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��ࡱ�>��	68����345������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������	�R�9�bjbj���8������+������������������			8A],	DC��n�


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�7C0DC�4R�Ka0^�K5�K�5�%%�0%%%%%BB�0%%%DC%%%%���������������������������������������������������������������������K%%%%%%%%%��:	Recent advances of targeted MRI contrast agents based on Ultrasmall supersmall superparamagnetic iron oxide
               Lijiang Hu  	Hao Wang  Wenxian Guan
[Abstract] Ultrasmall supersmall superparamagnetic iron oxide (USPIO) particles as T2-weighted MRI contrasts has gradually been putting into clinical application for its high spatial and temporal resolution,relative low noise in background and low toxicity in recent years, whereas low sensitivity is its major drawback;Over several years, along with the rapid development of molecular imaging and polymer technology, many kinds of tumor targeted MRI contrast agents based on USPIO have been lucubrated comprehensively; USPIO combined or crosslinked with different tumor targeting carriers in early diagnosis of different neoplasms,assessment of therapeutic effect and trace of cancer stem cells etc, which show us great potential and advantages compared to general USPIO (Ferumoxtran-10)or SPIONs(Resovist).
[Keywords]  USPIO; MRI; Targeted delivery system; Molecular imaging; Polymer
     
Introduction
Magnetic resonance imaging (MRI) as one excellent promising diagnostic imaging methods in offering noninvasive and real time location of diseases such as neoplasms, lymphatic metastasis and atherosclerotic disease currently ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Luciani, 2006 #71" 1,  HYPERLINK \l "_ENREF_2" \o "Saam, 2007 #70" 2]. In recent years,Ultrasmall supersmall superparamagnetic iron oxide (USPIO) has been putting into clinical application as MRI negative contrast agents with T2 and T2WI sequences ADDIN EN.CITE <EndNote><Cite><Author>Yancy</Author><Year>2005</Year><RecNum>54</RecNum><DisplayText>[3]</DisplayText><record><rec-number>54</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">54</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yancy, A. D.</author><author>Olzinski, A. R.</author><author>Hu, T. C. C.</author><author>Lenhard, S. C.</author><author>Aravindhan, K.</author><author>Gruver, S. M.</author><author>Jacobs, P. M.</author><author>Willette, R. N.</author><author>Jucker, B. M.</author></authors></contributors><titles><title>Differential uptake of ferumoxtran-10 and ferumoxytol, ultrasmall superparamagnetic iron oxide contrast agents in rabbit: Critical determinants of atherosclerotic plaque labeling</title><secondary-title>Journal Of Magnetic Resonance Imaging</secondary-title></titles><periodical><full-title>Journal of Magnetic Resonance Imaging</full-title></periodical><pages>432-442</pages><volume>21</volume><number>4</number><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1053-1807</isbn><accession-num>WOS:000228029900016</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000228029900016</url></related-urls></urls><electronic-resource-num>10.1002/jmri.20283</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_3" \o "Yancy, 2005 #54" 3],which manifested several outstanding virtues as following: (1)they display non-magnetically when they are not under the influence of an external magnetic field,thus preventing undesired magnetic agglomeration; (2)they can potentially identify the metastases independent of the lymph nodes size, the prolonged blood half life of USPIO allows their progressive access to the lymph nodes thus helping in further enhancement of the quality of image; (3)low toxicity, the macrophages taken up iron oxide (usuallymagnetite, Fe3O4, ormaghemite, �-Fe2O3) then transferred it into Fe ions which can be utilized by body.Vice versa, the conventional MRI positive contrast agents Gadolinium chelates did not possess those advantages. Generally speaking,the size of USPIO is less than 50 nm,which surface coated with biocompatiable and degradable polymer.Over the past decade, tremendous efforts have been made in both clinic and research fields in order to enhance USPIO�s biocompatibility and stability,acquire appropriate surface coating chemistries ADDIN EN.CITE <EndNote><Cite><Author>Bonnemain</Author><Year>1998</Year><RecNum>55</RecNum><DisplayText>[4]</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bonnemain, B.</author></authors></contributors><titles><title>Superparamagnetic agents in magnetic resonance imaging: Physicochemical characteristics and clinical applications - A review</title><secondary-title>Journal Of Drug Targeting</secondary-title></titles><periodical><full-title>Journal Of Drug Targeting</full-title></periodical><pages>167-174</pages><volume>6</volume><number>3</number><dates><year>1998</year><pub-dates><date>1998</date></pub-dates></dates><isbn>1061-186X</isbn><accession-num>WOS:000077608700001</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000077608700001</url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_4" \o "Bonnemain, 1998 #55" 4].
Ground-making work on magnetic nanoparticles investigated the utilization of antibodies ADDIN EN.CITE <EndNote><Cite><Author>Pirko</Author><Year>2004</Year><RecNum>57</RecNum><DisplayText>[5]</DisplayText><record><rec-number>57</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">57</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pirko, I.</author><author>Ciric, B.</author><author>Gamez, J.</author><author>Bieber, A. J.</author><author>Warrington, A. E.</author><author>Johnson, A. J.</author><author>Hanson, D. P.</author><author>Pease, L. R.</author><author>Macura, S. I.</author><author>Rodriguez, M.</author></authors></contributors><titles><title>A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS</title><secondary-title>Faseb Journal</secondary-title></titles><periodical><full-title>Faseb Journal</full-title></periodical><pages>1577-+</pages><volume>18</volume><number>11</number><dates><year>2004</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0892-6638</isbn><accession-num>WOS:000223554900007</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000223554900007</url></related-urls></urls><electronic-resource-num>10.1096/fj.04-2026fje</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_5" \o "Pirko, 2004 #57" 5] . The preparation maintained both the immunoreactivity of the antibody and the full relaxing capability of the magnetic particles ADDIN EN.CITE <EndNote><Cite><Author>Luchetti</Author><Year>2012</Year><RecNum>48</RecNum><DisplayText>[6]</DisplayText><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Luchetti, Alessandro</author><author>Milani, Davide</author><author>Ruffini, Francesca</author><author>Galli, Rossella</author><author>Falini, Andrea</author><author>Quattrini, Angelo</author><author>Scotti, Giuseppe</author><author>Comi, Giancarlo</author><author>Martino, Gianvito</author><author>Furlan, Roberto</author><author>Politi, Letterio S.</author></authors></contributors><titles><title>Monoclonal Antibodies Conjugated with Superparamagnetic Iron Oxide Particles Allow Magnetic Resonance Imaging Detection of Lymphocytes in the Mouse Brain</title><secondary-title>Molecular Imaging</secondary-title></titles><periodical><full-title>Molecular Imaging</full-title></periodical><pages>114-125</pages><volume>11</volume><number>2</number><dates><year>2012</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1535-3508</isbn><accession-num>WOS:000307645900003</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000307645900003</url></related-urls></urls><electronic-resource-num>10.2310/7290.2011.00032</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_6" \o "Luchetti, 2012 #48" 6]. In vivo, specific binding to the tumour was assessed by compared with the naked nanoparticles. Antibodies directed against several corresponding types of receptors have been tested either in vitro or in vivo (HER2/Neu,EGFR, lymphocyte, etc), Small pharmacophores such as peptides or small organic ligands are promising approaches. Peptide selection can be based on phage display technology or by using peptides which have already been identified in the therapeutic field. This approach opens up a wide range of targeting possibilities, but the difficulty will be to select the most promising pharmacophore for clinical imaging taking into account the sensitivity of MRI, which limits the selection of biological targets present in small quantities ADDIN EN.CITE <EndNote><Cite><Author>Siglienti</Author><Year>2006</Year><RecNum>58</RecNum><DisplayText>[7]</DisplayText><record><rec-number>58</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">58</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Siglienti, I.</author><author>Bendszus, M.</author><author>Kleinschnitz, C.</author><author>Stoll, G.</author></authors></contributors><titles><title>Cytokine profile of iron-laden macrophages: Implications for cellular magnetic resonance imaging</title><secondary-title>Journal Of Neuroimmunology</secondary-title></titles><periodical><full-title>Journal Of Neuroimmunology</full-title></periodical><pages>166-173</pages><volume>173</volume><number>1-2</number><dates><year>2006</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0165-5728</isbn><accession-num>WOS:000236824200018</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000236824200018</url></related-urls></urls><electronic-resource-num>10.1016/j.jneuroim.2005.11.011</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_7" \o "Siglienti, 2006 #58" 7]. those studies have shown the targeted MRI contrast agents possess marvelous potential in the imaging of tumors and metastasis. 
Meta analysis shows that the Ferumoxtran - 10 (USPIO coated with dextran , has been employing in clinical imaging) in the imaging of lymph node metastasis and performance in early diagnosis is obviously superior to the traditional contrast gadolinium spray acid meglumine ADDIN EN.CITE <EndNote><Cite><Author>Will</Author><Year>2006</Year><RecNum>3</RecNum><DisplayText>[8]</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Will, Olivia</author><author>Purkayastha, Sanjay</author><author>Chan, Christopher</author><author>Athanasiou, Thanos</author><author>Darzi, Ara W.</author><author>Gedroyc, Wady</author><author>Tekkis, Paris P.</author></authors></contributors><titles><title>Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: a meta-analysis</title><secondary-title>The Lancet Oncology</secondary-title></titles><periodical><full-title>The Lancet Oncology</full-title></periodical><pages>52-60</pages><volume>7</volume><number>1</number><dates><year>2006</year></dates><isbn>14702045</isbn><urls></urls><electronic-resource-num>10.1016/s1470-2045(05)70537-4</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_8" \o "Will, 2006 #3" 8] . With the speedy development in molecular imaging, The MRI contrast which based on USPIO in imaging of malignant neoplasms and stem cells has been deeply researched . While various proof of  studies have been performed, transposition to human applications is not yet available.Herein,we analysis the recent advance the targeted MRI contrast agents based on USPIO in order to find the evolutionary trendency in the field. According to the different structures , the targeted MRI contrast could be divided into two types: first, the core as a single USPIO and the organic modified surface crosslinked specific tumor targeting carrier; Second, synthesis such as amphoteric copolymer firstly, and then coupling the hydrophilic group end with specific tumor targeting carrier, through the ultrasonic polymerization or nanometer precipitation synthesis with hydrophobic segment embeded many smaller diameter USPIO (the diameter usually less than 10 nm) particals. Specific tumor targeting carrier mainly has the following several kinds: (1) the folic acid, vitamin b9-fortified namely; (2) antibodies, including EGF, VEGF and so on many kinds of cell growth factor monoclonal and polyclonal antibodies (3) contain arginine - glycine - aspartate (RGD) sequences of proteins and peptides and similar (4) transferrin (5) other small molecule polypeptide and enzymes ADDIN EN.CITE <EndNote><Cite><Author>Oh</Author><Year>2011</Year><RecNum>33</RecNum><DisplayText>[9]</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">33</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oh, Jung Kwon</author><author>Park, Jong Myung</author></authors></contributors><titles><title>Iron oxide-based superparamagnetic polymeric nanomaterials: Design, preparation, and biomedical application</title><secondary-title>Progress in Polymer Science</secondary-title></titles><periodical><full-title>Progress in Polymer Science</full-title></periodical><pages>168-189</pages><volume>36</volume><number>1</number><dates><year>2011</year></dates><isbn>00796700</isbn><urls></urls><electronic-resource-num>10.1016/j.progpolymsci.2010.08.005</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_9" \o "Oh, 2011 #33" 9] .
2 Targeted media
 2.1 Folic acid (FA, Folic acid) 
Folic acid receptor was observed obviously high expression in many epithelial neoplasms such as gastric cancer, ovarian cancer, liver cancer, gland carcinoma, accordingly which was researched comprehensive early.Furthermore, folic acid combined the folic acid receptor which expressed in tumor cells with high efficiency , it also makes folic acid has been as a malignant tumor targeted therapy and developer carrier studies so far. Earlier on ,Folate-conjugated USPIO was applied in cell culture which exhibited higher efficiency of intracellular uptake than only PEG-or FA-coated nanoparticles,but merely in vitro ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Zhang, 2005 #68" 10,  HYPERLINK \l "_ENREF_11" \o "Sonvico, 2005 #69" 11]; Meier etc demonstrated that P1133 (folate receptor targeting property USPIO, single USPIO core) injection in MDA - MB - 231 breast cancer cells animal models the folic acid receptor expression positive, signal decrease in the tumor area was observed after 24 hours, the results showed that P1133 combined with MRI can be used as a prognostic of breast cancer of non-invasive detection means ADDIN EN.CITE <EndNote><Cite><Author>Meier</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[12]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Meier, Reinhard</author><author>Henning, Tobias D.</author><author>Boddington, Sophie</author><author>Tavri, Sidhartha</author><author>Arora, Sandeep</author><author>Piontek, Guido</author><author>Rudelius, Martina</author><author>Corot, Claire</author><author>Daldrup-Link, Heike E.</author></authors></contributors><titles><title>Breast Cancers: MR Imaging of Folate-Receptor Expression with the Folate-Specific Nanoparticle P1133</title><secondary-title>Radiology</secondary-title></titles><periodical><full-title>Radiology</full-title></periodical><pages>527-535</pages><volume>255</volume><number>2</number><dates><year>2010</year><pub-dates><date>May</date></pub-dates></dates><isbn>0033-8419</isbn><accession-num>WOS:000276976200026</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000276976200026</url></related-urls></urls><electronic-resource-num>10.1148/radiol.10090050</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_12" \o "Meier, 2010 #1" 12] . The average diameter of 35 nm FA - PEG - PCL - USPIO particle with lower liver intaking and relatively long blood circulation retention  ADDIN EN.CITE <EndNote><Cite><Author>Bothun</Author><Year>2011</Year><RecNum>4</RecNum><DisplayText>[13]</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bothun, Geoffrey D.</author><author>Lelis, Alline</author><author>Chen, Yanjing</author><author>Scully, Kyle</author><author>Anderson, Linnea E.</author><author>Stoner, Matthew A.</author></authors></contributors><titles><title>Multicomponent folate-targeted magnetoliposomes: design, characterization, and cellular uptake</title><secondary-title>Nanomedicine-Nanotechnology Biology and Medicine</secondary-title></titles><periodical><full-title>Nanomedicine-Nanotechnology Biology and Medicine</full-title></periodical><pages>797-805</pages><volume>7</volume><number>6</number><dates><year>2011</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1549-9634</isbn><accession-num>WOS:000297699900015</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000297699900015</url><url>http://ac.els-cdn.com/S1549963411000918/1-s2.0-S1549963411000918-main.pdf?_tid=bdd8e756-377e-11e2-baa2-00000aab0f27&amp;acdnat=1353903006_78332d65c692ee67a91f1a320fbc75a5</url></related-urls></urls><electronic-resource-num>10.1016/j.nano.2011.02.007</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_13" \o "Bothun, 2011 #4" 13] . Gao wenhui etc constructed Folic acid-O-carboxymethyl chitosan ultrasmall superparamagnetic iron oxide nanoparticles (FA-OCMCS-USPIO-NPs) as a novel molecular targeting MR contrast agent ADDIN EN.CITE <EndNote><Cite><Author>Gao</Author><Year>2011</Year><RecNum>59</RecNum><DisplayText>[14]</DisplayText><record><rec-number>59</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">59</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gao, Wen-hui</author><author>Liu, Shi-ting</author><author>Fan, Cai-xia</author><author>Qi, Lin-yan</author><author>Chen, Zhi-liang</author></authors></contributors><titles><title>Pharmacokinetics, tissue distribution and magnetic resonance&apos;s response characterstics of folic acid-O-carboxymethyl chitosan ultrasmall superparamagnetic iron oxide nanoparticles in mice and rats</title><secondary-title>Yaoxue Xuebao</secondary-title></titles><periodical><full-title>Yaoxue Xuebao</full-title></periodical><pages>845-851</pages><volume>46</volume><number>7</number><dates><year>2011</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0513-4870</isbn><accession-num>BCI:BCI201100523787</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://BCI:BCI201100523787</url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_14" \o "Gao, 2011 #59" 14].However folic acid could not be consider as specific tumor targeting carrier insufficiently,for normal cells will also combine folic acid generally which would impact the imaging results and other issues.
2.2 RGD derivants  
Integrin is the dimer that combined with the � subunit and � subunits differently ;thus far, � subunit and 9 kinds of � subunits have found, more than twenty kinds of integrins have been discovered according to different combination of those subunits; Integrins has been identified in a wide variety of tumor surface and neovascular endothelial cells with high expression which plays an important role in tumor angiogenesis, among � v � 3 is particularly important. Proteins and peptides contain arginine - glycine - aspartate (RGD) sequences combined with integrin � v � 3 specially; Investigations proved that the circular RGD(cRGD) peptides has better compatibility, stability and receptor specificity compared to linear RGD peptides; recently it has been applied in tumor targeted drug therapy and imaging ADDIN EN.CITE <EndNote><Cite><Author>Garanger</Author><Year>2007</Year><RecNum>9</RecNum><DisplayText>[15]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garanger, Elisabeth</author><author>Boturyn, Didier</author><author>Dumy, Pascal</author></authors></contributors><titles><title>Tumor targeting with RGD peptide Ligands-Design of new molecular conjugates for Imaging and therapy of cancers</title><secondary-title>Anti-Cancer Agents in Medicinal Chemistry</secondary-title></titles><periodical><full-title>Anti-Cancer Agents in Medicinal Chemistry</full-title></periodical><pages>552-558</pages><volume>7</volume><number>5</number><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1871-5206</isbn><accession-num>WOS:000249469700007</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000249469700007</url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_15" \o "Garanger, 2007 #9" 15] . The chemical crosslinking method construct cRGD - USPIO MRI contrast agent for lung gland cancer A549 nude mouse transplantation tumor MRI diagnosis, the results showed that compared with USPIO group, cRGD - USPIO group tumor model significantly; The results of the study show that cRGD - USPIO may becomes a new type of cancer early diagnosis with specific MRI contrast agent ADDIN EN.CITE <EndNote><Cite><Author>Yi</Author><Year>2011</Year><RecNum>5</RecNum><DisplayText>[16]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yi, Xianghua</author><author>Ding, Yongmei</author><author>Zeng, Yu</author><author>Zhou, Caicun</author><author>Luo, Benfang</author><author>Meng, Shuyan</author><author>Rui, Weiwei</author><author>Zhao, Yinmin</author><author>Li, Wei</author></authors></contributors><titles><title>Magnetic Resonance Imaging Contrast Agent: cRGD-Ferric Oxide Nanometer Particle and Its Role in the Diagnosis of Tumor</title><secondary-title>Journal of Nanoscience and Nanotechnology</secondary-title></titles><periodical><full-title>Journal of Nanoscience and Nanotechnology</full-title></periodical><pages>3800-3807</pages><volume>11</volume><number>5</number><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1533-4880</isbn><accession-num>WOS:000290692400009</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000290692400009</url></related-urls></urls><electronic-resource-num>10.1166/jnn.2011.3861</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_16" \o "Yi, 2011 #5" 16]. Lin RenYen etc structured cRGD conjugated with 2 - (2 - pyridyl disulfide) ethylamine silane (PDA) packed USPIO for MRI detection in tumor model of different integrin expression, very significant signal reduced (51.3 plus or minus 6.7%) was observed in a MCF - 7 tumor model  ADDIN EN.CITE <EndNote><Cite><Author>Lin</Author><Year>2012</Year><RecNum>13</RecNum><DisplayText>[17]</DisplayText><record><rec-number>13</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">13</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lin, Ren-Yen</author><author>Dayananda, Kasala</author><author>Chen, Ting-Jung</author><author>Chen, Chiao-Yun</author><author>Liu, Gin-Chung</author><author>Lin, Kun-Liang</author><author>Wang, Yun-Ming</author></authors></contributors><titles><title>Targeted RGD nanoparticles for highly sensitive in vivo integrin receptor imaging</title><secondary-title>Contrast Media &amp; Molecular Imaging</secondary-title></titles><periodical><full-title>Contrast Media &amp; Molecular Imaging</full-title></periodical><pages>7-18</pages><volume>7</volume><number>1</number><dates><year>2012</year></dates><isbn>15554309</isbn><urls></urls><electronic-resource-num>10.1002/cmmi.457</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_17" \o "Lin, 2012 #13" 17]. Wu XinYing etc developed RGD - PLA - USPIO for testing vascular proliferatio in T2WI sequences, significant signal declination shows that the inhomogeneity of the tumor new blood vessels in Vx - 2 tumor model;thanks to RGD and tumor vascular endothelial cells � v � 3 specificity combined,which would be apprppriate for monitor changes of tumor vascular system during treatment  ADDIN EN.CITE <EndNote><Cite><Author>Wu</Author><Year>2010</Year><RecNum>24</RecNum><DisplayText>[18]</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wu, XinYing</author><author>Zhang, JingFeng</author><author>Lin, BingYing</author><author>Zhang, MinMing</author></authors></contributors><titles><title>Molecular imaging of tumor angiogenesis using RGD-labeled iron oxide nanoparticles</title><secondary-title>Chinese Science Bulletin</secondary-title></titles><periodical><full-title>Chinese Science Bulletin</full-title></periodical><pages>2662-2670</pages><volume>55</volume><number>24</number><dates><year>2010</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1001-6538</isbn><accession-num>WOS:000280920600012</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000280920600012</url></related-urls></urls><electronic-resource-num>10.1007/s11434-010-4004-8</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_18" \o "Wu, 2010 #24" 18] .Such as Wu Guoqiu etc found the non RGD peptides P1c derived from the connective tissue growth factor  can also specific binds to integrin v � 3 and puts forward the P1c - USPIO targeted MRI contrast agent for MRI detection in liver cancer cell Bel - 7402 tumor model; results show that signal significant reduced in the tumor area in T2WI sequences P1c - USPIO compared with ordinary USPIO(P < 0.05)  ADDIN EN.CITE <EndNote><Cite><Author>Wu</Author><Year>2011</Year><RecNum>14</RecNum><DisplayText>[19]</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wu, Guoqiu</author><author>Wang, Xiaodong</author><author>Deng, Gang</author><author>Wu, Linyuan</author><author>Ju, Shenghong</author><author>Teng, Gaojun</author><author>Yao, Yuyu</author><author>Wang, Xiyong</author><author>Liu, Naifeng</author></authors></contributors><titles><title>Novel peptide targeting integrin �v�3-rich tumor cells by magnetic resonance imaging</title><secondary-title>Journal of Magnetic Resonance Imaging</secondary-title></titles><periodical><full-title>Journal of Magnetic Resonance Imaging</full-title></periodical><pages>395-402</pages><volume>34</volume><number>2</number><dates><year>2011</year></dates><isbn>10531807</isbn><urls></urls><electronic-resource-num>10.1002/jmri.22620</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_19" \o "Wu, 2011 #14" 19].
2.3 antibodies
EGFR as receptors with high expression in many kinds of tumor, plays important role in tumor cell proliferation and metastasis; cetuximab C225 as targeted anti-tumor drugs has been putting into clinical application due to the special combination with EGFR , cetuximab as targeted media received a wide comprehensive research. Liposome encapsulated fluorescent dye and conjuated with EGFR was applied to delivery drug and imaging in bladder cancer transplantation model  ADDIN EN.CITE <EndNote><Cite><Author>Feng</Author><Year>2010</Year><RecNum>10</RecNum><DisplayText>[20]</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Feng, Bin</author><author>Tomizawa, Kazuhito</author><author>Michiue, Hiroyuki</author><author>Han, Xiao-Jian</author><author>Miyatake, Shin-ichi</author><author>Matsui, Hideki</author></authors></contributors><titles><title>Development of a bifunctional immunoliposome system for combined drug delivery and imaging in vivo</title><secondary-title>Biomaterials</secondary-title></titles><periodical><full-title>Biomaterials</full-title></periodical><pages>4139-4145</pages><volume>31</volume><number>14</number><dates><year>2010</year><pub-dates><date>May</date></pub-dates></dates><isbn>0142-9612</isbn><accession-num>WOS:000276541300043</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000276541300043</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2010.01.086</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_20" \o "Feng, 2010 #10" 20] ; Constructing C225 - USPIO for nasopharyngeal carcinoma cells in vitro MRI test showed that MRI T2 sequence signal decreases than IgG-USPIO, and the results show that C225 - USPIO would be used for early noninvasive detection in high expression of EGFR nasopharyngeal carcinoma  ADDIN EN.CITE <EndNote><Cite><Author>Liu</Author><Year>2011</Year><RecNum>8</RecNum><DisplayText>[21]</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liu, Dongbo</author><author>Chen, Chunli</author><author>Hu, Guangyuan</author><author>Mei, Qi</author><author>Qiu, Hong</author><author>Long, Guoxian</author><author>Hu, Guoqing</author></authors></contributors><titles><title>Specific targeting of nasopharyngeal carcinoma cell line CNE1 by C225-conjugated ultrasmall superparamagnetic iron oxide particles with magnetic resonance imaging</title><secondary-title>Acta Biochimica Et Biophysica Sinica</secondary-title></titles><periodical><full-title>Acta Biochimica Et Biophysica Sinica</full-title></periodical><pages>301-306</pages><volume>43</volume><number>4</number><dates><year>2011</year><pub-dates><date>2011</date></pub-dates></dates><isbn>1672-9145</isbn><accession-num>WOS:000288796200008</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000288796200008</url></related-urls></urls><electronic-resource-num>10.1093/abbs/gmr010</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_21" \o "Liu, 2011 #8" 21]. Another C225 - USPIO used for detection of A549 lung cancer cell research also shows that EGFR targeted MRI contrast agent shows the combination of good efficiency and specificity, also provides a novel method to assess EGFR expression level of malignant tumor  ADDIN EN.CITE <EndNote><Cite><Author>Chen</Author><Year>2012</Year><RecNum>7</RecNum><DisplayText>[22]</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chen, Chun-li</author><author>Hu, Guang-yuan</author><author>Mei, Qi</author><author>Qiu, Hong</author><author>Long, Guo-xian</author><author>Hu, Guo-qing</author></authors></contributors><titles><title>Epidermal growth factor receptor-targeted ultra-small superparamagnetic iron oxide particles for magnetic resonance molecular imaging of lung cancer cells in vitro</title><secondary-title>Chinese Medical Journal</secondary-title></titles><periodical><full-title>Chinese Medical Journal</full-title></periodical><pages>2322-2328</pages><volume>125</volume><number>13</number><dates><year>2012</year><pub-dates><date>Jul 5</date></pub-dates></dates><isbn>0366-6999</isbn><accession-num>WOS:000306382500015</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000306382500015</url></related-urls></urls><electronic-resource-num>10.3760/cma.j.issn.0366-6999.2012.13.015</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_22" \o "Chen, 2012 #7" 22]. Herceptin has been putting into clinical use in the treatment of HER - 2 positive breast cancer patients, USPIO�s surface glucan covalent binding Herceptin construct Herceptin - USPIO for rat breast cancer transplantation tumor model investgated with MRI T2WI sequences, significant negative enhancement was detected in the tumor location, indicated that the targeted contrast agent in tumor tissue of high concentrations of specific gathered ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_23" \o "Chen, 2009 #17" 23,  HYPERLINK \l "_ENREF_24" \o "Oghabian, 2011 #25" 24].
P230 is glycoprotein highly specific express in breast cancer, liver cancer, and other solid tumor cell surface, SM5-1is one monoclonal antibody anti P230; Kou Geng etc created SM - USPIO targeted MRI contrast agent for nude mouse liver cell carcinoma model imaging, signal reduced significantly was found under T2WI sequences, which has potential as a targeted diagnosis contrast agent of liver cell cancer  ADDIN EN.CITE <EndNote><Cite><Author>Kou</Author><Year>2008</Year><RecNum>26</RecNum><DisplayText>[25]</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kou, Geng</author><author>Wang, Shuhui</author><author>Cheng, Changming</author><author>Gao, Jie</author><author>Li, Bohua</author><author>Wang, Hao</author><author>Qian, Weizhu</author><author>Hou, Sheng</author><author>Zhang, Dapeng</author><author>Dai, Jianxin</author><author>Gu, Hongchen</author><author>Guo, Yajun</author></authors></contributors><titles><title>Development of SM5-1-conjugated ultrasmall superparamagnetic iron oxide nanoparticles for hepatoma detection</title><secondary-title>Biochemical and Biophysical Research Communications</secondary-title></titles><periodical><full-title>Biochemical and Biophysical Research Communications</full-title></periodical><pages>192-197</pages><volume>374</volume><number>2</number><dates><year>2008</year><pub-dates><date>Sep 19</date></pub-dates></dates><isbn>0006-291X</isbn><accession-num>WOS:000258600100004</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000258600100004</url></related-urls></urls><electronic-resource-num>10.1016/j.bbrc.2008.06.126</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_25" \o "Kou, 2008 #26" 25] .Chemokine receptor (CXCR4) plays an important role in promotion and transfer in pancreatic cancer cell circle, CXCR4 monoclonal antibody conjugated USPIO constructed  CXCR4 - USPIO MRI contrast agent for testing CXCR4 expression level of different pancreatic cancer cell lines, Results MR imaging revealed a linear correlation between DeltaR2 and DeltaR2* values of CXCR4-USPIO nanoparticles and the iron concentrations, The targeted probe CXCR4-USPIO was created for MR molecular imaging of pancreatic cancer cell lines. The T2 enhancement ratio and DeltaR2 values of CXCR4-USPIO nanoparticles could semi-quantitatively assess the cellular CXCR4 expression levels ADDIN EN.CITE <EndNote><Cite><Author>He</Author><Year>2012</Year><RecNum>18</RecNum><DisplayText>[26]</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>He, Yonglan</author><author>Song, Wei</author><author>Lei, Jing</author><author>Li, Zhuo</author><author>Cao, Jian</author><author>Huang, Shuai</author><author>Meng, Jie</author><author>Xu, Haiyan</author><author>Jin, Zhengyu</author><author>Xue, Huadan</author></authors></contributors><titles><title>Anti-CXCR4 monoclonal antibody conjugated to ultrasmall superparamagnetic iron oxide nanoparticles in an application of MR molecular imaging of pancreatic cancer cell lines</title><secondary-title>Acta radiologica (Stockholm, Sweden : 1987)</secondary-title></titles><periodical><full-title>Acta radiologica (Stockholm, Sweden : 1987)</full-title></periodical><pages>1049-58</pages><volume>53</volume><number>9</number><dates><year>2012</year><pub-dates><date>2012-Nov-1</date></pub-dates></dates><isbn>1600-0455</isbn><accession-num>MEDLINE:23012484</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://MEDLINE:23012484</url></related-urls></urls><electronic-resource-num>10.1258/ar.2012.120055</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_26" \o "He, 2012 #18" 26] .
Wen song etcanti-mouse OxLDL polyclonalantibody and nonspecifi c IgG antibody were conjugated to polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, and a carotid perivascular collar model in apolipoprotein E-defi cient mice was imaged at 7.0 Tesla MRI; This report shows that anti-OxLDL-USPIO nanoparticles can be used to
directly detect OxLDL and image atherosclerotic lesions within24 h of nanoparticle administration and suggests a strategy for the therapeutic evaluation of atherosclerotic plaques in vivo  ADDIN EN.CITE <EndNote><Cite><Author>Wen</Author><Year>2012</Year><RecNum>20</RecNum><DisplayText>[27]</DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wen, S.</author><author>��,</author><author>Liu, D. F.</author><author>���,</author><author>Liu, Z.</author><author>Harris, S.</author><author>Yao, Y. Y.</author><author>Ding, Q.</author><author>Nie, F.</author><author>Lu, T.</author><author>Chen, H. J.</author><author>An, Y. L.</author><author>Zang, F. C.</author><author>Teng, G. J.</author></authors></contributors><titles><title>OxLDL-targeted iron oxide nanoparticles for in vivo MRI detection of perivascular carotid collar induced atherosclerotic lesions in ApoE-deficient mice</title><secondary-title>The Journal of Lipid Research</secondary-title></titles><periodical><full-title>The Journal of Lipid Research</full-title></periodical><pages>829-838</pages><volume>53</volume><number>5</number><dates><year>2012</year></dates><isbn>0022-2275</isbn><urls></urls><electronic-resource-num>10.1194/jlr.M018895</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_27" \o "Wen, 2012 #20" 27] .
Pursue to provide a novel early diagnostic method and targeted therapy for pancreatic cancer, a multifunctional nanoimmunoliposome with high loading of ultrasmall superparamagnetic iron oxides (USPIOs) and doxorubicin (DOX) was prepared by transient binding and reverse-phase evaporation method, and was conjugated with anti-mesothelin monoclonal antibody by post-insertion method to target anti-mesothelin-overexpressed pancreatic cancer cells,              The in vivo antitumor study demonstrated that compared with FD (free DOX) and PLDU, M-PLDU possessed higher inhibitory effect on tumor growth and the tissue distribution assay further proved that M-PLDUs could selectively accumulate in the tumor xenograft. These results indicated that M-PLDU not only well retained the inherent MRI capability of USPIOs, but significantly improved the targeting distribution of USPIOs and therapeutic agents in pancreatic tumor tissues. They may serve as a promising theranostic nanomedicine not only for early detection but also for MRI-monitored targeting therapy of human pancreatic cancer ADDIN EN.CITE <EndNote><Cite><Author>Deng</Author><Year>2012</Year><RecNum>21</RecNum><DisplayText>[28]</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Deng, Li</author><author>Ke, Xingfa</author><author>He, Zhiying</author><author>Yang, Daoqiu</author><author>Gong, Hai</author><author>Zhang, Yingying</author><author>Jing, Xiaolong</author><author>Yao, Jianzhong</author><author>Chen, Jianming</author></authors></contributors><titles><title>A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer</title><secondary-title>International Journal of Nanomedicine</secondary-title></titles><periodical><full-title>International Journal of Nanomedicine</full-title></periodical><pages>5053-5065</pages><volume>7</volume><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><isbn>1178-2013</isbn><accession-num>WOS:000308857200001</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000308857200001</url></related-urls></urls><electronic-resource-num>10.2147/ijn.s34801</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_28" \o "Deng, 2012 #21" 28] .Riboflavin carrier protein (RCP) was found high expression in the active metabolizing    cancer cells, the carrier of flavin mononucleotide (flavin mononucleotide) and flavin adenine dinucleotide (FAD) to maintain normal cell growth and function is very important; Jayapaul etc  developed FMN USPIO 0FLUSPIO and FAD - USPIO for the MRI imaging of prostate cancer animal transplantation model , found that FAD - USPIO and FLUSPIO can specific to located in tumor and blood vessel area, which is beneficial to evaluate tumor blood essels metabolic process ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_29" \o "Jayapaul, 2012 #28" 29,  HYPERLINK \l "_ENREF_30" \o "Jayapaul, 2011 #30" 30] . GPC3(Phospholipid acyl alcohol proteoglycan) is rich in most liver cell cancer cell surface, antiGPC3 - USPIO was synthesised to detect hepatic cell cancer, the results showed that antiGPC3 � USPIO could significantly shorten the T1 and T2 value quantitatively, antiGPC3 � USPIO may fitable used for early detection of liver cell cancer  ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2012</Year><RecNum>29</RecNum><DisplayText>[31]</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, Youwei</author><author>Chen, Zhengguang</author><author>Li, Fei</author><author>Wang, Jichen</author><author>Zhang, Zongming</author></authors></contributors><titles><title>Preparation and in vitro studies of MRI-specific superparamagnetic iron oxide antiGPC3 probe for hepatocellular carcinoma</title><secondary-title>International Journal of Nanomedicine</secondary-title></titles><periodical><full-title>International Journal of Nanomedicine</full-title></periodical><pages>4593-4611</pages><volume>7</volume><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><isbn>1178-2013</isbn><accession-num>WOS:000308076900001</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000308076900001</url></related-urls></urls><electronic-resource-num>10.2147/ijn.s32196</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_31" \o "Li, 2012 #29" 31] .
Although different specific antibody combined USPIO strategies can be targeted corresponding  tumor; But diverse tumors have heterogeneous gene and the amount of receptor is extremely various;consequently those tumors or metastasis with bits of receptor were difficult to detect.Therefore the genetic heterogeneity caused the major drawback of antibody combined USPIO.
2.4 transferrin 
TfR(Transferrin recepto)r is a transmembrane glycoprotein,its primary function is domain intracellular intake of iron. Current researches show that TfR was expressing highly in lung adenocarcinoma, glioma, prostate cancer,bladder cancer and other kinds of tumor  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_32" \o "Daniels, 2006 #19" 32] ;as a result , Transferrin as a potential targeting media has draw more much attention in the field of molecular targeted therapeutic strategy and molecular imaging toward many kinds of carcinoma  ADDIN EN.CITE <EndNote><Cite><Author>Zhang</Author><Year>2008</Year><RecNum>11</RecNum><DisplayText>[33]</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhang, Clare Y.</author><author>Lu, Jing</author><author>Tsourkas, Andrew</author></authors></contributors><titles><title>Iron chelator-based amplification strategy for improved targeting of transferrin receptor with SPIO</title><secondary-title>Cancer Biology &amp; Therapy</secondary-title></titles><periodical><full-title>Cancer Biology &amp; Therapy</full-title></periodical><pages>889-895</pages><volume>7</volume><number>6</number><dates><year>2008</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1538-4047</isbn><accession-num>WOS:000257394700015</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000257394700015</url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_33" \o "Zhang, 2008 #11" 33] . Wang Kai etc constructed Tf � USPIO and used for imaging of MDA - MB - 231 breast cancer model,results show that Endostatin therapeutic gene expression was visualized successfully using TfR reporter gene and Tf-USPIO MR reporter probe, which indicates that MR reporter gene imaging may be valuable in gene therapy to evaluate therapeutic gene expression and treatment efficacy  ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2010</Year><RecNum>12</RecNum><DisplayText>[34]</DisplayText><record><rec-number>12</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">12</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, Kai</author><author>Wang, Kezheng</author><author>Shen, Baozhong</author><author>Huang, Tao</author><author>Sun, Xilin</author><author>Li, Weihua</author><author>Jin, Gang</author><author>Li, Lin</author><author>Bu, Lihong</author><author>Li, Renfei</author><author>Wang, Dan</author><author>Chen, Xiaoyuan</author></authors></contributors><titles><title>MR Reporter Gene Imaging of Endostatin Expression and Therapy</title><secondary-title>Molecular Imaging and Biology</secondary-title></titles><periodical><full-title>Molecular Imaging and Biology</full-title></periodical><pages>520-529</pages><volume>12</volume><number>5</number><dates><year>2010</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1536-1632</isbn><accession-num>WOS:000282273200008</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000282273200008</url></related-urls></urls><electronic-resource-num>10.1007/s11307-009-0286-0</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_34" \o "Wang, 2010 #12" 34] . Lactoferrin (Lf) belongs to transferrin family, shall the 60% - 80% sequences of transferrin; Xie Hui constructed Lf - USPIO used for imaging of brain glioma model which express TfR highly, Lf-SPIONs provided a better picture or more sensitivity to depict brain glioma on MR images than that of SPIONs Significantly enhanced T(2)-weighted images of brain glioma were documented in vivo with Lf-SPIONs until 48 h after injection. Moreover Lf-SPIONs were clearly observed around vascular region of the tumor slices after 48 h High level expression of Lf receptors was confirmed in brain tumor tissues by RT-PCR and Western Blot compared to normal brain tissues. These findings suggested that Lf-SPIONs could be potentially employed as a sensitive and specific MRI contrast agent in the diagnosis of brain glioma ADDIN EN.CITE <EndNote><Cite><Author>Xie</Author><Year>2011</Year><RecNum>15</RecNum><DisplayText>[35]</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">15</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Xie, Hui</author><author>Zhu, Yanhong</author><author>Jiang, Weili</author><author>Zhou, Qing</author><author>Yang, Hai</author><author>Gu, Ning</author><author>Zhang, Yu</author><author>Xu, Huibi</author><author>Xu, Haibo</author><author>Yang, Xiangliang</author></authors></contributors><titles><title>Lactoferrin-conjugated superparamagnetic iron oxide nanoparticles as a specific MRI contrast agent for detection of brain glioma in vivo</title><secondary-title>Biomaterials</secondary-title></titles><periodical><full-title>Biomaterials</full-title></periodical><pages>495-502</pages><volume>32</volume><number>2</number><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0142-9612</isbn><accession-num>WOS:000285401500018</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000285401500018</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2010.09.024</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_35" \o "Xie, 2011 #15" 35] .
2.5 Other small molecular peptides and proteins
   Cell penetrating peptide (CPPs) has the ability to pass through the cell membranes, Tat is derived from HIV - 1 Tat protein, which can transport proteins,particles, liposomes, drugs and contrast agents etc into cell through cellular membrane; prepared FITC - Tat - MNPs through crosslinking fluorescein FITC, Caco - 2 cells cultured with FITC - Tat - MNPs and FITC - MNPs  observed under fluorescent microscope,results revealed that uptake of FITC - Tat - MNPs more than FITC � MNPs, these results were confirmed using confocal laser scanning microscopy (LSCM), which further demonstrated that the FITC-Tat MNPs accumulated in the cytoplasm and nucleus while the FITCMNPs were localized in the cell membrane compartments                                                                                     ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2012</Year><RecNum>16</RecNum><DisplayText>[36]</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, Chenhong</author><author>Qiao, Lei</author><author>Zhang, Quan</author><author>Yan, Husheng</author><author>Liu, Keliang</author></authors></contributors><titles><title>Enhanced cell uptake of superparamagnetic iron oxide nanoparticles through direct chemisorption of FITC-Tat-PEG600-b-poly(glycerol monoacrylate)</title><secondary-title>International Journal of Pharmaceutics</secondary-title></titles><periodical><full-title>International Journal of Pharmaceutics</full-title></periodical><pages>372-380</pages><volume>430</volume><number>1-2</number><dates><year>2012</year></dates><isbn>03785173</isbn><urls></urls><electronic-resource-num>10.1016/j.ijpharm.2012.04.035</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_36" \o "Wang, 2012 #16" 36]. Amyloid plaques are one of the pathological hallmarks of Alzheimer's disease (AD). The visualization of amyloid plaques in the brain is important to monitor AD progression and to evaluate the efficacy of therapeutic interventions.Yang jing etc used ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with A beta 1-42 peptide to detect amyloid deposition along with mannitol for in vivo mu MRI by femoral intravenous injection. A 3D gradient multi-echo sequence was used for imaging with a 100 mu m isotropic resolution. The amyloid plaques detected by T2*-weighted mu MRI were confirmed with matched histological sections.The regional differences seen in VBM comparing USPIO-A beta 1-42 injected APP/PS1 and wild-type mice correlated with the amyloid plaque distribution histologically, contrasting with no differences between the two groups of mice without contrast agent injection in regions of the brain with amyloid deposition.Results demonstrated that both approaches were able to identify the differences between AD transgenic mice and wildtype mice, after injected with USPIO-A beta 1-42. The feasibility of using less invasive intravenous femoral injections for amyloid plaque detection in AD transgenic mice facilitates using this method for longitudinal studies in the pathogenesis of AD  ADDIN EN.CITE <EndNote><Cite><Author>Yang</Author><Year>2011</Year><RecNum>23</RecNum><DisplayText>[37]</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yang, Jing</author><author>Wadghiri, Youssef Zaim</author><author>Hoang, Dung Minh</author><author>Tsui, Wai</author><author>Sun, Yanjie</author><author>Chung, Erika</author><author>Li, Yongsheng</author><author>Wang, Andrew</author><author>de Leon, Mony</author><author>Wisniewski, Thomas</author></authors></contributors><titles><title>Detection of amyloid plaques targeted by USPIO-A beta 1-42 in Alzheimer&apos;s disease transgenic mice using magnetic resonance microimaging</title><secondary-title>Neuroimage</secondary-title></titles><periodical><full-title>Neuroimage</full-title></periodical><pages>1600-1609</pages><volume>55</volume><number>4</number><dates><year>2011</year><pub-dates><date>Apr 15</date></pub-dates></dates><isbn>1053-8119</isbn><accession-num>WOS:000288843500022</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000288843500022</url></related-urls></urls><electronic-resource-num>10.1016/j.neuroimage.2011.01.023</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_37" \o "Yang, 2011 #23" 37] .
conclusions
USPIO has been proved available and high-efficiency in clinical applications because of their negative enhancement effect on T2/T2*-weighted imaging sequences. This predominant effect on
the T2/T2* relaxation time does not prevent the use of the properties of these agents on T1 relaxation time when suitable sequences and doses are used.with the help of technology of molecular imaging,targeted USPIO further uses in track tumor stem cell and immune cell in vivo, most of the research has concerned cellular imaging relied on in vivo macrophage activity, almost entire studies are at stage of further researching,principally in animal models ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_38" \o "Corot, 2006 #31" 38].
The physicochemical characteristics not only determine the efficacy of the superparamagnetic particles in MRI, but also their stability, biodistribution, opsonization and metabolism as well as their clearance from the vascular system.
   
 
Based on MRI target contrast in animal tumor model of USPIO enhancement tracer has made significant progress, but it is limited to small animal models; In clinical use is difficult, to analyze its reasons may be: (1) animal model needs less targeting the dose of USPIO enhancement, few milligrams can satisfy the need, to transition to a larger dose of animal and human trials need to increase a few orders of magnitude, such a large dose of synthesis is difficult; (2) targeted carriers such as single resistance are more expensive, even if other aspects of performance parameters meet the demand of clinical development, eventually too high prices may still be blocked in the commercial production of the door. Needs to solve the problem as follows: (1) to improve its physical and chemical properties analysis of physical and chemical properties not only determines the MRI enhancement effect and its stability, distribution and metabolic clearance has the same effect; (2) iron core structure, to modify the surface of polymer material and so on each part of the nature of the accurate qualitative; 3. On the premise of guarantee the enhancement effect as far as possible to simplify the synthesis procedures and improve the efficiency of synthesis, conducive to mass production, greatly reduce the production cost; 4. How to further reduce the liver and spleen on its removal. To solve these problems, will promote targeted USPIO MRI contrast to clinical use.

 ADDIN EN.REFLIST [1] A. Luciani, E. Itti, A. Rahmouni, M. Meignan, O. Clement, Lymph node imaging: Basic principles, European Journal Of Radiology, 58 (2006) 338-344.
[2] T. Saam, T.S. Hatsukami, N. Takaya, B. Chu, H. Underhill, W.S. Kerwin, J. Cai, M.S. Ferguson, C. Yuan, The vulnerable, or high-risk, atherosclerotic plaque: Noninvasive MR imaging for characterization and assessment, Radiology, 244 (2007) 64-77.
[3] A.D. Yancy, A.R. Olzinski, T.C.C. Hu, S.C. Lenhard, K. Aravindhan, S.M. Gruver, P.M. Jacobs, R.N. Willette, B.M. Jucker, Differential uptake of ferumoxtran-10 and ferumoxytol, ultrasmall superparamagnetic iron oxide contrast agents in rabbit: Critical determinants of atherosclerotic plaque labeling, Journal Of Magnetic Resonance Imaging, 21 (2005) 432-442.
[4] B. Bonnemain, Superparamagnetic agents in magnetic resonance imaging: Physicochemical characteristics and clinical applications - A review, Journal Of Drug Targeting, 6 (1998) 167-174.
[5] I. Pirko, B. Ciric, J. Gamez, A.J. Bieber, A.E. Warrington, A.J. Johnson, D.P. Hanson, L.R. Pease, S.I. Macura, M. Rodriguez, A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS, Faseb Journal, 18 (2004) 1577-+.
[6] A. Luchetti, D. Milani, F. Ruffini, R. Galli, A. Falini, A. Quattrini, G. Scotti, G. Comi, G. Martino, R. Furlan, L.S. Politi, Monoclonal Antibodies Conjugated with Superparamagnetic Iron Oxide Particles Allow Magnetic Resonance Imaging Detection of Lymphocytes in the Mouse Brain, Molecular Imaging, 11 (2012) 114-125.
[7] I. Siglienti, M. Bendszus, C. Kleinschnitz, G. Stoll, Cytokine profile of iron-laden macrophages: Implications for cellular magnetic resonance imaging, Journal Of Neuroimmunology, 173 (2006) 166-173.
[8] O. Will, S. Purkayastha, C. Chan, T. Athanasiou, A.W. Darzi, W. Gedroyc, P.P. Tekkis, Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: a meta-analysis, The Lancet Oncology, 7 (2006) 52-60.
[9] J.K. Oh, J.M. Park, Iron oxide-based superparamagnetic polymeric nanomaterials: Design, preparation, and biomedical application, Progress in Polymer Science, 36 (2011) 168-189.
[10] Y. Zhang, J. Zhang, Surface modification of monodisperse magnetite nanoparticles for improved intracellular uptake to breast cancer cells, Journal Of Colloid And Interface Science, 283 (2005) 352-357.
[11] F. Sonvico, S. Mornet, S. Vasseur, C. Dubernet, D. Jaillard, J. Degrouard, J. Hoebeke, E. Duguet, P. Colombo, P. Couvreur, Folate-conjugated iron oxide nanoparticles for solid tumor targeting as potential specific magnetic hyperthermia mediators: Synthesis, physicochemical characterization, and in vitro experiments, Bioconjugate Chemistry, 16 (2005) 1181-1188.
[12] R. Meier, T.D. Henning, S. Boddington, S. Tavri, S. Arora, G. Piontek, M. Rudelius, C. Corot, H.E. Daldrup-Link, Breast Cancers: MR Imaging of Folate-Receptor Expression with the Folate-Specific Nanoparticle P1133, Radiology, 255 (2010) 527-535.
[13] G.D. Bothun, A. Lelis, Y. Chen, K. Scully, L.E. Anderson, M.A. Stoner, Multicomponent folate-targeted magnetoliposomes: design, characterization, and cellular uptake, Nanomedicine-Nanotechnology Biology and Medicine, 7 (2011) 797-805.
[14] W.-h. Gao, S.-t. Liu, C.-x. Fan, L.-y. Qi, Z.-l. Chen, Pharmacokinetics, tissue distribution and magnetic resonance's response characterstics of folic acid-O-carboxymethyl chitosan ultrasmall superparamagnetic iron oxide nanoparticles in mice and rats, Yaoxue Xuebao, 46 (2011) 845-851.
[15] E. Garanger, D. Boturyn, P. Dumy, Tumor targeting with RGD peptide Ligands-Design of new molecular conjugates for Imaging and therapy of cancers, Anti-Cancer Agents in Medicinal Chemistry, 7 (2007) 552-558.
[16] X. Yi, Y. Ding, Y. Zeng, C. Zhou, B. Luo, S. Meng, W. Rui, Y. Zhao, W. Li, Magnetic Resonance Imaging Contrast Agent: cRGD-Ferric Oxide Nanometer Particle and Its Role in the Diagnosis of Tumor, Journal of Nanoscience and Nanotechnology, 11 (2011) 3800-3807.
[17] R.-Y. Lin, K. Dayananda, T.-J. Chen, C.-Y. Chen, G.-C. Liu, K.-L. Lin, Y.-M. Wang, Targeted RGD nanoparticles for highly sensitive in vivo integrin receptor imaging, Contrast Media & Molecular Imaging, 7 (2012) 7-18.
[18] X. Wu, J. Zhang, B. Lin, M. Zhang, Molecular imaging of tumor angiogenesis using RGD-labeled iron oxide nanoparticles, Chinese Science Bulletin, 55 (2010) 2662-2670.
[19] G. Wu, X. Wang, G. Deng, L. Wu, S. Ju, G. Teng, Y. Yao, X. Wang, N. Liu, Novel peptide targeting integrin �v�3-rich tumor cells by magnetic resonance imaging, Journal of Magnetic Resonance Imaging, 34 (2011) 395-402.
[20] B. Feng, K. Tomizawa, H. Michiue, X.-J. Han, S.-i. Miyatake, H. Matsui, Development of a bifunctional immunoliposome system for combined drug delivery and imaging in vivo, Biomaterials, 31 (2010) 4139-4145.
[21] D. Liu, C. Chen, G. Hu, Q. Mei, H. Qiu, G. Long, G. Hu, Specific targeting of nasopharyngeal carcinoma cell line CNE1 by C225-conjugated ultrasmall superparamagnetic iron oxide particles with magnetic resonance imaging, Acta Biochimica Et Biophysica Sinica, 43 (2011) 301-306.
[22] C.-l. Chen, G.-y. Hu, Q. Mei, H. Qiu, G.-x. Long, G.-q. Hu, Epidermal growth factor receptor-targeted ultra-small superparamagnetic iron oxide particles for magnetic resonance molecular imaging of lung cancer cells in vitro, Chinese Medical Journal, 125 (2012) 2322-2328.
[23] T.-J. Chen, T.-H. Cheng, C.-Y. Chen, S.C.N. Hsu, T.-L. Cheng, G.-C. Liu, Y.-M. Wang, Targeted Herceptin-dextran iron oxide nanoparticles for noninvasive imaging of HER2/neu receptors using MRI, Journal of Biological Inorganic Chemistry, 14 (2009) 253-260.
[24] M.A. Oghabian, M. Jeddi-Tehrani, A. Zolfaghari, F. Shamsipour, S. Khoei, S. Amanpour, Detectability of Her2 Positive Tumors Using Monoclonal Antibody Conjugated Iron Oxide Nanoparticles in MRI, Journal of Nanoscience and Nanotechnology, 11 (2011) 5340-5344.
[25] G. Kou, S. Wang, C. Cheng, J. Gao, B. Li, H. Wang, W. Qian, S. Hou, D. Zhang, J. Dai, H. Gu, Y. Guo, Development of SM5-1-conjugated ultrasmall superparamagnetic iron oxide nanoparticles for hepatoma detection, Biochemical and Biophysical Research Communications, 374 (2008) 192-197.
[26] Y. He, W. Song, J. Lei, Z. Li, J. Cao, S. Huang, J. Meng, H. Xu, Z. Jin, H. Xue, Anti-CXCR4 monoclonal antibody conjugated to ultrasmall superparamagnetic iron oxide nanoparticles in an application of MR molecular imaging of pancreatic cancer cell lines, Acta radiologica (Stockholm, Sweden : 1987), 53 (2012) 1049-1058.
[27] S. Wen, ��, D.F. Liu, ���, Z. Liu, S. Harris, Y.Y. Yao, Q. Ding, F. Nie, T. Lu, H.J. Chen, Y.L. An, F.C. Zang, G.J. Teng, OxLDL-targeted iron oxide nanoparticles for in vivo MRI detection of perivascular carotid collar induced atherosclerotic lesions in ApoE-deficient mice, The Journal of Lipid Research, 53 (2012) 829-838.
[28] L. Deng, X. Ke, Z. He, D. Yang, H. Gong, Y. Zhang, X. Jing, J. Yao, J. Chen, A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer, International Journal of Nanomedicine, 7 (2012) 5053-5065.
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ڜ�՞��h�A�E�����������������������������$a$gd:C/apaul, S. Arns, W. Lederle, T. Lammers, P. Comba, J. Gatjens, F. Kiessling, Riboflavin carrier protein-targeted fluorescent USPIO for the assessment of vascular metabolism in tumors, Biomaterials, 33 (2012) 8822-8829.
[30] J. Jayapaul, M. Hodenius, S. Arns, W. Lederle, T. Lammers, P. Comba, F. Kiessling, J. Gaetjens, FMN-coated fluorescent iron oxide nanoparticles for RCP-mediated targeting and labeling of metabolically active cancer and endothelial cells, Biomaterials, 32 (2011) 5863-5871.
[31] Y. Li, Z. Chen, F. Li, J. Wang, Z. Zhang, Preparation and in vitro studies of MRI-specific superparamagnetic iron oxide antiGPC3 probe for hepatocellular carcinoma, International Journal of Nanomedicine, 7 (2012) 4593-4611.
[32] T.R. Daniels, T. Delgado, J.A. Rodriguez, G. Helguera, M.L. Penichet, The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer, Clin. Immunol., 121 (2006) 144-158.
[33] C.Y. Zhang, J. Lu, A. Tsourkas, Iron chelator-based amplification strategy for improved targeting of transferrin receptor with SPIO, Cancer Biology & Therapy, 7 (2008) 889-895.
[34] K. Wang, K. Wang, B. Shen, T. Huang, X. Sun, W. Li, G. Jin, L. Li, L. Bu, R. Li, D. Wang, X. Chen, MR Reporter Gene Imaging of Endostatin Expression and Therapy, Molecular Imaging and Biology, 12 (2010) 520-529.
[35] H. Xie, Y. Zhu, W. Jiang, Q. Zhou, H. Yang, N. Gu, Y. Zhang, H. Xu, H. Xu, X. Yang, Lactoferrin-conjugated superparamagnetic iron oxide nanoparticles as a specific MRI contrast agent for detection of brain glioma in vivo, Biomaterials, 32 (2011) 495-502.
[36] C. Wang, L. Qiao, Q. Zhang, H. Yan, K. Liu, Enhanced cell uptake of superparamagnetic iron oxide nanoparticles through direct chemisorption of FITC-Tat-PEG600-b-poly(glycerol monoacrylate), International Journal of Pharmaceutics, 430 (2012) 372-380.
[37] J. Yang, Y.Z. Wadghiri, D.M. Hoang, W. Tsui, Y. Sun, E. Chung, Y. Li, A. Wang, M. de Leon, T. Wisniewski, Detection of amyloid plaques targeted by USPIO-A beta 1-42 in Alzheimer's disease transgenic mice using magnetic resonance microimaging, Neuroimage, 55 (2011) 1600-1609.
[38] C. Corot, P. Robert, J.M. Idee, M. Port, Recent advances in iron oxide nanocrystal technology for medical imaging, Advanced drug delivery reviews, 58 (2006) 1471-1504.










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Radiology</full-title></periodical><pages>338-344</pages><volume>58</volume><number>3</number><dates><year>2006</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0720-048X</isbn><accession-num>WOS:000238435500002</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000238435500002</url></related-urls></urls><electronic-resource-num>10.1016/j.ejrad.2005.12.038</electronic-resource-num></record></Cite><Cite><Author>Saam</Author><Year>2007</Year><RecNum>70</RecNum><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saam, Tobias</author><author>Hatsukami, Thomas S.</author><author>Takaya, Norihide</author><author>Chu, Baocheng</author><author>Underhill, Hunter</author><author>Kerwin, William S.</author><author>Cai, Jianming</author><author>Ferguson, Marina S.</author><author>Yuan, Chun</author></authors></contributors><titles><title>The vulnerable, or high-risk, atherosclerotic plaque: Noninvasive MR imaging for characterization and assessment</title><secondary-title>Radiology</secondary-title></titles><periodical><full-title>Radiology</full-title></periodical><pages>64-77</pages><volume>244</volume><number>1</number><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0033-8419</isbn><accession-num>WOS:000247436500007</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000247436500007</url></related-urls></urls><electronic-resource-num>10.1148/radiol.2441051769</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1sD���y������K�	_ENREF_2sD���y������K�	_ENREF_3sD���y������K�	_ENREF_4sD���y������K�	_ENREF_5sD���y������K�	_ENREF_6sD���y������K�	_ENREF_7sD���y������K�	_ENREF_8sD���y������K�	_ENREF_9�	D<EndNote><Cite><Author>Zhang</Author><Year>2005</Year><RecNum>68</RecNum><DisplayText>[10, 11]</DisplayText><record><rec-number>68</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">68</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhang, Y.</author><author>Zhang, J.</author></authors></contributors><titles><title>Surface modification of monodisperse magnetite nanoparticles for improved intracellular uptake to breast cancer cells</title><secondary-title>Journal Of Colloid And Interface Science</secondary-title></titles><periodical><full-title>Journal Of Colloid And Interface Science</full-title></periodical><pages>352-357</pages><volume>283</volume><number>2</number><dates><year>2005</year><pub-dates><date>Mar 15</date></pub-dates></dates><isbn>0021-9797</isbn><accession-num>WOS:000227393300009</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000227393300009</url></related-urls></urls><electronic-resource-num>10.1016/j.jcis.2004.09.042</electronic-resource-num></record></Cite><Cite><Author>Sonvico</Author><Year>2005</Year><RecNum>69</RecNum><record><rec-number>69</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">69</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sonvico, F.</author><author>Mornet, S.</author><author>Vasseur, S.</author><author>Dubernet, C.</author><author>Jaillard, D.</author><author>Degrouard, J.</author><author>Hoebeke, J.</author><author>Duguet, E.</author><author>Colombo, P.</author><author>Couvreur, P.</author></authors></contributors><titles><title>Folate-conjugated iron oxide nanoparticles for solid tumor targeting as potential specific magnetic hyperthermia mediators: Synthesis, physicochemical characterization, and in vitro experiments</title><secondary-title>Bioconjugate Chemistry</secondary-title></titles><periodical><full-title>Bioconjugate Chemistry</full-title></periodical><pages>1181-1188</pages><volume>16</volume><number>5</number><dates><year>2005</year><pub-dates><date>Sep-Oct</date></pub-dates></dates><isbn>1043-1802</isbn><accession-num>WOS:000232070200019</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000232070200019</url></related-urls></urls><electronic-resource-num>10.1021/bc050050z</electronic-resource-num></record></Cite></EndNote>uD���y������K�
_ENREF_10uD���y������K�
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_ENREF_22�	D<EndNote><Cite><Author>Chen</Author><Year>2009</Year><RecNum>17</RecNum><DisplayText>[23, 24]</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">17</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chen, Ting-Jung</author><author>Cheng, Tsan-Hwang</author><author>Chen, Chiao-Yun</author><author>Hsu, Sodio C. N.</author><author>Cheng, Tian-Lu</author><author>Liu, Gin-Chung</author><author>Wang, Yun-Ming</author></authors></contributors><titles><title>Targeted Herceptin-dextran iron oxide nanoparticles for noninvasive imaging of HER2/neu receptors using MRI</title><secondary-title>Journal of Biological Inorganic Chemistry</secondary-title></titles><periodical><full-title>Journal of Biological Inorganic Chemistry</full-title></periodical><pages>253-260</pages><volume>14</volume><number>2</number><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0949-8257</isbn><accession-num>WOS:000264102000010</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000264102000010</url></related-urls></urls><electronic-resource-num>10.1007/s00775-008-0445-9</electronic-resource-num></record></Cite><Cite><Author>Oghabian</Author><Year>2011</Year><RecNum>25</RecNum><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">25</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oghabian, M. A.</author><author>Jeddi-Tehrani, M.</author><author>Zolfaghari, A.</author><author>Shamsipour, F.</author><author>Khoei, S.</author><author>Amanpour, S.</author></authors></contributors><titles><title>Detectability of Her2 Positive Tumors Using Monoclonal Antibody Conjugated Iron Oxide Nanoparticles in MRI</title><secondary-title>Journal of Nanoscience and Nanotechnology</secondary-title></titles><periodical><full-title>Journal of Nanoscience and Nanotechnology</full-title></periodical><pages>5340-5344</pages><volume>11</volume><number>6</number><dates><year>2011</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1533-4880</isbn><accession-num>WOS:000291568100098</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000291568100098</url></related-urls></urls><electronic-resource-num>10.1166/jnn.2011.3775</electronic-resource-num></record></Cite></EndNote>uD���y������K�
_ENREF_23uD���y������K�
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D<EndNote><Cite><Author>Jayapaul</Author><Year>2012</Year><RecNum>28</RecNum><DisplayText>[29, 30]</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jayapaul, J.</author><author>Arns, S.</author><author>Lederle, W.</author><author>Lammers, T.</author><author>Comba, P.</author><author>Gatjens, J.</author><author>Kiessling, F.</author></authors></contributors><auth-address>Department of Experimental Molecular Imaging, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; Anorganisch-Chemisches Institut, Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.</auth-address><titles><title>Riboflavin carrier protein-targeted fluorescent USPIO for the assessment of vascular metabolism in tumors</title><secondary-title>Biomaterials</secondary-title><alt-title>Biomaterials</alt-title></titles><periodical><full-title>Biomaterials</full-title></periodical><alt-periodical><full-title>Biomaterials</full-title></alt-periodical><pages>8822-9</pages><volume>33</volume><number>34</number><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1878-5905 (Electronic)&#xD;0142-9612 (Linking)</isbn><accession-num>22959180</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22959180</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2012.08.036</electronic-resource-num></record></Cite><Cite><Author>Jayapaul</Author><Year>2011</Year><RecNum>30</RecNum><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jayapaul, J.</author><author>Hodenius, M.</author><author>Arns, S.</author><author>Lederle, W.</author><author>Lammers, T.</author><author>Comba, P.</author><author>Kiessling, F.</author><author>Gaetjens, J.</author></authors></contributors><auth-address>Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.</auth-address><titles><title>FMN-coated fluorescent iron oxide nanoparticles for RCP-mediated targeting and labeling of metabolically active cancer and endothelial cells</title><secondary-title>Biomaterials</secondary-title><alt-title>Biomaterials</alt-title></titles><periodical><full-title>Biomaterials</full-title></periodical><alt-periodical><full-title>Biomaterials</full-title></alt-periodical><pages>5863-71</pages><volume>32</volume><number>25</number><keywords><keyword>Cell Line, Tumor</keyword><keyword>Endothelium, Vascular/*metabolism/pathology</keyword><keyword>Ferric Compounds/*chemistry</keyword><keyword>Flavin Mononucleotide/*chemistry</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Magnetics</keyword><keyword>*Metal Nanoparticles</keyword><keyword>Microscopy, Electron, Transmission</keyword><keyword>Neoplasms/*metabolism/pathology</keyword><keyword>Powder Diffraction</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1878-5905 (Electronic)&#xD;0142-9612 (Linking)</isbn><accession-num>21605902</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21605902</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2011.04.056</electronic-resource-num></record></Cite></EndNote>uD���y������K�
_ENREF_29uD���y������K�
_ENREF_30uD���y������K�
_ENREF_31r
D<EndNote><Cite><Author>Daniels</Author><Year>2006</Year><RecNum>19</RecNum><DisplayText>[32]</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Daniels, T. R.</author><author>Delgado, T.</author><author>Rodriguez, J. A.</author><author>Helguera, G.</author><author>Penichet, M. L.</author></authors></contributors><auth-address>Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Div Surg Oncol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Mol Genet &amp; Immunol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA.&#xD;Penichet, ML (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Div Surg Oncol, 10833 Le Conte Ave CHS 54-140 Mail Code 178218, Los Angeles, CA 90095 USA.&#xD;penichet@microbio.ucla.edu</auth-address><titles><title>The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer</title><secondary-title>Clinical Immunology</secondary-title><alt-title>Clin. Immunol.</alt-title></titles><periodical><full-title>Clinical Immunology</full-title><abbr-1>Clin. Immunol.</abbr-1></periodical><alt-periodical><full-title>Clinical Immunology</full-title><abbr-1>Clin. Immunol.</abbr-1></alt-periodical><pages>144-158</pages><volume>121</volume><number>2</number><keywords><keyword>transferrin receptor</keyword><keyword>iron</keyword><keyword>receptor-mediated endocytosis</keyword><keyword>monoclonal</keyword><keyword>antibodies</keyword><keyword>recombinant antibodies</keyword><keyword>immunotherapy</keyword><keyword>cancer</keyword><keyword>cell-surface glycoprotein</keyword><keyword>hereditary hemochromatosis protein</keyword><keyword>antireceptor monoclonal-antibody</keyword><keyword>human bone-marrow</keyword><keyword>t-cell</keyword><keyword>iron-metabolism</keyword><keyword>drug-delivery</keyword><keyword>breast-cancer</keyword><keyword>lymphocytic-leukemia</keyword><keyword>phenotypic analysis</keyword></keywords><dates><year>2006</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1521-6616</isbn><accession-num>WOS:000241638900003</accession-num><work-type>Review</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000241638900003</url></related-urls></urls><electronic-resource-num>10.1016/j.clim.2006.06.010</electronic-resource-num><language>English</language></record></Cite></EndNote>uD���y������K�
_ENREF_32uD���y������K�
_ENREF_33uD���y������K�
_ENREF_34uD���y������K�
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_ENREF_37�D<EndNote><Cite><Author>Corot</Author><Year>2006</Year><RecNum>31</RecNum><DisplayText>[38]</DisplayText><record><rec-number>31</rec-number><foreign-keys><key app="EN" db-id="xvx5aezadwp22uerd5upt5exfw9pevf29fvx">31</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Corot, C.</author><author>Robert, P.</author><author>Idee, J. M.</author><author>Port, M.</author></authors></contributors><auth-address>Guerbet Research, BP 57400, 95943 Roissy CDG, France. Claire.corot@guerbet-group.com</auth-address><titles><title>Recent advances in iron oxide nanocrystal technology for medical imaging</title><secondary-title>Adv Drug Deliv Rev</secondary-title><alt-title>Advanced drug delivery reviews</alt-title></titles><periodical><full-title>Adv Drug Deliv Rev</full-title><abbr-1>Advanced drug delivery reviews</abbr-1></periodical><alt-periodical><full-title>Adv Drug Deliv Rev</full-title><abbr-1>Advanced drug delivery reviews</abbr-1></alt-periodical><pages>1471-504</pages><volume>58</volume><number>14</number><keywords><keyword>Animals</keyword><keyword>Contrast Media/*pharmacokinetics/pharmacology</keyword><keyword>Dextrans</keyword><keyword>*Diagnostic Imaging/methods/trends</keyword><keyword>*Ferric Compounds/chemistry/diagnostic use/pharmacokinetics</keyword><keyword>Ferumoxytol</keyword><keyword>Half-Life</keyword><keyword>Humans</keyword><keyword>Iron/diagnostic use/*pharmacokinetics</keyword><keyword>Macrophages/*metabolism</keyword><keyword>Magnetite Nanoparticles</keyword><keyword>*Metal Nanoparticles</keyword><keyword>Molecular Biology/*trends</keyword><keyword>Neoplasms/*metabolism</keyword><keyword>Oxides/diagnostic use/*pharmacokinetics</keyword><keyword>Particle Size</keyword><keyword>Tissue Distribution</keyword></keywords><dates><year>2006</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>0169-409X (Print)&#xD;0169-409X (Linking)</isbn><accession-num>17116343</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17116343</url></related-urls></urls><electronic-resource-num>10.1016/j.addr.2006.09.013</electronic-resource-num></record></Cite></EndNote>uD���y������K�
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