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1 Focused Issue of This Month Multifunctional Nanoparticles for Molecular Imaging Eunah Kang, Ph.DKwangmeyung Kim, Ph.DIck Chan Kwon, Ph.D iomedical Research Center, Korea Institute of Science & Technology E - mail : ekang@kist.re.krkim@kist.re.krikwon@kist.re.kr J Korean Med ssoc 2009; 52(2): bstract Molecular imaging is a bioimaging that can detect biochemically and genetically relevant events in molecular level in cells and tissues via quantitative imaging signal. Molecular imaging provides potential advantages to examine early diagnosis of specific diseases, to screen new candidates of a drug, to monitor therapeutic effects in real time, and to communicate with both diagnosis and therapeutics. These diverse advantages of molecular imaging can be allowed by development of nanoplatform technology. The nanoplatform-based probes for molecular imaging is widely investigated to grant multimodal molecular imaging and drug delivery together with medical imagings, which includes the issues of biocompatibility, targeting moiety, proteasespecific peptide substrate, quenching/dequenching system etc. In this paper, nanoplatformbased probes are reviewed in aspects of cancer targeting for diagnosis and therapy and multimodal molecular imaging with inorganic/organic hybrid nanoparticles. Keywords: ioimaging; Multimodality; Nanoparticles; ctivatable; Targeting; iodistribution 125

2 Kang EKim KMKwon IC 126

3 Multifunctional Nanoparticles for Molecular Imaging Figure 1. Hydrophobically modified chitosan (HGC) nanoparticles targeting for atherosclerosis via homing peptide, () Schematic picture of atherosclerotic homing peptide conjugated HGC, () NIR fluorescence imaging that HGCs were localized on atherosclerotic regions in vivo, (C) histological morphology of atherosclerotic region of aorta vessel. Modified with permission from Ref. 5. Copyright 2008 Elsevier C.V. C 127

Modified with permission from ref. 6. Cpolyright 2005 PNS.

4 Kang EKim KMKwon IC Figure 2. Nanostructure of polymersome, () schematic nanostructure of polymersome and dye loading within hydrophobic bilayer, () NIR fluorescence imaging in vivo via polymersome probe. Modified with permission from ref. 6. Cpolyright 2005 PNS. glycol chitosan shell Tumor Whole body Tumor to background ratio(tr) 1 h 6 h 12 h 24 h 36 h 48 h 72 h Time (hour) White light C MIR Liver Lung Kidney Intensity(NC) 2.11e e e e+003 Spleen Heart Tumor Figure 3. HGC nanoparticle for cancer imaging, () schematic picture of Cy 5.5 labeled HGC, () NIR fluorescence imaging in vivo for tumor targeting using Cy 5.5 labeled HGC nanoparticles, (C) Quantitative analysis of fluorescence signal for tumor to background signal ratio, (D) biodistribution in organs ex vivo. Modifiedwith permission from ref. 7. Copyright 2008 Elsevier.V. 0 D 128

Multifunctional Nanoparticles for Molecular Imaging Figure 4. ph sensitive micelle with cell penetrating peptide TT, () schematic picture to show the structural change of micelle at ph variance.

5 Multifunctional Nanoparticles for Molecular Imaging Figure 4. ph sensitive micelle with cell penetrating peptide TT, () schematic picture to show the structural change of micelle at ph variance. TT moieties are faced outward at weak acid of tumor site. () NIR fluorescence imaging in vivo of tumor targeting via ph sensitive micelle with TT moieties. Modified with permission from ref. 12. Copyright 2008 Elsevier.V. Figure 5. Protease-specific nanoparticle probe, () Schematic picture of poly (L-Lysine) nanoparticles, () Schematric picture of selective degradation of polymer main backbone by protease, (C) NIR fluorescence bioimaging that was emitted by the cleavage of lysine substrates. Modified with permission from ref. 21. Copyright 1999, Nature Publishing Group. C 129

6 Kang EKim KMKwon IC Table 1. Target protease and peptide substrates for specific cancers and diseases Target protease Disease Peptide substrate Cathepsin reast cancer K/K Lymph nodes Lung cancer Rheumatoid arthritis therosclerosis Cathepsin D reast cancer PICF/FRL MMP-2 Fibrosarcoma PLG/VRG MMP-9 Myocardial infarction SGKGPRQ/IT MMP-2/-9 therosclerosis GGPRQ/ITG Macrophage MMP-7 Fibrosarcoma GVPLS/LTMGC Thrombin Cardiovascular F(PiP)R/S FXIIIa Cardiovascular NQ/EQVS Caspase -1 poptosis WEHD/DEVD Caspase-3 Urokinase Cancer GR/SN plasminogen activator (P) HIV protease HSV GV/SQNY/PIVG DPP -IV GP/GP * This table was modified with permission (33). 130

7 Multifunctional Nanoparticles for Molecular Imaging Figure 6. MMP specific peptide probes () Schematic picture of cleavage mechanism between MMP and MMP specific peptide substrate that was quenched by Cy5.5/ HQ system, () Sensitive fluorescence emission by MMP cleavage dependence in vitro characterization, (C) NIR fluorescence bioimaging that was activated by MMP in tumor site via MMP activatable probe. Modified with permission from 19. Copyright 2008, merican Chemical Society. C 131

MMP dependence of MMP activatable gold nanoparticles, (C) NIR fluorescence imaging, Fluorescence intensity is emitted in only tumor site by MMP cleavage of peptide substrate that

Modified with permission from ref. 18. Copyright 2008 WILEY-VCH Verlag GmbH & Co. C Figure 8.

8 Kang EKim KMKwon IC C Figure 7. Inorganic MMP activatable gold nanoprobe () schematic picture of gold nanoprobe that is activated by cleavage of MMP specific peptide substrate, () in vitro characterization of MMP dependence of MMP activatable gold nanoparticles, (C) NIR fluorescence imaging, Fluorescence intensity is emitted in only tumor site by MMP cleavage of peptide substrate that was conjugated on gold nanoparticle. Quenched fluorescence probe by gold nanoparticles was emitted as Cy 5.5 was departed from gold nanoparticles. Modified with permission from ref. 18. Copyright 2008 WILEY-VCH Verlag GmbH & Co. C Figure 8. Multifunctional quantum dots with dual imaging modality, () schematic picture of multifunctional quantum dot nanoparticles with multimodality. Multifunctional nanocomplex;paramagnetic lipid for MRI and quantum doe for fluorescence, RGD peptide for targeting, PEG for biocompatibility, () MRI image administered with multifunctional quantum dots, (C) Fluorescence bioimaging. Modified with permission from ref. 29. Copyright 2008 Springer. 132

9 Multifunctional Nanoparticles for Molecular Imaging 11. Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature 2003; 422: Park K, Kim JH, Nam YS, Lee S, Nam HY, Kim K, Park JH, Kim IS, Choi K, Kim SY, Kwon IC. Effect of polymer molecular weight on the tumor targeting characteristics of selfassembled glycol chitosan nanoparticles. J Control Release 2007; 122: Thapa N, Hong HY, Sangeetha P, Kim IS, Yoo J, Rhee K, Oh GT, Kwon IC, Lee H. Identification of a peptide ligand recognizing dysfunctional endothelial cells for targeting atherosclerosis. J Control Release 2008; 131: Hong HY, Lee HY, Kwak W, Yoo J, Na MH, So IS, Kwon TH, Park HS, Huh S, Oh GT, Kwon IC, Kim IS, Lee H. Phage Display Selection of Peptides that Home to therosclerotic Plaques: IL-4 Receptor as a Candidate Target in therosclerosis. J Cell Mol Med Park K, Hong HY, Moon HJ, Lee H, Kim IS, Kwon IC, Rhee K. new atherosclerotic lesion probe based on hydrophobically modified chitosan nanoparticles functionalized by the atherosclerotic plaque targeted peptides. J Control Release 2008; 128: Ghoroghchian PP, Frail PR, Susumu K, lessington D, rannan K, ates FS, Chance, Hammer D, Therien MJ. Near-infrared-emissive polymersomes: self-assembled soft matter for in vivo optical imaging. Proc Natl cad Sci U S 2005; 102: Hwang HY, Kim IS, Kwon IC, Kim YH. Tumor targetability and antitumor effect of docetaxel-loaded hydrophobically modified glycol chitosan nanoparticles. J Control Release 2008; 128: Cho YW, Park S, Han TH, Son DH, Park JS, Oh SJ, Moon DH, Cho KJ, hn CH, yun Y, Kim IS, Kwon IC, Kim SY. In vivo tumor targeting and radionuclide imaging with selfassembled nanoparticles: mechanisms, key factors, and their implications. iomaterials 2007; 28: Min KH, Park K, Kim YS, ae SM, Lee S, Jo HG, Park RW, Kim IS, Jeong SY, Kim K, Kwon IC. Hydrophobically modified glycol chitosan nanoparticles-encapsulated camptothecin enhance the drug stability and tumor targeting in cancer therapy. J Control Release 2008; 127: Kim JH, Kim YS, Park K, Lee S, Nam HY, Min KH, Jo HG, Park JH, Choi K, Jeong SY, Park RW, Kim IS, Kim K, Kwon IC. ntitumor efficacy of cisplatin-loaded glycol chitosan nanopar-ticles in tumor-bearing mice. J Control Release 2008; 127: Yin H, Lee ES, Kim D, Lee KH, Oh KT, ae YH. Physicochemical characteristics of ph-sensitive poly (L-histidine)-b-poly (ethylene glycol)/poly (L-lactide)-b-poly (ethylene glycol) mixed micelles. J Control Release 2008; 126: Lee ES, Gao Z, Kim D, Park K, Kwon IC, ae YH. Super phsensitive multifunctional polymeric micelle for tumor ph (e) specific TT exposure and multidrug resistance. J Control Release 2008; 129: Pham W, Pantazopoulos P, Moore. Imaging Farnesyl Protein Transferase Using a Topologically ctivated Probe. J m Chem Sco 2006; 128: Ntziachristos V, Schellenberger E, Ripoll J, Yessayan D, Graves E, ogdanov, Josephson L, Weissleder R. Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V-Cy5.5 conjugate. Proc Natl cad Sci U S 2004; 101: Jaffer F, Kim DE, Quinti L, Tung CH, ikawa E, Pande N, Kohler RH, Shi GP, Libby P, Weissleder R. Optical Visualization of Cathepsin K ctivity in therosclerosis With a Novel, Protease-ctivatable Fluorescence Sensor. Circulation 2007; 115: Fischer R, achle D, Fotin-Mleczek M, Jung G, Kalbacher H, 133

10 Kang EKim KMKwon IC rock R. targeted protease substrate for a quantitative determination of protease activities in the endolysosomal pathway. Chembiochem 2006; 7: remer C, Tung CH, Weissleder R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med 2001; 7: Lee S, Cha EJ, Park K, Lee SY, Hong JK, Sun IC, Kim SY, Choi K, Kwon IC, Kim K, hn CH. near-infrared-fluorescencequenched gold-nanoparticle imaging probe for in vivo drug screening and protease activity determination. ngew Chem Int Ed Engl 2008; 47: Lee S, Park K, Lee SY, Ryu JH, Park JW, hn HJ, Kwon IC, Youn IC, Kim K, Choi K. Dark quenched matrix metalloproteinase fluorogenic probe for imaging osteoarthritis development in vivo. ioconjug Chem 2008; 19: Lee S, Park K, Kim K, Choi K, Kwon IC. ctivatable imaging probes with amplified fluorescent signals. Chem Commun (Camb) 2008: Weissleder R, Tung CH, Mahmood U, ogdanov, Jr. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat iotechnol 1999; 17: Wunder, Tung CH, Muller-Ladner U, Weissleder R, Mahmood U. In vivo imaging of protease activity in arthritis: a novel approach for monitoring treatment response. rthritis Rheum 2004; 50: Law, Weissleder R, Tung C-H. Mechanism-ased Fluorescent Reporter for Protein Kinase Detection. ChemioChem 2005; 6: Rabin O, Manuel Perez J, Grimm J, Wojtkiewicz G, Weissleder R. n X-ray computed tomography imaging agent based on long-circulating bismuth sulphide nanoparticles. Nat Mater 2006; 5: Perez JM, Josephson L, O Loughlin T, Högemann D, Weissleder R. Magnetic relaxation switches capable of sensing molecular interactions. Nat iotechnol 2002; 20: von zur Muhlen C, von Elverfeldt D, Moeller J, Choudhury RP, Paul D, Hagemeyer CE, Olschewski M, ecker, Neudorfer I, assler N, Schwarz M, ode C, Peter K. Magnetic resonance imaging contrast agent targeted toward activated platelets allows in vivo detection of thrombosis and monitoring of thrombolysis. Circulation 2008; 118: Gao X, Yang L, Petros J, Marshall FF, Simons JW, Nie S. In vivo molecular and cellular imaging with quantum dots. Curr Opin iotechnol 2005; 16: Kamaly N, Kalber T, hmad, Oliver MH, So PW, Herlihy H, ell JD, Jorgensen MR, Miller D. imodal paramagnetic and fluorescent liposomes for cellular and tumor magnetic resonance imaging. ioconjug Chem 2008; 19: Mulder WJ, Castermans K, van eijnum JR, Oude Egbrink MG, Chin PT, Fayad Z, Lowik CW, Kaijzel EL, Que I, Storm G, Strijkers GJ, Griffioen W, Nicolay K. Molecular imaging of tumor angiogenesis using alphavbeta3-integrin targeted multimodal quantum dots. ngiogenesis Gerstl F, Windischberger C, Mitterhauser M, Wadsak W, Holik, Kletter K, Moser E, Kasper S, Lanzenberger R. Multimodal imaging of human early visual cortex by combining functional and molecular measurements with fmri and PET. Neuroimage 2008; 41: Choi JH, Nguyen FT, arone PW, Heller D, Moll E, Patel D, oppart S, Strano MS. Multimodal biomedical imaging with asymmetric single-walled carbon nanotube/iron oxide nanoparticle complexes. Nano Lett 2007; 7: Cheon J, Lee JH. Synergistically Integrated Nanoparticles as Multimodal Probes for Nanobiotechnology. cc Chem Res Nam HY, Park JH, Kwon IC. Polymer for ioimaging. Polymer Sci Technol 2008; 19: Peer Reviewers Commentary 134

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon