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. 2015 Oct 20;6(32):33733-42.
doi: 10.18632/oncotarget.5254.

Imaging of carbonic anhydrase IX with an 111In-labeled dual-motif inhibitor

Xing Yang  1 , Il Minn  1 , Steven P Rowe  1 , Sangeeta Ray Banerjee  1 , Michael A Gorin  2 , Mary Brummet  1 , Hye Soo Lee  1 , Soo Min Koo  1 , Polina Sysa-Shah  1 , Ronnie C Mease  1 , Sridhar Nimmagadda  1 , Mohamad E Allaf  2 , Martin G Pomper  1
Affiliations

Imaging of carbonic anhydrase IX with an 111In-labeled dual-motif inhibitor

Xing Yang et al. Oncotarget. .

Abstract

We developed a new scaffold for radionuclide-based imaging and therapy of clear cell renal cell carcinoma (ccRCC) targeting carbonic anhydrase IX (CAIX). Compound XYIMSR-01, a DOTA-conjugated, bivalent, low-molecular-weight ligand, has two moieties that target two separate sites on CAIX, imparting high affinity. We synthesized [111In]XYIMSR-01 in 73.8-75.8% (n = 3) yield with specific radioactivities ranging from 118 - 1,021 GBq/μmol (3,200-27,600 Ci/mmol). Single photon emission computed tomography of [111In]XYIMSR-01 in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors revealed radiotracer uptake in tumor as early as 1 h post-injection. Biodistribution studies demonstrated 26% injected dose per gram of radioactivity within tumor at 1 h. Tumor-to-blood, muscle and kidney ratios were 178.1 ± 145.4, 68.4 ± 29.0 and 1.7 ± 1.2, respectively, at 24 h post-injection. Retention of radioactivity was exclusively observed in tumors by 48 h, the latest time point evaluated. The dual targeting strategy to engage CAIX enabled specific detection of ccRCC in this xenograft model, with pharmacokinetics surpassing those of previously described radionuclide-based probes against CAIX.

Keywords: CAIX; indium-111; molecular imaging; renal cell carcinoma; single photon emission computed tomography.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no relevant conflicts of interest.

Figures

Figure 1
Figure 1. Dual-motif CAIX-targeting small molecule labeled with FITC 8 binds to CAIX-expressing SK-RC-52 cells
A. Structure of 8. B. FACS analysis of 8 for binding to CAIX-negative BxPC3 cells (left) and CAIX-expressing SK-RC-52 cells (right). Compound 8 showed significant binding to CAIX-expressing SK-RC-52 cells at concentrations as low as 10 nM.
Figure 2
Figure 2. FITC-labeled 8 binds to the surface of CAIX-expressing SK-RC-52 cells
Fluorescence microscopic analyses of BxPC3 A and B, and SK-RC-52 C and D. Cells are non-labeled (A and C) and labeled with 8 (B and D). Compound 8 bound to the cell surface of SK-RC-52. Scale bar = 50 μm.
Figure 3
Figure 3. Compounds 1, XYIMSR-01 and [113/115In]XYIMSR-01 demonstrate high binding affinity to CAIX
IC50 values of positive control CAIX targeting agent 1 A. XYIMSR-01 B. and [113/115In]XYIMSR-01 C. were determined relative to the inhibition of fluorescence polarization of FITC labeled 8 with a known Kd of 0.2 nM for CAIX [27].
Figure 4
Figure 4. Compound 8 had higher binding affinity to CAIX compared to CAII and CAXII
Saturation binding curves for CAII, CAIX, and CAXII were generated. 5 nM of compound 8 was titrated by increasing concentrations of CAII, CAIX, and CAXII and the resultant fluorescence polarization (mP) was measured, with EC50 values calculated.
Figure 5
Figure 5. [111In]XYIMSR-01 enabled specific imaging of CAIX-expressing SK-RC-52 tumors
SPECT/CT imaging of two mice harboring CAIX-expressing SKRC-52 tumors within the lower left flank. Images were obtained at 1, 4, 8, 24 and 48 h after injection of 14.8 MBq (400 μCi) of [111In]XYIMSR-01 via the tail vein. Arrows indicate tumors.
None
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References

    1. Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, Hes O, Moch H, Montironi R, Tickoo SK, Zhou M, Argani P, Panel IRT. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. The American journal of surgical pathology. 2013;37:1469–1489. - PubMed
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: a cancer journal for clinicians. 2015;65:5–29. - PubMed
    1. Pichler M, Hutterer GC, Chromecki TF, Jesche J, Kampel-Kettner K, Eberhard K, Hoefler G, Pummer K, Zigeuner R. Trends of stage, grade, histology and tumour necrosis in renal cell carcinoma in a European centre surgical series from 1984 to 2010. Journal of clinical pathology. 2012;65:721–724. - PubMed
    1. Lipworth L, Morgans AK, Edwards TL, Barocas DA, Chang SS, Herrell SD, Penson DF, Resnick MJ, Smith JA, Clark PE. Renal cell cancer histologic subtype distribution differs by race and sex. BJU international. 2014 - PubMed
    1. Umbreit EC, Shimko MS, Childs MA, Lohse CM, Cheville JC, Leibovich BC, Blute ML, Thompson RH. Metastatic potential of a renal mass according to original tumour size at presentation. BJU international. 2012;109:190–194. discussion 194. - PubMed

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