . _:b428211128 . . _:b428211173 . _:b428211359 "2"^^ . _:b7259883 . _:b428211419 . . . _:b428211358 "2"^^ . _:b428211580 . _:b428211353 "2"^^ . _:b428211352 "2"^^ . _:b7259951 "The \u03B1v\u03B23 and \u03B1v\u03B25 integrins are highly expressed in tumor endothelium, and their level of expression may be highest in the vessels of the most malignant tumors (Erdreich-Epstein et al., >>2000<<). Enhanced drug delivery with vascular homing peptides has been accomplished using a cyclic peptide containing the integrin-binding RGD motif (CRGDC) to deliver doxorubicin to tumors (Arap et al., 1998)." . . _:b428211766 . . _:b428211355 "2"^^ . _:b428211595 . . _:b428211354 "2"^^ . . . _:b428211365 "2"^^ . _:b428211162 . . _:b428211297 . . _:b428211364 "2"^^ . _:b7259876 "The expression of many of these proteins in tumor vessels is associated with angiogenesis, and they are often functionally important in that process (Hanahan and Folkman, >>1996<<; Alitalo and Carmeliet, 2002)." . _:b428211540 . _:b428211137 . _:b428211367 "2"^^ . . _:b428211115 . _:b428211134 . _:b428211366 "2"^^ . . . _:b7259932 "al., 2008Cell surface plectin-1Kelly et al., 2008Fibronectin ED-BNilsson et al., 2001Fibrin\u2013fibronectin complexesPilch et al., 2006; Simberg et al., 2007Interleukin-11 receptor \u03B1Lewis et al., 2009Protease-cleaved collagen IVXu et al., >>2001<<; Mueller et al., 2009Stage-specific markers." . _:b428211361 "2"^^ . . . _:b428211360 "2"^^ . _:b428211562 . . _:b7259865 "such molecules were detected with antibodies, but screening of peptide and aptamer libraries has greatly expanded the number of tools available for selective binding to tumor cells (for reviews see Ruoslahti, 2002; Peer et al., >>2007<<). Leukemia and lymphoma treatments with antibodies conjugated to a radioisotope have been in clinical use for several years (Sharkey and Goldenberg, 2005)." . . _:b428211356 . _:b428211363 "2"^^ . _:b428211190 . _:b428211362 "2"^^ . _:b428211283 . . . _:b428211488 . _:b428211373 "2"^^ . _:b7259904 . _:b428211428 . _:b428211372 "2"^^ . _:b428211375 "2"^^ . _:b428211748 . _:b428211136 . . . _:b428211374 "2"^^ . . _:b428211369 "2"^^ . . _:b428211368 "2"^^ . _:b7259941 . _:b428211538 . _:b428211295 . _:b428211784 . _:b428211371 "2"^^ . _:b428211168 . . . _:b428211156 . _:b428211330 . _:b428211157 . _:b428211370 "2"^^ . _:b428211158 . _:b428211159 . _:b428211407 . _:b428211152 . _:b428211153 . _:b428211381 "2"^^ . _:b428211154 . _:b428211250 . _:b428211155 . _:b428211164 . _:b428211165 . _:b428211380 "2"^^ . _:b428211166 . _:b428211167 . _:b428211160 . _:b428211161 . _:b428211383 "2"^^ . _:b428211237 . _:b428211162 . _:b428211352 . _:b428211163 . . _:b428211140 . _:b428211141 . _:b428211382 "2"^^ . _:b428211142 . . _:b428211143 . . _:b428211136 . _:b428211137 . _:b428211377 "2"^^ . _:b428211138 . _:b428211139 . _:b428211148 . _:b428211149 . _:b428211376 "2"^^ . _:b428211150 . _:b428211151 . _:b428211144 . _:b428211145 . _:b428211379 "2"^^ . _:b428211146 . _:b428211147 . _:b428211188 . _:b428211184 . _:b428211189 . _:b428211378 "2"^^ . _:b428211190 . _:b428211191 . _:b428211453 . _:b428211184 . _:b428211185 . _:b7259890 . _:b428211389 "2"^^ . _:b428211186 . _:b428211187 . . _:b428211196 . _:b428211729 . _:b428211197 . _:b428211388 "2"^^ . _:b428211198 . . . _:b428211199 . _:b428211192 . _:b428211193 . _:b428211391 "2"^^ . _:b428211194 . . _:b428211195 . _:b428211172 . _:b428211121 . _:b428211173 . _:b428211390 "2"^^ . _:b428211174 . . _:b428211175 . _:b428211168 . _:b7259958 . _:b428211169 . _:b428211385 "2"^^ . _:b428211170 . . _:b428211171 . . _:b428211180 . _:b428211279 . _:b428211181 . _:b428211384 "2"^^ . . _:b428211182 . _:b428211183 . _:b428211176 . _:b428211177 . _:b428211387 "2"^^ . _:b7259908 . _:b428211178 . _:b428211179 . . _:b428211496 . _:b428211681 . _:b428211386 "2"^^ . . _:b428211397 "2"^^ . _:b428211100 . _:b428211101 . . _:b428211102 . _:b428211396 "2"^^ . _:b428211103 . _:b428211399 "2"^^ . _:b428211099 . . _:b7259882 . _:b428211398 "2"^^ . _:b428211719 . _:b428211393 "2"^^ . _:b7259898 . _:b428211392 "2"^^ . . . _:b428211395 "2"^^ . _:b428211124 . _:b428211125 . _:b428211394 "2"^^ . _:b428211126 . . _:b428211127 . _:b428211120 . _:b428211570 . _:b428211121 . _:b428211405 "2"^^ . _:b428211122 . _:b428211123 . _:b428211132 . _:b428211133 . _:b428211404 "2"^^ . _:b428211134 . _:b428211135 . _:b428211128 . . _:b428211129 . _:b428211407 "2"^^ . _:b428211130 . _:b428211131 . _:b428211108 . _:b428211109 . _:b428211786 . _:b428211406 "2"^^ . _:b428211110 . _:b428211111 . _:b428211104 . _:b428211105 . . _:b428211106 . _:b428211401 "2"^^ . _:b428211107 . _:b428211116 . . _:b428211117 . _:b428211400 "2"^^ . _:b428211118 . . _:b428211119 . _:b428211472 . _:b428211112 . _:b428211113 . _:b428211403 "2"^^ . _:b428211114 . _:b428211115 . _:b428211402 "2"^^ . _:b428211568 . . _:b428211413 "2"^^ . _:b428211412 "2"^^ . _:b428211240 . _:b428211415 "2"^^ . _:b428211758 . _:b428211414 "2"^^ . _:b428211202 . _:b428211396 . _:b428211409 "2"^^ . . _:b7259863 _:b7259960 . . _:b7259863 _:b7259961 . _:b7259863 _:b7259962 . _:b428211408 "2"^^ . _:b7259863 _:b7259963 . _:b7259949 "Both F3 and the NGR motif peptides have been used to target drugs to tumors (Curnis et al., 2004; Reddy et al., >>2006<<; Henke et al., 2008), and aptamers that bind nucleolin are being pursued in phase I clinical trials (Laber, D., V.R. Sharma, D.A. Laber, V.R. Sharma, L." . _:b7259863 _:b7259964 . _:b7259931 . _:b7259863 _:b7259965 . _:b7259863 _:b7259966 . _:b428211411 "2"^^ . _:b7259863 _:b7259967 . _:b7259863 _:b7259952 . _:b428211374 . _:b7259863 _:b7259953 . . _:b7259863 _:b7259954 . _:b7259927 . _:b428211549 . _:b428211410 "2"^^ . _:b7259863 _:b7259955 . _:b7259863 _:b7259956 . _:b7259963 . _:b7259863 _:b7259957 . _:b7259863 _:b7259958 . _:b428211421 "2"^^ . _:b7259863 _:b7259959 . _:b428211341 . _:b7259863 _:b7259944 . _:b428211231 . _:b7259863 _:b7259945 . _:b7259863 _:b7259946 . _:b428211420 "2"^^ . . _:b428211687 . . . _:b7259863 _:b7259947 . _:b7259863 _:b7259948 . _:b7259863 _:b7259949 . _:b7259863 _:b7259950 . _:b428211423 "2"^^ . _:b7259863 _:b7259951 . _:b428211318 . _:b7259863 _:b7259936 . _:b7259863 _:b7259937 . _:b7259863 _:b7259938 . _:b428211422 "2"^^ . _:b7259863 _:b7259939 . _:b7259863 _:b7259940 . _:b7259863 _:b7259941 . _:b7259863 _:b7259942 . _:b428211717 . . _:b428211410 . _:b428211417 "2"^^ . _:b7259863 _:b7259943 . _:b7259863 _:b7259928 . _:b7259863 _:b7259929 . _:b7259863 _:b7259930 . _:b428211416 "2"^^ . _:b7259863 _:b7259931 . . _:b7259863 _:b7259932 . _:b7259863 _:b7259933 . _:b7259863 _:b7259934 . . _:b428211419 "2"^^ . _:b7259863 _:b7259935 . . . _:b7259863 _:b7259920 . _:b7259863 _:b7259921 . _:b7259863 _:b7259922 . _:b428211418 "2"^^ . _:b7259863 _:b7259923 . _:b7259863 _:b7259924 . _:b7259863 _:b7259925 . _:b7259863 _:b7259926 . _:b428211429 "2"^^ . _:b7259863 _:b7259927 . . _:b428211180 . _:b7259863 _:b7259912 . _:b7259863 _:b7259913 . _:b7259863 _:b7259914 . _:b428211428 "2"^^ . _:b7259863 _:b7259915 . _:b428211233 . _:b7259863 _:b7259916 . _:b7259863 _:b7259917 . _:b7259863 _:b7259918 . _:b7259920 . _:b428211431 "2"^^ . _:b7259863 _:b7259919 . _:b7259863 _:b7259904 . _:b7259863 _:b7259905 . _:b7259863 _:b7259906 . _:b428211430 "2"^^ . _:b7259863 _:b7259907 . _:b7259863 _:b7259908 . _:b7259863 _:b7259909 . _:b7259950 . _:b7259863 _:b7259910 . _:b428211425 "2"^^ . _:b7259863 _:b7259911 . _:b428211424 "2"^^ . _:b7259865 . _:b428211427 "2"^^ . _:b428211226 . . _:b7259863 _:b7260016 . _:b7259863 _:b7260017 . _:b7259873 . . _:b7259863 _:b7260018 . _:b428211426 "2"^^ . _:b7259863 _:b7260019 . . _:b7259863 _:b7260020 . _:b7260006 . . _:b428211437 "2"^^ . _:b7259863 _:b7260008 . _:b428211791 . _:b7259863 _:b7260009 . . _:b7259863 _:b7260010 . _:b428211198 . _:b428211436 "2"^^ . _:b7259863 _:b7260011 . _:b7259863 _:b7260012 . _:b7259869 "Second, tumors have a high interstitial pressure thought to result from dysfunctional lymphatics, which causes tissue fluid to flow out of the tumor, working against diffusion of drugs from the blood vessels into the tumor (Jain, >>1999<<; Heldin et al., 2004)." . _:b7259863 _:b7260013 . _:b7259863 _:b7260014 . _:b428211439 "2"^^ . _:b7259863 _:b7260015 . _:b7259863 _:b7260000 . _:b7259863 _:b7260001 . _:b7259863 _:b7260002 . _:b428211438 "2"^^ . _:b7259863 _:b7260003 . _:b7259863 _:b7260004 . _:b7259863 _:b7260005 . _:b7259863 _:b7260006 . _:b428211433 "2"^^ . _:b7259863 _:b7260007 . _:b7259863 _:b7259992 . _:b7259972 "to five cell diameters from blood vessels, which leaves more distantly located tumor cells without any drug or exposes them to low drug concentrations that are likely to facilitate the development of resistance (Hambley and Hait, >>2009<<). Despite these limitations, a homing peptide that binds to the Her2 receptor (Gee et al., 2008) has been used to deliver compounds to tumors that overexpress this receptor." . _:b428211351 . _:b7259863 _:b7259993 . _:b7259863 _:b7259994 . _:b428211432 "2"^^ . _:b7259863 _:b7259995 . _:b428211577 . . _:b7259863 _:b7259996 . _:b7259863 _:b7259997 . _:b428211210 . _:b7259863 _:b7259998 . _:b428211435 "2"^^ . _:b7259863 _:b7259999 . _:b7259863 _:b7259984 . _:b7259863 _:b7259985 . _:b7259977 "The iRGD peptide penetrates into tumor tissue and is capable of carrying 10 times more drug cargo into a tumor than a conventional RGD peptide (Sugahara et al., >>2009<<)." . _:b7259863 _:b7259986 . _:b428211434 "2"^^ . _:b7259863 _:b7259987 . _:b7259863 _:b7259988 . . _:b428211101 . _:b7259863 _:b7259989 . _:b7259863 _:b7259990 . _:b428211445 "2"^^ . _:b7259863 _:b7259991 . _:b7259882 "Other unbiased methods, such as antibody-based screens (Jacobson et al., 1996), cloning strategies (Carson-Walter et al., 2001), and in vivo biotinylation (Borgia et al., >>2010<<), have also been used successfully in analyzing tumor vasculature." . . _:b7259900 "This protein is the receptor for the tumor-homing peptide LyP-1, originally discovered using in vivo phage display (Laakkonen et al., >>2002<<)." . _:b428211100 . _:b7259863 _:b7259976 . _:b7259863 _:b7259977 . _:b7259863 _:b7259978 . _:b428211444 "2"^^ . _:b7259863 _:b7259979 . _:b428211383 . _:b7259863 _:b7259980 . _:b428211103 . _:b7259863 _:b7259981 . _:b7259863 _:b7259982 . _:b428211447 "2"^^ . _:b7259863 _:b7259983 . _:b7259863 _:b7259968 . _:b428211102 . _:b7259863 _:b7259969 . _:b7259863 _:b7259970 . _:b428211446 "2"^^ . _:b7259863 _:b7259971 . _:b7259863 _:b7259972 . _:b7259863 _:b7259973 . _:b7259863 _:b7259974 . _:b428211441 "2"^^ . _:b7259863 _:b7259975 . _:b428211643 . _:b428211440 "2"^^ . _:b428211099 . . _:b428211443 "2"^^ . _:b428211247 . . _:b428211442 "2"^^ . _:b7259903 . _:b428211109 . _:b428211453 "2"^^ . . _:b428211759 . _:b428211108 . _:b7260020 . _:b428211452 "2"^^ . . . _:b428211111 . _:b428211455 "2"^^ . _:b7259870 "a high interstitial pressure thought to result from dysfunctional lymphatics, which causes tissue fluid to flow out of the tumor, working against diffusion of drugs from the blood vessels into the tumor (Jain, 1999; Heldin et al., >>2004<<). The leakiness of tumor vessels partially makes up for the poor penetration (the so-called enhanced permeability and retention [EPR] effect), but EPR is not very effective, and its size dependency and variability from tumor to tumor" . _:b428211110 . _:b428211454 "2"^^ . . _:b428211105 . . _:b7259914 . _:b428211449 "2"^^ . _:b428211104 . . . _:b7259915 . _:b428211448 "2"^^ . _:b428211107 . . _:b428211451 "2"^^ . _:b428211106 . _:b428211738 . _:b428211450 "2"^^ . . . _:b428211117 . _:b428211461 "2"^^ . . _:b428211116 . _:b428211460 "2"^^ . _:b428211119 . _:b428211543 . _:b428211463 "2"^^ . _:b428211508 . _:b428211118 . _:b428211462 "2"^^ . _:b7259960 . _:b428211113 . _:b428211457 "2"^^ . _:b7259863 _:b7259896 . _:b428211112 . _:b7259863 _:b7259897 . . _:b7259863 _:b7259898 . _:b428211456 "2"^^ . _:b7259863 _:b7259899 . _:b7259863 _:b7259900 . _:b428211115 . _:b7259863 _:b7259901 . _:b7259863 _:b7259902 . _:b428211459 "2"^^ . _:b7259863 _:b7259903 . _:b7259863 _:b7259888 . _:b428211114 . _:b7259863 _:b7259889 . _:b428211481 . _:b7259863 _:b7259890 . _:b428211458 "2"^^ . _:b7259863 _:b7259891 . _:b7259863 _:b7259892 . _:b428211125 . _:b7259863 _:b7259893 . _:b7259954 "These same peptides have also been used to deliver tissue factor to induce blood clotting specifically in tumor blood vessels, with resulting occlusion of the vessels and tumor necrosis (Bieker et al., >>2009<<). A targeted TNF is currently in clinical trials (Paoloni et al. 2009; Gregorc et al., 2010)." . . _:b428211445 . _:b428211469 "2"^^ . _:b7259863 _:b7259894 . _:b7259863 _:b7259895 . _:b7259863 _:b7259880 . _:b428211124 . . _:b7259863 _:b7259881 . _:b7259863 _:b7259882 . _:b428211468 "2"^^ . _:b7259863 _:b7259883 . _:b7259863 _:b7259884 . _:b428211127 . _:b7259863 _:b7259885 . _:b7259863 _:b7259886 . _:b428211471 "2"^^ . _:b428211149 . _:b428211709 . . . _:b7259863 _:b7259887 . _:b7259863 _:b7259872 . _:b428211126 . _:b7259863 _:b7259873 . _:b7259863 _:b7259874 . _:b428211470 "2"^^ . _:b7259863 _:b7259875 . . _:b7259863 _:b7259876 . _:b428211618 . _:b428211121 . _:b7259863 _:b7259877 . _:b7259930 . _:b428211327 . _:b7259863 _:b7259878 . _:b428211264 . _:b428211465 "2"^^ . _:b428211187 . _:b7259863 _:b7259879 . _:b7259863 _:b7259864 . _:b428211120 . _:b7259863 _:b7259865 . . _:b428211464 "2"^^ . _:b7259863 _:b7259866 . _:b7259863 _:b7259867 . _:b7259863 _:b7259868 . _:b428211123 . _:b7259863 _:b7259869 . _:b7259863 _:b7259870 . _:b428211467 "2"^^ . _:b7259863 _:b7259871 . _:b428211122 . _:b7259939 "The idea that this level of specificity can be achieved with tumor vessels has been demonstrated with tumor type\u2013specific peptides (Hoffman et al., 2003; Joyce et al., >>2003<<; Laakkonen et al., 2004)." . . _:b428211466 "2"^^ . _:b428211597 . _:b428211133 . . . _:b428211477 "2"^^ . _:b428211099 . _:b428211132 . . _:b428211476 "2"^^ . . _:b7259897 "In addition to aforementioned nucleolin, the cytoplasmic proteins annexin1 (Oh et al., >>2004<<) and plectin-1 (Kelly et al., 2008) have been found to be present at the cell surface of endothelial cells in tumors but not in normal tissues." . _:b428211680 . _:b428211135 . _:b428211479 "2"^^ . . . _:b428211134 . . _:b428211478 "2"^^ . _:b428211544 . _:b428211129 . _:b7259957 "of an antibacterial peptide, which destroys mitochondria in mammalian cells causing apoptosis, with either the RGD or NGR peptide also inhibited tumor growth in mice, whereas either peptide alone was inactive (Ellerby et al., >>1999<<). Moreover, targeting the same proapoptotic peptide to the blood vessels of the normal prostate caused partial destruction of the prostate and delayed the development of cancers in transgenic prostate cancer mice (Arap et al., 2002)." . _:b428211473 "2"^^ . . _:b428211128 . _:b428211472 "2"^^ . _:b7260001 "Coupling a small molecular mass drug or probe to polyethylene glycol is commonly used to increase molecular mass above the kidney filtration cut-off size of 5 nm (Choi et al., >>2007<<). Polyethylene glycol coating is also a strategy used to minimize elimination of protein therapeutics. Preventing RES uptake is particularly important when nanoparticles are used in drug delivery." . _:b428211823 . . _:b428211503 . _:b428211131 . _:b428211475 "2"^^ . _:b428211130 . _:b428211474 "2"^^ . . _:b428211141 . _:b428211485 "2"^^ . _:b428211515 . . _:b428211140 . . _:b428211484 "2"^^ . _:b428211143 . . _:b428211487 "2"^^ . . _:b428211142 . _:b428211486 "2"^^ . . _:b428211137 . _:b428211481 "2"^^ . _:b428211136 . . _:b428211480 "2"^^ . _:b428211140 . . _:b428211139 . _:b7259995 "Thus, phage display complements other target discovery methods such as those based on antibodies (Jacobson et al., 1996; Oh et al., 2004) or cloning methods (Seaman et al., >>2007<<). The enhanced avidity from multivalency is usually the result of an unaffected binding rate (on rate [kon]) but a reduction in off rate (koff) for the multiple interactions. Multivalency is important in nanoparticle-based targeting" . _:b428211483 "2"^^ . _:b428211138 . _:b428211336 . _:b428211482 "2"^^ . _:b428211149 . _:b428211685 . _:b428211440 . _:b428211186 . _:b428211309 . _:b428211493 "2"^^ . _:b428211148 . _:b428211492 "2"^^ . _:b428211151 . _:b428211495 "2"^^ . _:b428211603 . . . _:b428211150 . _:b428211170 . _:b428211494 "2"^^ . _:b428211461 . . _:b428211394 . _:b428211425 . _:b428211145 . . _:b428211489 "2"^^ . _:b428211144 . _:b7259877 . _:b428211488 "2"^^ . _:b428211147 . _:b428211491 "2"^^ . _:b428211146 . . _:b428211490 "2"^^ . _:b428211157 . _:b428211501 "2"^^ . _:b428211156 . _:b428211366 . _:b428211500 "2"^^ . _:b428211329 . _:b7260006 "Iron oxide nanoparticles coated with the CREKA peptide bind and accumulate in tumor vessels where they cause additional clotting (Simberg et al., >>2007<<). The approach is similar to clotting induced in tumor vessels by tumor-targeted tissue factor (Huang et al., 1997; Bieker et al., 2009) with the exception that the CREKA system is based on self-amplified nanoparticle homing. The clotting" . _:b428211159 . _:b428211503 "2"^^ . . _:b428211158 . . _:b428211713 . _:b428211502 "2"^^ . _:b428211153 . _:b428211497 "2"^^ . _:b428211345 . _:b428211152 . _:b428211496 "2"^^ . _:b428211155 . _:b428211499 "2"^^ . _:b428211154 . _:b428211498 "2"^^ . _:b428211165 . _:b428211509 "2"^^ . . _:b428211164 . . _:b428211508 "2"^^ . _:b428211235 . _:b428211167 . _:b428211110 . _:b428211511 "2"^^ . _:b428211166 . _:b428211510 "2"^^ . _:b428211161 . _:b428211505 "2"^^ . . _:b428211746 . _:b428211621 . _:b428211160 . _:b428211754 . . _:b428211504 "2"^^ . _:b428211163 . _:b7259966 "Finally, RGD and other tumor-homing peptides have been used to alter the host range of viral gene therapy vectors (Wickham, 2000; Haviv et al., >>2002<<). Several homing peptides that bind to receptors other than integrins have also been successfully used in preclinical studies to target gene therapy vectors, drugs, and biologicals into tumors (M\u00FCller et al., 2003; Hamzah et al., 2008;" . _:b428211507 "2"^^ . _:b428211162 . _:b428211506 "2"^^ . _:b7259931 "2004Cell surface p32/gC1q receptorFogal et al., 2008Cell surface plectin-1Kelly et al., 2008Fibronectin ED-BNilsson et al., 2001Fibrin\u2013fibronectin complexesPilch et al., 2006; Simberg et al., 2007Interleukin-11 receptor \u03B1Lewis et al., >>2009< . _:b428211173 . _:b428211429 . _:b428211517 "2"^^ . _:b428211172 . . _:b428211516 "2"^^ . _:b428211175 . _:b428211238 . _:b428211519 "2"^^ . _:b428211174 . _:b428211230 . _:b428211518 "2"^^ . _:b428211169 . _:b428211737 . _:b428211513 "2"^^ . _:b428211168 . _:b7259907 . _:b428211512 "2"^^ . _:b428211171 . _:b428211515 "2"^^ . _:b428211486 . _:b428211170 . _:b428211732 . _:b428211514 "2"^^ . . _:b428211181 . . _:b428211525 "2"^^ . _:b428211180 . . . . _:b428211524 "2"^^ . _:b428211183 . _:b428211644 . . _:b428211527 "2"^^ . _:b7259993 . _:b428211182 . _:b7259902 . _:b428211526 "2"^^ . _:b428211177 . _:b428211800 . . _:b428211521 "2"^^ . . _:b428211176 . _:b428211594 . . _:b428211653 . _:b428211520 "2"^^ . _:b428211179 . _:b428211523 "2"^^ . _:b7259922 . _:b7259987 . _:b428211178 . . _:b428211522 "2"^^ . _:b428211189 . _:b428211533 "2"^^ . _:b428211188 . . _:b428211532 "2"^^ . _:b428211191 . _:b428211426 . _:b428211535 "2"^^ . _:b7260014 "to guide the surgical procedure (by magnetic resonance imaging) and a high resolution mapping that can be visualized during surgery to identify surgical margins (by fluorescence imaging of quantum dots; Wang et al., 2004; Kim et al., >>2005<<; Sathe et al., 2006; Kim and Taton, 2007; Song et al., 2007; Park et al., 2008; Ye et al., 2008)." . _:b428211678 . _:b428211190 . _:b428211534 "2"^^ . _:b428211185 . _:b7260017 . . _:b428211529 "2"^^ . . _:b428211184 . _:b428211528 "2"^^ . _:b428211187 . _:b428211117 . . _:b428211531 "2"^^ . _:b428211761 . _:b428211186 . . _:b428211530 "2"^^ . _:b428211596 . _:b428211197 . . _:b428211541 "2"^^ . _:b7259916 . _:b428211196 . . . _:b428211540 "2"^^ . _:b428211199 . _:b428211543 "2"^^ . _:b428211561 . _:b428211617 . _:b428211198 . _:b428211542 "2"^^ . _:b428211193 . _:b428211537 "2"^^ . _:b428211185 . _:b428211192 . _:b428211536 "2"^^ . _:b428211195 . _:b428211730 . . _:b428211539 "2"^^ . _:b428211194 . . _:b428211538 "2"^^ . . . _:b428211549 "2"^^ . _:b428211447 . _:b428211152 . _:b428211267 . _:b428211548 "2"^^ . . _:b428211634 . _:b428211832 . _:b428211551 "2"^^ . . . _:b428211550 "2"^^ . _:b428211628 . _:b428211545 "2"^^ . _:b428211188 . _:b428211544 "2"^^ . _:b428211183 . . _:b428211547 "2"^^ . _:b7259942 . . _:b428211221 . . . _:b7260018 . _:b428211546 "2"^^ . _:b7259935 "Peptide probes that distinguish between the blood vessels of premalignant and fully malignant lesions of some de novo cancers in mice have been reported (Hoffman et al., >>2003<<; Joyce et al., 2003)." . _:b428211557 "2"^^ . . _:b428211556 "2"^^ . _:b428211806 . _:b428211559 "2"^^ . _:b428211369 . _:b428211558 "2"^^ . . _:b7259940 . _:b428211553 "2"^^ . _:b428211257 . _:b7259947 "Like nucleolin, aminopeptidase N is functionally important in the angiogenesis process (Pasqualini et al., 2000; Rangel et al., >>2007<<). These findings serve as a paradigm to illustrate a discovery process in which a new homing peptide is discovered in phage screening, the receptor for the peptide is identified by biochemical methods such as affinity chromatography, and" . _:b428211301 . _:b428211552 "2"^^ . . _:b428211555 "2"^^ . _:b428211216 . _:b428211554 "2"^^ . _:b428211783 . _:b428211565 "2"^^ . _:b428211564 "2"^^ . _:b428211124 . _:b428211567 "2"^^ . . _:b7259887 . _:b428211501 . _:b7259863 . _:b428211565 . . _:b428211566 "2"^^ . . _:b428211561 "2"^^ . _:b428211560 "2"^^ . . . _:b428211605 . _:b428211563 "2"^^ . . _:b7259913 "complexes in the walls of tumor vessels and in the tumor interstitial stroma can be accessed with peptides derived from phage screening, such as the nine\u2013amino acid cyclic peptide CLT-1 (Pilch et al., 2006; Ye et al., >>2008<<) and the pentapeptide CREKA (Simberg et al., 2007). Fibrin-binding peptides isolated for the purpose of targeting blood clots in cardiovascular disease would presumably behave similarly if tested for tumor homing." . _:b428211562 "2"^^ . _:b428211378 . . _:b7259892 . _:b428211423 . . _:b428211753 . _:b428211573 "2"^^ . . _:b428211572 "2"^^ . _:b428211575 "2"^^ . . _:b428211824 . _:b428211574 "2"^^ . . _:b428211478 . _:b428211569 "2"^^ . . _:b428211568 "2"^^ . . . _:b428211720 . _:b7260012 "3; von Maltzahn et al., 2009; Park et al., >>2010<<). Other biological cascades, such as the protease activity that activates CendR peptides in tumors (Sugahara et al., 2009), can be exploited." . _:b428211571 "2"^^ . _:b428211158 . . _:b428211570 "2"^^ . _:b428211581 "2"^^ . _:b428211466 . _:b428211535 . _:b428211580 "2"^^ . . . _:b428211583 "2"^^ . . _:b428211582 "2"^^ . _:b428211303 . _:b428211577 "2"^^ . _:b428211694 . . _:b428211576 "2"^^ . . . _:b428211579 "2"^^ . . _:b428211578 "2"^^ . . . _:b428211408 . _:b428211589 "2"^^ . _:b428211360 . _:b428211588 "2"^^ . _:b428211591 "2"^^ . _:b428211638 . _:b428211590 "2"^^ . _:b428211112 . _:b7259973 "Despite these limitations, a homing peptide that binds to the Her2 receptor (Gee et al., >>2008<<) has been used to deliver compounds to tumors that overexpress this receptor." . _:b428211103 . _:b428211557 . . _:b428211585 "2"^^ . _:b428211584 "2"^^ . _:b428211587 "2"^^ . _:b7259941 "The \u03B1v integrins play an important role in angiogenesis, although the details of their involvement in this process remain to be fully elucidated (Desgrosellier and Cheresh, >>2010<<). Peptides containing an NGR sequence motif had previously been shown to bind weakly to the RGD-binding site of integrins (Koivunen et al., 1994), but this motif was later identified as the binding motif in tumor-homing peptides that were" . _:b428211556 . _:b428211586 "2"^^ . . _:b428211597 "2"^^ . _:b428211774 . _:b428211596 "2"^^ . _:b7259896 . _:b7259996 . _:b428211599 "2"^^ . . . _:b428211598 "2"^^ . _:b7259884 . _:b428211593 "2"^^ . . _:b428211672 . _:b428211592 "2"^^ . . _:b428211595 "2"^^ . _:b428211796 . . _:b428211797 . _:b428211798 . _:b428211594 "2"^^ . _:b428211799 . _:b428211792 . . _:b428211793 . _:b7259989 . _:b428211794 . _:b428211605 "2"^^ . _:b428211795 . _:b428211804 . . _:b428211805 . _:b7259897 . _:b428211806 . _:b428211604 "2"^^ . _:b428211807 . . _:b428211800 . . _:b428211801 . _:b428211802 . _:b428211607 "2"^^ . _:b428211803 . _:b428211780 . _:b428211781 . _:b428211782 . _:b428211606 "2"^^ . _:b428211783 . _:b428211776 . _:b428211777 . _:b428211778 . _:b428211601 "2"^^ . _:b428211779 . _:b428211788 . _:b428211789 . . _:b428211790 . _:b428211600 "2"^^ . _:b428211791 . _:b428211784 . _:b428211794 . _:b428211785 . . _:b428211786 . _:b428211603 "2"^^ . _:b428211787 . _:b428211828 . . _:b428211829 . _:b428211830 . _:b428211652 . _:b428211602 "2"^^ . . . _:b428211831 . _:b428211274 . _:b428211824 . _:b428211825 . _:b428211581 . _:b428211826 . _:b428211613 "2"^^ . _:b428211827 . _:b428211648 . _:b7260004 . _:b428211612 "2"^^ . _:b428211832 . _:b428211833 . _:b428211834 . _:b428211615 "2"^^ . _:b428211812 . _:b428211813 . _:b428211814 . _:b428211614 "2"^^ . _:b428211815 . _:b428211116 . _:b428211808 . _:b428211809 . _:b428211810 . _:b428211609 "2"^^ . _:b428211811 . . _:b428211820 . _:b428211821 . _:b428211822 . _:b428211614 . _:b428211608 "2"^^ . . _:b428211823 . _:b428211816 . . _:b428211817 . _:b428211818 . _:b7259912 "These fibrin\u2013fibronectin complexes in the walls of tumor vessels and in the tumor interstitial stroma can be accessed with peptides derived from phage screening, such as the nine\u2013amino acid cyclic peptide CLT-1 (Pilch et al., >>2006<<; Ye et al., 2008) and the pentapeptide CREKA (Simberg et al., 2007). Fibrin-binding peptides isolated for the purpose of targeting blood clots in cardiovascular disease would presumably behave similarly if tested for tumor homing." . _:b428211611 "2"^^ . _:b428211819 . _:b428211732 . _:b428211733 . _:b428211734 . _:b428211610 "2"^^ . _:b428211735 . _:b428211728 . _:b428211729 . _:b428211730 . _:b428211621 "2"^^ . _:b428211731 . _:b428211259 . _:b428211740 . _:b7259872 "the poor penetration (the so-called enhanced permeability and retention [EPR] effect), but EPR is not very effective, and its size dependency and variability from tumor to tumor limit its usefulness (Maeda et al., 2000; Iyer et al., >>2006<<; Sugahara et al., 2009). Interstitial fibrosis can further retard the diffusion of compounds through tumors (Olive et al., 2009)." . _:b428211741 . . _:b428211742 . _:b428211620 "2"^^ . _:b428211743 . _:b428211736 . _:b428211737 . _:b428211738 . _:b428211623 "2"^^ . _:b428211739 . . _:b428211716 . _:b428211717 . _:b428211718 . _:b428211622 "2"^^ . _:b428211719 . _:b428211712 . _:b428211150 . _:b428211713 . _:b428211249 . _:b428211714 . _:b428211617 "2"^^ . _:b428211397 . _:b428211715 . _:b428211724 . _:b428211725 . _:b428211726 . _:b428211616 "2"^^ . _:b428211727 . _:b428211720 . _:b428211721 . . _:b428211722 . _:b428211619 "2"^^ . _:b428211723 . _:b428211764 . . . . _:b428211765 . _:b428211766 . _:b428211618 "2"^^ . _:b428211767 . _:b428211760 . . _:b428211761 . . _:b428211762 . _:b428211629 "2"^^ . _:b428211763 . _:b428211772 . _:b428211773 . _:b428211774 . _:b428211650 . _:b428211628 "2"^^ . _:b428211775 . _:b428211768 . _:b428211769 . _:b428211770 . _:b428211631 "2"^^ . _:b428211771 . _:b428211748 . _:b428211749 . _:b428211750 . _:b428211630 "2"^^ . _:b428211751 . _:b428211744 . _:b7259896 "in vivo screening of phage libraries has also produced several potent tumor-homing peptides, the target molecules of which remain to be identified (Hoffman et al., 2003; Joyce et al., 2003; J\u00E4rvinen and Ruoslahti, 2007; Chang et al., >>2009<<)." . _:b428211745 . _:b428211746 . _:b428211625 "2"^^ . _:b428211747 . _:b428211756 . _:b428211757 . _:b7259925 . _:b428211758 . _:b428211624 "2"^^ . _:b428211759 . _:b7259881 . _:b428211752 . . _:b428211753 . _:b428211754 . _:b428211627 "2"^^ . _:b428211273 . . _:b428211755 . _:b428211532 . _:b428211626 "2"^^ . _:b428211358 . _:b428211637 "2"^^ . . _:b428211636 "2"^^ . _:b7260002 "Tumor-responsive, cleavable stealth coatings have been used to mitigate this problem (Harris et al., >>2008<<), but the RES/MPS uptake of nanoparticles remains a major problem in the use of nanoparticles in nanomedicine." . _:b428211269 . _:b428211639 "2"^^ . _:b428211448 . . _:b428211799 . _:b428211638 "2"^^ . _:b428211555 . . _:b428211533 . _:b428211633 "2"^^ . _:b7259967 "Several homing peptides that bind to receptors other than integrins have also been successfully used in preclinical studies to target gene therapy vectors, drugs, and biologicals into tumors (M\u00FCller et al., >>2003<<; Hamzah et al., 2008; Chang et al., 2009; Karmali et al., 2009)." . . _:b428211632 "2"^^ . _:b7259974 "Folic acid is another probe commonly used to target the folate receptor, which is overexpressed by tumor cells in many tumors (for review see Salazar and Ratnam, >>2007<<). Experimental and theoretical results indicate that this increase in efficacy is not dominated by changes in overall drug uptake by the tumor (i.e., increased volumetric concentration) but rather changes in cellular internalization of" . _:b428211635 "2"^^ . . _:b7259866 . . _:b428211778 . _:b428211634 "2"^^ . . _:b428211480 . _:b7259864 "Traditionally, such molecules were detected with antibodies, but screening of peptide and aptamer libraries has greatly expanded the number of tools available for selective binding to tumor cells (for reviews see Ruoslahti, >>2002<<; Peer et al., 2007)." . _:b428211645 "2"^^ . . . _:b7259868 "This low penetration appears to arise from two main factors: first, tumor vessels are poorly perfused with blood and are dysfunctional, which limits the delivery of blood-borne compounds to tumors (Jain, >>1999<<). Second, tumors have a high interstitial pressure thought to result from dysfunctional lymphatics, which causes tissue fluid to flow out of the tumor, working against diffusion of drugs from the blood vessels into the tumor (Jain, 1999;" . _:b428211644 "2"^^ . _:b428211647 "2"^^ . _:b428211284 . . . _:b428211646 "2"^^ . _:b7259889 . . _:b428211641 "2"^^ . . _:b428211640 "2"^^ . _:b428211364 . _:b7259982 . _:b428211262 . _:b428211691 . _:b428211643 "2"^^ . _:b428211642 "2"^^ . . _:b428211653 "2"^^ . _:b428211104 . . _:b7259871 "makes up for the poor penetration (the so-called enhanced permeability and retention [EPR] effect), but EPR is not very effective, and its size dependency and variability from tumor to tumor limit its usefulness (Maeda et al., >>2000<<; Iyer et al., 2006; Sugahara et al., 2009). Interstitial fibrosis can further retard the diffusion of compounds through tumors (Olive et al., 2009)." . . _:b428211652 "2"^^ . _:b428211299 . _:b428211304 . _:b7259925 "and \u03B1v\u03B25)Ruoslahti, 2002; Desgrosellier and Cheresh, 2010Aminopeptidase NPasqualini et al., 2000TEMsCarson-Walter et al., 2001EndosialinChristian et al., 2001Cell surface nucleolinChristian et al., 2003Cell surface annexin-1Oh et al., >>2004< "A prime example is the overexpression of \u03B1v\u03B23 and \u03B1v\u03B25 integrins in angiogenic vessels (Brooks et al., 1994; Erdreich-Epstein et al., 2000; Desgrosellier and Cheresh, >>2010<<). These integrins are prime targets for synaphic drug delivery. Vascular markers expressed on the surface of the endothelium, such as the integrins, are most readily available for the binding of blood-borne compounds. However, the ECM" . _:b428211655 "2"^^ . . _:b428211319 . . _:b428211454 . _:b428211654 "2"^^ . _:b428211742 . . _:b428211649 "2"^^ . _:b428211648 "2"^^ . _:b7259952 . _:b428211107 . _:b7260007 . _:b428211651 "2"^^ . _:b428211590 . _:b428211619 . _:b428211751 . _:b428211650 "2"^^ . . _:b428211219 . _:b428211661 "2"^^ . _:b428211615 . _:b428211660 "2"^^ . _:b428211457 . _:b428211663 "2"^^ . . _:b428211662 "2"^^ . _:b428211657 "2"^^ . . _:b428211656 "2"^^ . _:b428211127 . . _:b428211659 "2"^^ . . _:b428211658 "2"^^ . . _:b428211669 "2"^^ . . _:b428211787 . _:b428211668 "2"^^ . _:b428211222 . . _:b428211671 "2"^^ . _:b7259945 "It was subsequently shown that the NGR peptides recognize aminopeptidase N (Pasqualini et al., 2000) and potentially, after a chemical alteration, \u03B1v integrins (Curnis et al., >>2008<<). Like nucleolin, aminopeptidase N is functionally important in the angiogenesis process (Pasqualini et al., 2000; Rangel et al., 2007). These findings serve as a paradigm to illustrate a discovery process in which a new homing peptide is" . . _:b428211670 "2"^^ . . _:b428211716 . _:b428211665 "2"^^ . _:b7259917 . _:b7259933 "plectin-1Kelly et al., 2008Fibronectin ED-BNilsson et al., 2001Fibrin\u2013fibronectin complexesPilch et al., 2006; Simberg et al., 2007Interleukin-11 receptor \u03B1Lewis et al., 2009Protease-cleaved collagen IVXu et al., 2001; Mueller et al., >>2009< . . _:b428211664 "2"^^ . . _:b7259944 "It was subsequently shown that the NGR peptides recognize aminopeptidase N (Pasqualini et al., >>2000<<) and potentially, after a chemical alteration, \u03B1v integrins (Curnis et al., 2008)." . _:b428211692 . _:b428211320 . _:b428211667 "2"^^ . _:b7259943 . . _:b428211666 "2"^^ . _:b428211677 "2"^^ . _:b7259937 "It may also be possible to develop targeting probes that distinguish between physiological and tumor angiogenesis (Seaman et al., >>2007<<)." . _:b428211676 "2"^^ . _:b428211679 "2"^^ . . _:b7259948 "Both F3 and the NGR motif peptides have been used to target drugs to tumors (Curnis et al., >>2004<<; Reddy et al., 2006; Henke et al., 2008), and aptamers that bind nucleolin are being pursued in phase I clinical trials (Laber, D., V.R. Sharma, D.A. Laber, V.R. Sharma, L." . _:b428211678 "2"^^ . . . _:b428211673 "2"^^ . _:b7259954 . . _:b428211672 "2"^^ . _:b428211609 . _:b428211460 . . _:b7259923 "ReceptorReferencesRGD-directed integrins (\u03B1v\u03B23 and \u03B1v\u03B25)Ruoslahti, 2002; Desgrosellier and Cheresh, 2010Aminopeptidase NPasqualini et al., 2000TEMsCarson-Walter et al., 2001EndosialinChristian et al., >>2001< "2"^^ . . _:b428211723 . _:b428211563 . _:b428211674 "2"^^ . _:b7259871 . _:b428211339 . _:b428211462 . . _:b428211685 "2"^^ . _:b428211599 . _:b428211684 "2"^^ . . _:b428211687 "2"^^ . _:b428211686 "2"^^ . _:b428211361 . . _:b428211681 "2"^^ . _:b428211680 "2"^^ . _:b428211683 "2"^^ . . _:b428211682 "2"^^ . _:b7260016 "resonance imaging) and a high resolution mapping that can be visualized during surgery to identify surgical margins (by fluorescence imaging of quantum dots; Wang et al., 2004; Kim et al., 2005; Sathe et al., 2006; Kim and Taton, >>2007<<; Song et al., 2007; Park et al., 2008; Ye et al., 2008)." . . _:b428211693 "2"^^ . _:b428211430 . _:b428211692 "2"^^ . _:b428211385 . _:b428211695 "2"^^ . _:b428211694 "2"^^ . _:b428211458 . _:b7260003 . _:b428211689 "2"^^ . _:b428211688 "2"^^ . _:b7259994 . _:b428211691 "2"^^ . _:b428211175 . _:b428211412 . _:b428211413 . _:b428211414 . _:b428211690 "2"^^ . _:b428211415 . _:b428211408 . _:b428211350 . _:b428211409 . _:b428211410 . _:b428211701 "2"^^ . _:b428211411 . _:b428211675 . _:b428211420 . . _:b428211421 . . _:b428211422 . _:b428211700 "2"^^ . _:b428211423 . _:b428211416 . _:b428211417 . _:b428211418 . _:b428211703 "2"^^ . _:b428211419 . _:b428211396 . . _:b428211397 . . _:b428211398 . _:b428211702 "2"^^ . _:b428211399 . _:b428211392 . _:b428211393 . _:b428211394 . _:b428211697 "2"^^ . _:b428211260 . _:b428211395 . _:b428211404 . _:b428211405 . . . _:b428211696 "2"^^ . . _:b428211406 . _:b428211407 . _:b428211400 . _:b428211401 . _:b428211405 . _:b428211402 . _:b428211699 "2"^^ . . _:b428211403 . _:b428211444 . _:b428211445 . _:b428211446 . _:b428211698 "2"^^ . _:b428211447 . _:b7260011 "3; von Maltzahn et al., >>2009<<; Park et al., 2010). Other biological cascades, such as the protease activity that activates CendR peptides in tumors (Sugahara et al., 2009), can be exploited." . . _:b428211440 . _:b428211441 . _:b428211442 . _:b428211709 "2"^^ . . _:b428211443 . _:b428211452 . _:b428211453 . _:b428211454 . _:b428211708 "2"^^ . _:b428211455 . _:b428211448 . _:b428211449 . _:b428211450 . _:b428211711 "2"^^ . . _:b428211438 . . _:b428211451 . _:b428211204 . _:b428211428 . _:b428211429 . _:b428211430 . _:b428211710 "2"^^ . _:b428211431 . _:b428211424 . _:b428211412 . _:b428211425 . . . _:b428211426 . _:b428211705 "2"^^ . _:b428211427 . _:b428211436 . _:b428211437 . _:b428211438 . _:b428211704 "2"^^ . _:b428211439 . _:b428211432 . _:b428211433 . . _:b428211434 . _:b428211707 "2"^^ . _:b428211435 . _:b428211348 . _:b428211349 . _:b428211350 . _:b428211706 "2"^^ . _:b428211351 . _:b428211344 . _:b7259886 . _:b428211113 . _:b428211345 . _:b428211346 . _:b428211347 . _:b428211356 . _:b428211357 . _:b428211358 . . _:b428211359 . _:b428211352 . _:b428211353 . _:b428211354 . _:b428211355 . _:b428211332 . _:b428211333 . _:b428211334 . _:b428211335 . _:b428211328 . _:b428211329 . _:b428211330 . . _:b428211331 . _:b428211340 . _:b428211341 . _:b7260014 . _:b428211342 . _:b428211343 . _:b428211336 . _:b428211337 . _:b428211338 . . _:b428211339 . _:b428211380 . _:b428211381 . _:b7260008 . _:b428211567 . . . _:b428211665 . _:b428211382 . _:b428211383 . _:b428211376 . _:b428211377 . _:b428211378 . _:b428211379 . _:b7259970 . . . _:b428211388 . _:b428211389 . _:b428211390 . _:b428211391 . _:b428211780 . _:b428211384 . _:b428211446 . _:b428211385 . _:b428211386 . _:b428211300 . _:b428211387 . _:b428211364 . _:b428211365 . _:b428211366 . _:b428211156 . _:b428211367 . _:b7259866 "Leukemia and lymphoma treatments with antibodies conjugated to a radioisotope have been in clinical use for several years (Sharkey and Goldenberg, >>2005<<). However, this approach has not been as successful with solid tumors. The apparent reason is the difficulty in delivering drugs into these tumors; drugs only penetrate a few cell diameters into the extravascular tumor tissue from blood" . _:b428211790 . _:b428211360 . _:b428211361 . _:b428211362 . _:b428211600 . _:b428211363 . _:b428211372 . _:b428211373 . . _:b428211373 . _:b428211374 . _:b428211375 . _:b428211368 . _:b428211369 . _:b428211370 . _:b428211371 . _:b428211284 . . _:b428211285 . _:b428211286 . _:b428211287 . _:b428211280 . _:b428211281 . _:b428211282 . _:b428211283 . _:b428211292 . . _:b428211293 . _:b428211294 . _:b428211295 . _:b428211288 . _:b428211289 . _:b428211290 . _:b428211291 . _:b428211268 . _:b428211269 . _:b428211270 . _:b428211271 . _:b428211264 . _:b428211265 . _:b428211266 . _:b428211267 . . _:b428211276 . . _:b428211277 . . _:b428211278 . _:b428211279 . _:b7259983 . _:b428211272 . _:b428211273 . _:b428211274 . _:b428211275 . _:b428211316 . _:b428211317 . . _:b428211318 . _:b428211319 . _:b428211312 . _:b428211313 . _:b428211314 . _:b428211315 . . _:b428211324 . _:b428211325 . _:b428211326 . _:b428211327 . _:b428211320 . _:b428211321 . _:b7259965 "Finally, RGD and other tumor-homing peptides have been used to alter the host range of viral gene therapy vectors (Wickham, >>2000<<; Haviv et al., 2002)." . _:b428211322 . _:b428211323 . _:b7259984 . _:b428211683 . _:b428211300 . . _:b428211301 . _:b428211302 . _:b428211303 . _:b428211296 . _:b428211297 . _:b428211298 . _:b428211299 . _:b428211308 . . _:b428211309 . _:b428211310 . _:b428211252 . _:b428211311 . _:b428211288 . _:b7260013 "Other biological cascades, such as the protease activity that activates CendR peptides in tumors (Sugahara et al., >>2009<<), can be exploited." . _:b428211770 . _:b428211304 . _:b428211305 . _:b428211306 . . _:b428211307 . _:b428211220 . _:b428211221 . _:b7259979 "F3 (Porkka et al., 2002), LyP-1 (Laakkonen et al., >>2002<<), and CRGRRST (Joyce et al., 2003) each contain a potential CendR sequence." . _:b428211222 . _:b428211223 . _:b428211216 . _:b428211217 . _:b428211218 . _:b428211219 . . _:b428211228 . _:b428211229 . _:b428211230 . _:b428211231 . _:b428211224 . _:b428211225 . _:b428211584 . _:b428211226 . _:b428211227 . _:b428211204 . _:b428211205 . _:b428211206 . _:b428211207 . _:b428211200 . _:b428211498 . _:b428211201 . . _:b428211202 . _:b428211343 . _:b428211203 . . _:b428211212 . _:b428211213 . _:b428211214 . _:b428211215 . _:b428211208 . _:b428211620 . _:b428211209 . _:b428211210 . _:b428211211 . _:b7259864 . _:b428211252 . . _:b428211253 . _:b428211254 . _:b428211255 . _:b428211248 . _:b428211249 . _:b7259863 "introduction" . _:b428211250 . . _:b428211251 . _:b428211260 . _:b428211476 . _:b428211261 . _:b428211512 . . _:b428211262 . _:b428211263 . _:b428211256 . _:b428211257 . _:b428211431 . _:b428211258 . . _:b428211259 . _:b428211236 . _:b428211237 . . _:b428211238 . _:b428211239 . _:b428211828 . _:b428211232 . _:b428211233 . . _:b428211234 . _:b428211235 . . _:b428211244 . _:b7259980 "F3 (Porkka et al., 2002), LyP-1 (Laakkonen et al., 2002), and CRGRRST (Joyce et al., >>2003<<) each contain a potential CendR sequence." . _:b428211434 . . _:b428211367 . _:b428211265 . _:b428211245 . _:b428211246 . _:b428211247 . . _:b428211240 . . _:b428211241 . _:b428211242 . _:b7259905 "Proteolytically processed type IV collagen is another matrix component that can be detected with antibodies or peptides (Roth et al., >>2006<<; Mueller et al., 2009)." . _:b428211243 . _:b428211470 . _:b428211668 . _:b428211669 . _:b428211670 . _:b428211671 . _:b428211664 . _:b428211665 . . _:b428211666 . _:b428211667 . _:b428211676 . _:b428211677 . _:b428211678 . _:b428211679 . _:b7259875 . _:b428211582 . . _:b428211399 . _:b428211672 . . _:b428211673 . _:b428211674 . _:b428211767 . . _:b428211675 . _:b428211652 . _:b428211653 . _:b428211717 . _:b428211654 . _:b428211655 . _:b428211648 . . _:b428211649 . _:b428211716 . . _:b428211650 . _:b428211827 . _:b428211651 . _:b428211660 . _:b428211661 . _:b428211719 . _:b428211662 . _:b428211663 . _:b428211656 . _:b428211657 . _:b428211718 . _:b428211658 . _:b428211659 . . _:b428211700 . _:b428211701 . _:b428211713 . _:b428211702 . _:b428211703 . _:b428211696 . _:b428211697 . _:b428211712 . _:b428211698 . _:b428211699 . _:b428211708 . _:b428211709 . _:b428211715 . _:b428211710 . _:b428211313 . _:b428211711 . _:b428211704 . _:b428211705 . _:b428211714 . _:b428211706 . . _:b428211707 . _:b428211684 . . _:b428211685 . _:b428211811 . _:b428211725 . . _:b428211686 . . _:b428211687 . _:b428211680 . _:b428211681 . _:b428211724 . _:b428211682 . _:b428211683 . _:b428211692 . . _:b428211693 . _:b428211727 . _:b428211499 . _:b428211694 . . _:b428211695 . _:b428211688 . . _:b428211689 . _:b428211726 . _:b428211690 . . _:b428211105 . _:b428211691 . _:b428211604 . _:b428211605 . _:b428211721 . _:b428211606 . _:b428211649 . _:b428211607 . _:b7259891 . _:b428211600 . _:b428211601 . _:b7259973 . _:b428211720 . _:b428211602 . _:b428211155 . _:b428211603 . _:b428211612 . _:b428211613 . _:b428211723 . _:b428211614 . _:b428211199 . _:b428211467 . _:b428211615 . _:b428211608 . _:b428211182 . _:b428211609 . _:b428211722 . _:b428211610 . _:b428211611 . _:b428211285 . _:b428211588 . _:b428211589 . _:b428211733 . _:b428211590 . _:b428211591 . . _:b428211584 . _:b428211585 . _:b428211732 . _:b428211586 . _:b428211587 . _:b428211596 . _:b428211597 . _:b428211735 . _:b428211415 . _:b428211598 . _:b428211599 . _:b428211592 . . _:b7259878 "Tumors also contain lymphatic vessels, and many tumors produce growth factors that stimulate lymphangiogenesis (Karpanen and Alitalo, >>2008<<). Lymphatics are not necessary for tumor growth but are important conduits of metastasis. Like tumor blood vessels, tumor lymphatics can also express specific molecular markers." . _:b428211734 . _:b428211593 . _:b428211594 . _:b428211595 . _:b428211636 . _:b428211637 . _:b428211729 . _:b428211638 . _:b428211639 . _:b428211632 . _:b428211633 . _:b428211728 . . _:b428211634 . _:b428211635 . . _:b428211493 . _:b428211644 . _:b428211645 . _:b428211731 . _:b428211484 . _:b428211646 . _:b428211647 . _:b428211302 . _:b428211640 . . _:b428211641 . _:b428211730 . _:b428211642 . _:b428211696 . _:b428211643 . _:b428211620 . _:b428211621 . _:b428211741 . _:b428211622 . _:b428211623 . . _:b428211616 . _:b428211617 . _:b428211740 . _:b428211618 . _:b428211619 . _:b428211628 . _:b428211629 . _:b428211743 . _:b428211630 . . _:b428211631 . _:b428211624 . . _:b428211625 . _:b428211742 . _:b428211626 . _:b428211627 . _:b428211315 . _:b428211540 . _:b428211541 . _:b428211737 . _:b428211542 . _:b428211543 . . _:b428211536 . _:b428211537 . _:b428211736 . _:b428211538 . _:b428211539 . _:b428211798 . _:b428211548 . _:b428211549 . _:b428211739 . _:b428211550 . _:b428211536 . . _:b428211551 . _:b428211544 . . _:b428211545 . _:b428211738 . _:b428211546 . _:b428211547 . _:b428211524 . . _:b428211749 . _:b428211337 . _:b428211525 . _:b428211526 . . _:b428211527 . _:b428211520 . _:b428211521 . _:b428211748 . _:b428211522 . _:b428211523 . _:b428211532 . . _:b428211751 . _:b428211533 . _:b428211534 . _:b428211535 . _:b428211528 . _:b428211529 . _:b428211750 . _:b428211530 . _:b428211531 . _:b428211572 . _:b428211573 . _:b428211745 . _:b428211574 . _:b428211575 . _:b428211568 . _:b428211569 . _:b428211744 . _:b428211570 . _:b428211571 . _:b428211580 . _:b428211731 . _:b428211581 . _:b428211747 . . _:b428211582 . _:b428211583 . _:b428211576 . _:b428211577 . _:b428211746 . _:b428211578 . _:b7259883 "Phage screening has uncovered a large number of tumor-homing peptides that have been used to identify the corresponding binding protein (receptor). An early study on tumor-homing peptides (Arap et al., >>1998<<) validated the method by producing tumor-homing peptides with RGD (arginine/glycine/aspartice acid) and NGR (asparagine/glycine/arginine) motifs, which had been previously identified in screens for integrin-binding peptides performed in" . _:b428211579 . _:b428211556 . _:b428211557 . _:b428211757 . _:b428211558 . _:b428211559 . _:b428211775 . . _:b428211552 . _:b428211553 . _:b428211756 . _:b428211554 . _:b428211555 . _:b428211564 . _:b428211565 . _:b428211759 . _:b428211566 . _:b428211567 . _:b7259919 . _:b428211465 . _:b428211560 . _:b428211561 . _:b7259999 . _:b428211758 . _:b428211562 . _:b7260003 "Kupffer cell receptors in the liver is thought to underlie this phenomenon, but the unfortunate fact is that the molecular mechanisms of the uptake of nanoparticles by the RES are not really understood (for review see Moghimi et al., >>2001<<). It has been empirically shown that particle charge (anionic or neutral), size (<100 nm), and ability to prevent complement binding can reduce rates of RES uptake and extend circulation time in mice (for review see Peer et al., 2007)." . . _:b428211563 . _:b428211476 . _:b428211477 . _:b428211753 . . _:b428211478 . _:b428211479 . _:b428211472 . _:b7259876 . _:b428211676 . _:b428211473 . _:b428211752 . . _:b428211474 . _:b428211475 . _:b428211484 . _:b428211485 . _:b428211755 . _:b428211486 . _:b428211795 . _:b428211487 . _:b428211480 . _:b428211481 . _:b428211754 . _:b428211482 . _:b7259962 "Drug-loaded nanoparticles have also been targeted with RGD peptides to suppress tumor growth or metastasis (Hood et al., >>2002<<; Murphy et al., 2008; Sugahara et al., 2009)." . . _:b428211483 . _:b428211460 . _:b428211461 . _:b428211765 . _:b428211462 . _:b428211463 . _:b428211456 . _:b428211457 . _:b428211764 . _:b428211458 . _:b428211459 . _:b428211338 . _:b428211468 . _:b428211469 . _:b428211767 . _:b428211470 . _:b428211471 . . _:b428211464 . _:b428211465 . _:b428211766 . _:b428211466 . _:b428211467 . _:b428211797 . _:b428211508 . _:b428211509 . _:b7260018 "mapping that can be visualized during surgery to identify surgical margins (by fluorescence imaging of quantum dots; Wang et al., 2004; Kim et al., 2005; Sathe et al., 2006; Kim and Taton, 2007; Song et al., 2007; Park et al., >>2008<<; Ye et al., 2008). Recently, we have also designed iron oxide nanoparticles (nanoworms; Park et al., 2009b) with improved properties and nontoxic silicon-based quantum dots (Park et al., 2009a) for such purposes." . _:b428211761 . _:b428211510 . _:b428211511 . _:b428211504 . _:b428211589 . _:b428211505 . _:b428211760 . _:b428211506 . _:b7259894 "The in vivo screening of phage libraries has also produced several potent tumor-homing peptides, the target molecules of which remain to be identified (Hoffman et al., 2003; Joyce et al., >>2003<<; J\u00E4rvinen and Ruoslahti, 2007; Chang et al., 2009)." . _:b428211507 . _:b428211442 . _:b428211516 . . _:b428211517 . _:b428211763 . _:b428211518 . _:b428211612 . _:b428211519 . _:b7259950 "Both F3 and the NGR motif peptides have been used to target drugs to tumors (Curnis et al., 2004; Reddy et al., 2006; Henke et al., >>2008<<), and aptamers that bind nucleolin are being pursued in phase I clinical trials (Laber, D., V.R. Sharma, D.A. Laber, V.R. Sharma, L." . _:b428211512 . _:b428211513 . _:b428211762 . _:b428211514 . _:b428211209 . _:b428211515 . _:b428211492 . _:b428211626 . _:b428211493 . _:b428211773 . _:b428211494 . _:b428211495 . _:b428211488 . _:b7259938 "The idea that this level of specificity can be achieved with tumor vessels has been demonstrated with tumor type\u2013specific peptides (Hoffman et al., >>2003<<; Joyce et al., 2003; Laakkonen et al., 2004)." . . _:b428211489 . _:b428211772 . _:b428211490 . _:b428211491 . _:b428211500 . _:b428211452 . . _:b428211775 . _:b428211501 . _:b428211502 . _:b7259924 . _:b428211503 . . _:b428211496 . . _:b428211774 . _:b428211529 . . _:b428211479 . _:b428211497 . . _:b428211498 . _:b428211499 . _:b428211147 . _:b428211769 . _:b428211768 . _:b7259965 . _:b7259968 . _:b428211195 . _:b428211771 . _:b428211770 . _:b428211331 . _:b7259952 "Enhanced drug delivery with vascular homing peptides has been accomplished using a cyclic peptide containing the integrin-binding RGD motif (CRGDC) to deliver doxorubicin to tumors (Arap et al., >>1998<<)." . _:b428211781 . . _:b428211780 . _:b7259879 . _:b428211783 . _:b428211782 . . _:b428211451 . _:b7259946 "Like nucleolin, aminopeptidase N is functionally important in the angiogenesis process (Pasqualini et al., >>2000<<; Rangel et al., 2007)." . _:b428211559 . _:b428211777 . _:b428211469 . _:b428211776 . _:b7259953 . _:b7260019 "can be visualized during surgery to identify surgical margins (by fluorescence imaging of quantum dots; Wang et al., 2004; Kim et al., 2005; Sathe et al., 2006; Kim and Taton, 2007; Song et al., 2007; Park et al., 2008; Ye et al., >>2008<<). Recently, we have also designed iron oxide nanoparticles (nanoworms; Park et al., 2009b) with improved properties and nontoxic silicon-based quantum dots (Park et al., 2009a) for such purposes." . . _:b428211779 . . . _:b7259908 "One of the PDFG receptors is another marker that is expressed at high levels in pericytes (Song et al., >>2005<<)." . . _:b428211778 . _:b428211212 . _:b7259929 "nucleolinChristian et al., 2003Cell surface annexin-1Oh et al., 2004Cell surface p32/gC1q receptorFogal et al., 2008Cell surface plectin-1Kelly et al., 2008Fibronectin ED-BNilsson et al., 2001Fibrin\u2013fibronectin complexesPilch et al., >>2006<<; Simberg et al., 2007Interleukin-11 receptor \u03B1Lewis et al., 2009Protease-cleaved collagen IVXu et al., 2001; Mueller et al., 2009Stage-specific markers." . _:b428211789 . _:b428211125 . _:b428211788 . . . _:b428211791 . _:b428211790 . _:b7259960 "RGD peptides and antibodies to \u03B1v\u03B23 integrin have also been successfully used in targeted delivery of diagnostic probes to tumors (Sipkins et al., 1998; Stollman et al., >>2009<<; Sugahara et al., 2009), and imaging probes based on this approach are in clinical trials." . _:b428211785 . _:b428211464 . _:b428211784 . _:b428211787 . _:b7259874 "Interstitial fibrosis can further retard the diffusion of compounds through tumors (Olive et al., >>2009<<). Targeting treatments to selective markers in tumor vessels does not suffer from some of these drawbacks of targeting tumor cells; in particular, no tissue penetration is required for the compound to reach its target. The luminal side of" . . _:b428211786 . _:b428211381 . _:b428211324 . . _:b428211272 . _:b428211797 . _:b428211796 . . _:b7259885 . _:b428211799 . . . _:b7259967 . . _:b428211798 . _:b428211542 . . _:b428211793 . _:b7259949 . _:b428211792 . . _:b428211234 . _:b7259914 "and in the tumor interstitial stroma can be accessed with peptides derived from phage screening, such as the nine\u2013amino acid cyclic peptide CLT-1 (Pilch et al., 2006; Ye et al., 2008) and the pentapeptide CREKA (Simberg et al., >>2007<<). Fibrin-binding peptides isolated for the purpose of targeting blood clots in cardiovascular disease would presumably behave similarly if tested for tumor homing." . _:b428211795 . . _:b428211763 . _:b428211794 . _:b428211805 . _:b7259948 . _:b428211816 . _:b428211804 . _:b428211807 . _:b7259983 "LyP-1 have been shown to cause extravasation of their cargo, which can be as large as a nanoparticle, with subsequent uptake into tumor endothelial cells and tumor cells (Porkka et al., 2002; Laakkonen et al., 2004; Karmali et al., >>2009<<). Coating of abraxane, which is a nanoparticle drug composed of paclitaxel and albumin, with the LyP-1 or iRGD peptide made the drug capable of penetrating into tumor tissue, resulting in several-fold higher activity than that of the" . _:b428211806 . _:b428211801 . _:b7259946 . _:b428211800 . . _:b428211803 . _:b7259944 . _:b428211290 . _:b7259887 "In vitro, all cells seem to be positive for cell surface nucleolin (Borer et al., 1989; Bonnet et al., >>1996<<) presumably because cultured cells resemble cells that have been activated in vivo." . _:b428211534 . _:b428211802 . _:b428211545 . _:b428211813 . _:b428211143 . "10.1083%2Fjcb.200910104" . _:b7259951 . _:b7259901 . _:b428211552 . . _:b428211812 . _:b428211349 . _:b428211815 . . _:b428211814 . . _:b428211670 . _:b428211809 . . _:b428211684 . . _:b428211808 . _:b7259905 . _:b428211811 . _:b7259910 . _:b428211810 . _:b7259901 "A prime example is the overexpression of \u03B1v\u03B23 and \u03B1v\u03B25 integrins in angiogenic vessels (Brooks et al., >>1994<<; Erdreich-Epstein et al., 2000; Desgrosellier and Cheresh, 2010)." . . . . _:b428211821 . . _:b428211820 . _:b428211823 . . . . _:b428211822 . . _:b428211817 . . _:b428211145 . _:b428211816 . _:b428211769 . _:b7259872 . _:b428211819 . _:b7259911 . _:b428211818 . _:b7259912 . _:b428211829 . _:b428211828 . . . _:b428211831 . _:b428211130 . _:b428211830 . _:b428211825 . _:b428211824 . _:b428211443 . _:b428211827 . _:b428211211 . _:b428211261 . _:b7259921 . _:b428211826 . _:b428211409 . . _:b428211530 . . _:b428211413 . . . _:b428211111 . _:b428211833 . _:b428211189 . . _:b428211832 . _:b428211706 . _:b428211834 . _:b7259929 . _:b428211704 . _:b428211804 . . . _:b428211181 . _:b428211368 . . . _:b7259909 "Leaked fibrinogen is converted to a fibrin meshwork by tissue-procoagulant proteins such as tissue factor (Dvorak et al., >>1985<<; Abe et al., 1999; Pilch et al., 2006)." . _:b428211736 . _:b428211642 .