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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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3,3-Diphenylpropylamido-indocyanine sulfonamide

VM315
, PhD
VisEn Medical, Woburn, MA, moc.lacidemnesiv@eyhdapojarm

Created: ; Last Update: January 26, 2007.

Chemical name:2-{5-[1,1-Dimethyl-6,8-disulfo-3-(3-sulfo-propyl)-1,3-dihydro-benzo[e]indol-2-ylidene]-penta-1,3-dienyl}-6-{[3-(3,3-diphenyl-propylcarbamoyl)-propyl]-methyl-sulfamoyl}-1,1-dimethyl-3-(3-sulfo-propyl)-1H-benzo[e]indoliumimage 17171982 in the ncbi pubchem database
Abbreviated name:3,3-Diphenylpropylamido-indocyanine sulfonamide
Synonym:VM315
Agent Category:Small molecule
Target:Albumin
Target Category:Binding
Method of detection:Near infrared fluorescence (NIRF)
Source of signal:NIR Fluorophore
Activation:Yes
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Near infrared fluorophores (NIRF), described for in vivo fluorescence imaging of disease (1, 2) have been generally classified into nonspecific enhancers (e.g. ICG (3)), molecularly targeted fluorochromes (e.g. RGD-Cy (4, 5) or enzyme activatable agents (e.g. cathepsin sensitive NIRF probes) (6). These agents have shown great potential for invivo imaging of specific molecular targets, biological processes and cells (7). Specific fluorophores have been used to image angiogenesis, apoptosis, protease activity, receptor status, macrophage activity and to track cells (2, 8).

Most of the affinity agents developed to date have molecular weights in excess of several thousand to millions (6, 9-11) to carry affinity ligands and/or to allow efficient quenching/de-quenching in large molecular weight constructs.

Small molecule fluorophores with affinity to albumin could potentially exhibit an increase in fluorescence upon binding; thus a family of “activatable” fluorophores could be developed that consequently would provide enhanced or superior in vivo target-to-background ratios in live animals. As proof-of-principal, VM315, an NIRF containing a 3,3-diphenylpropyl moiety that provides a structural feature capable of non-covalent albumin binding was developed and tested. Those studies showed that VM315 exhibited a remarkable increase in fluorescence upon albumin binding (12).

Such a molecule might be used to improve the detection of small cancers in vivo. Given the established role of fluorescent albumins in studying microvascular permeability in disease processes, VM315 may potentially represent a viable option for obtaining similar measurements clinically.

Synthesis

[PubMed]

VM315 was prepared by Montet et al. (12) as follows: VivoTag-S680® (1.1 mg, 1 µmol) and 3,3-diphenylpropylamine (1.1 mg, 5 µmol, Aldrich) were combined in approximately 100 µl of anhydrous DMF and kept at room temperature for one hour. The product of the reaction was then purified by RP-HPLC (25 mM triethylammonium acetate, pH 7, acetonitrile gradient) and isolated as a lyophilized solid (yield 90%). It was possible to complete the procedure of synthesis and purification in a day, with the time required for lyophilization dependent on the lyophilizer used. (ESI-MS m/e 1231.32065 [M]+: calculated for C59H67N4O15S5+, was 1231.3207).

In Vitro Studies

[PubMed]

In vitro studies (12) showed that VM315 was fully soluble in water with an octanol/water partition coefficient of 11%. The absorption maximum was found to be at 685 nm and the emission maximum at 705 nm.

The fluorescence emission of VM315 in saline and serum exhibited an increase of over 210% in fluorescence upon albumin binding. Additional experiments at variable concentrations confirmed that the fluorescence increase was not due to quenching effects at the baseline state that can occur with less water soluble indocyanines such as indocyanine green (13).

VM315 showed selective albumin binding with >90% (determined by HPLC) of fluorochrome attached at diagnostic concentrations. The compound did not bind to any other plasma proteins (e.g. globulins) as determined by gel chromatography. Ki and EC50 were not available, but the the combined vascular half-life was approximately 108 min, as determined by intravital confocal microscopy (12).

Animal Studies

Rodents

[PubMed]

Montet et al. (12) investigated the use of VM315 in detecting small cancers in rodents by performing a series of imaging studies using intravital confocal microscopy, reflectance fluorescence and tomography imaging on 25 mice (5 groups of 5) bearing Lewis lung carcinoma (LLC), rodent gliosarcoma (9 L) and human colon adenocarcinoma (CT26). The animals were injected intravenously with VM315 (130 nmol/kg bodyweight corresponding to 4 nmol/mouse) prior to imaging.

Intravital confocal microscopy images of normal microvasculature of the ear were first obtained and signal intensity (SI) was recorded inside a vessel; mono-exponential decay function was used to calculate the blood half-lives of the compounds. Results showed a rapid (1 minute) increase in vascular fluorescence followed by a further steady but slower increase over the subsequent 30 minutes, presumably due to “albumin activation”. Beyond 30 min, microvascular fluorescence slowly decreased due to elimination (T1/2 76 min). The apparent combined vascular half-life was found to be 108 min, and considerably longer than for other small molecule indocyanines (e.g. < 10 min for ICG). Over time, Montet et al. (12) observed a slow interstitial vascular leak, with kinetics similar to covalently FITC labeled albumins (14, 15).

Montet et al. (12) hypothesized that tumoral accumulation of brightly labeled serum albumin could be used as a marker for abnormal by enhanced permeability and retention (EPR effect) (19), and therefore studied the kinetics of tumoral accumulation of VM315 in a heterotopic CT26 colon cancer model, using reflectance fluorescence imaging. Serial images were obtained at 0.25, 5, 10, 20, 30, 60, 120, 240 and 1440 min after intravenous injection and SI was recorded for tumors and skin using a Cy5.5 channel. Regions of interest (ROI) were defined by the outlines of the tumor from the white light image and non-tumor ROIs were taken from adjacent skin. A third ROI was placed outside the animal to obtain the noise of the system. The tumor-to-background ratio (TBR) was calculated as: TBR = SItumor-noise / SIskin-noise. Results showed that VM315 exhibited a pronounced tumoral accumulation over time with maximum contrast values obtained 2 hours after intravenous injection. Maximum tumor-background ratio was 2, corresponding to a 290% increase in signal intensity over baseline.

In order to evaluate the extent of accumulation enabling the detection of small orthotopic tumors (< 3 mm in diameter) and a greater depth penetration and quantification, Montet et al. (12) performed fluorescence molecular tomography (FMT) imaging (16) - instead of surface weighted reflectance imaging - on nude mice bearing 9 L, LLC and CT26 tumors injected intravenously with VM315, for a 2 h time period. All tumors were detectable by FMT, and fluorochrome mapping results in similar amounts per tumor were found to be consistent with those performed on excised specimen. In vivo measurements (in pmol of fluorochrome per tumor of ~ 4 mm, ± 5-10%) were as follows: 68 for lung cancer (LLC), 143 for glioma (9 L), and 46 for colon cancer (CT26). Histology confirmed the presence of tumors and fluorescence microscopy, the presence of fluorochrome within individual lesions.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

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Ntziachristos V , Yodh AG , Schnall M , Chance B . Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement. Proc Natl Acad Sci U S A. 2000;97(6):2767–2772. [PMC free article: PMC16004] [PubMed: 10706610]
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Achilefu S , Bloch S , Markiewicz MA , Zhong T , Ye Y , Dorshow RB , Chance B , Liang K . Synergistic effects of light-emitting probes and peptides for targeting and monitoring integrin expression. Proc Natl Acad Sci U S A. 2005;102(22):7976–7981. [PMC free article: PMC1142399] [PubMed: 15911748]
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Licha K , Hessenius C , Becker A , Henklein P , Bauer M , Wisniewski S , Wiedenmann B , Semmler W . Synthesis, characterization, and biological properties of cyanine-labeled somatostatin analogues as receptor-targeted fluorescent probes. Bioconjug Chem. 2001;12(1):44–50. [PubMed: 11170364]
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Weissleder R , Tung CH , Mahmood U , Bogdanov A . In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat Biotechnol. 1999;17(4):375–378. [PubMed: 10207887]
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Ntziachristos V , Ripoll J , Wang LV , Weissleder R . Looking and listening to light: the evolution of whole-body photonic imaging. Nat Biotechnol. 2005;23(3):313–320. [PubMed: 15765087]
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Zhang J , Campbell RE , Ting AY , Tsien RY . Creating new fluorescent probes for cell biology. Nat Rev Mol Cell Biol. 2002;3(12):906–918. [PubMed: 12461557]
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Achilefu S . Lighting up tumors with receptor-specific optical molecular probes. Technol Cancer Res Treat. 2004;3(4):393–409. [PubMed: 15270591]
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Kircher MF , Mahmood U , King RS , Weissleder R , Josephson L . A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation. Cancer Res. 2003;63(23):8122–8125. [PubMed: 14678964]
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Kim S , Lim YT , Soltesz EG . A.M. De Grand, J. Lee, A. Nakayama, J.A. Parker, T. Mihaljevic, R.G. Laurence, D.M. Dor, L.H. Cohn, M.G. Bawendi, and J.V. Frangioni, Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol. 2004;22(1):93–97. [PMC free article: PMC2346610] [PubMed: 14661026]
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Montet X , Rajopadhye M , Weissleder R . An albumin-activated far-red fluorochrome for in vivo imaging. ChemMedChem. 2006;1(1):66–69. [PubMed: 16892337]
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Moody ED , Viskari PJ , Colyer CL . Non-covalent labeling of human serum albumin with indocyanine green: a study by capillary electrophoresis with diode laser-induced fluorescence detection. J Chromatogr B Biomed Sci Appl. 1999;729(1-2):55–64. [PubMed: 10410927]
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Lombry C , Bosquillon C , Preat V , Vanbever R . Confocal imaging of rat lungs following intratracheal delivery of dry powders or solutions of fluorescent probes. J Control Release. 2002;83(3):331–341. [PubMed: 12387942]
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Yuan F , Dellian M , Fukumura D , Leunig M , Berk DA , Torchilin VP , Jain RK . Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 1995;55(17):3752–3756. [PubMed: 7641188]
16.
Montet X , Ntziachristos V , Grimm J , Weissleder R . Tomographic fluorescence mapping of tumor targets. Cancer Res. 2005;65(14):6330–6336. [PubMed: 16024635]

This MICAD chapter is not included in the Open Access Subset, because it was authored / co-authored by one or more investigators who was not a member of the MICAD staff.

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