68Ga-Galmydar: A PET imaging tracer for noninvasive detection of Doxorubicin-induced cardiotoxicity.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Cardiotoxicity/*diagnostic imaging ; Coordination Complexes/*administration & dosage ; Doxorubicin/*adverse effects ; Positron Emission Tomography Computed Tomography/*methods; Animals ; Cardiotoxicity/metabolism ; Cell Line, Tumor ; Coordination Complexes/chemistry ; Coordination Complexes/pharmacokinetics ; Disease Models, Animal ; Rats ; Sensitivity and Specificity ; Tissue Distribution ; X-Ray Microtomography

Background: Cancer patients undergoing Doxorubicin (DOX) treatment are susceptible to acute and chronic cardiac anomalies, including aberrant arrhythmias, ventricular dysfunction, and heart failure. To stratify patients at high risk for DOX -related heart failure (CHF), diagnostic techniques have been sought. While echocardiography is used for monitoring LVEF and LV volumes due to its wide-availability and cost-efficiency, it may not identify early stages of the initiation of DOX-induced systolic heart failure. To address these limitations, PET tracers could also provide noninvasive assessment of early and reversible metabolic changes of the myocardium.
Objective: Herein, we report a preliminary investigation of 68Ga-Galmydar potential to monitor Dox-induced cardiomyopathy in vivo, ex vivo, and in cellulo employing both nuclear- and optical imaging.
Methods and Results: To assess 68Ga-Galmydar ability for monitoring DOX-induced cardiomyopathy, microPET imaging was performed 5 d post treatment of rats either with a single dose of DOX (15 mg/kg) or vehicle as a control (saline) and images were co-registered for anatomical reference using CT. Following tail-vein injection of the radiotracer in rats at 60 min, micro-PET/CT static scan (10 min acquisition), 68Ga-Galmydar demonstrated 1.91-fold lower uptake in hearts of DOX-treated (standard uptake value; SUV: 0.92, n = 3) rats compared with their vehicle treated (SUV: 1.76, n = 3) control counterparts. For correlation of PET imaging data, post-imaging quantitative biodistribution studies were also performed, wherein excised organs were counted for γ activity, and normalized to injected dose. The post imaging pharmacokinetic data also demonstrated heart uptake values of 2.0 fold lower for DOX treated rats(%ID/g; DOX: 0.44 ± 0.1, n = 3) compared to their vehicle-treated controls (%ID/g; Control: 0.89 ± 0.03, n = 3, p = 0.04). Employing the fluorescent traits of Galmydar, live cell fluorescence imaging indicated a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment, while indicating dose-dependent and time-dependent uptake profiles. Following depolarization of electronegative transmembrane gradients at the mitochondrial membrane, the uptake of the probe was decreased in H9c2 cells, and the uptake profiles were found to be identical, using both fluorescence and radiotracer bioassays. Finally, the decreased uptake of the metalloprobe in H9c2 cells also correlated with caspase-3 expression resulting from DOX-induced cardiotoxicity and cell death.
Conclusions: 68Ga-Galmydar could provide a noninvasive assessment of DOX-related and likely reversible metabolic changes at earliest stages. Further studies with other chemotherapeutics (potentially capable of inducing cardiomyopathy) are underway.
Competing Interests: The authors have declared that no competing interests exist.

Methods Enzymol. 2014;547:225-50. (PMID: 25416361)
Pharmacol Ther. 1990;47(2):219-31. (PMID: 2203071)
Ther Clin Risk Manag. 2010 Oct 05;6:463-83. (PMID: 20957139)
Future Oncol. 2012 Jun;8(6):697-702. (PMID: 22764767)
PLoS One. 2014 Oct 29;9(10):e109361. (PMID: 25353349)
Dalton Trans. 2010 Jul 7;39(25):5842-50. (PMID: 20505882)
Heart Lung Circ. 2010 Mar;19(3):193-209. (PMID: 20138581)
Nature. 2001 Jun 28;411(6841):1016. (PMID: 11429594)
Ann Nucl Med. 2005 May;19(3):197-200. (PMID: 15981672)
Br J Pharmacol. 2016 Jan;173(2):357-71. (PMID: 26507774)
Biochim Biophys Acta. 1992 Aug 17;1132(1):43-8. (PMID: 1380833)
J Oncol Pract. 2016 Mar;12(3):208-16. (PMID: 26962160)
Br J Cancer. 2013 Nov 12;109(10):2560-5. (PMID: 24136151)
Curr Treat Options Cardiovasc Med. 2014 Jun;16(6):315. (PMID: 24748018)
Bioconjug Chem. 2004 Nov-Dec;15(6):1464-74. (PMID: 15546216)
J Nucl Med. 1990 Apr;31(4):464-72. (PMID: 2324822)
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6542-7. (PMID: 16617111)
J Biol Chem. 1985 Nov 5;260(25):13844-50. (PMID: 4055760)
Horm Metab Res. 2008 Mar;40(3):210-3. (PMID: 18348081)
Hematology Am Soc Hematol Educ Program. 2007;:453-9. (PMID: 18024664)
World J Radiol. 2014 Jul 28;6(7):486-92. (PMID: 25071889)
Nat Med. 2012 Nov;18(11):1639-42. (PMID: 23104132)
React Oxyg Species (Apex). 2016;2(5):361-370. (PMID: 29721549)
Oncology (Williston Park). 2007 Nov;21(12):1503-8; discussion 1511, 1513, 1516 passim. (PMID: 18077994)
J Immunol. 2013 Apr 15;190(8):4196-204. (PMID: 23487424)
Anticancer Res. 2008 Jul-Aug;28(4C):2519-27. (PMID: 18751444)
Cancer Chemother Pharmacol. 1993;32(5):385-91. (PMID: 8339390)
Crit Rev Oncol Hematol. 1998 Jan;27(1):53-68. (PMID: 9548017)
Am J Physiol. 1996 Nov;271(5 Pt 2):H2079-85. (PMID: 8945928)
Cardiovasc Res. 2008 Jan 15;77(2):334-43. (PMID: 18006487)
Cell Cycle. 2014;13(9):1400-12. (PMID: 24626186)
Ann Oncol. 2017 Oct 1;28(10):2559-2566. (PMID: 28961837)
FEBS Lett. 2001 Mar 9;492(1-2):4-8. (PMID: 11248227)
Oncogene. 2002 Sep 5;21(39):6132-7. (PMID: 12203125)
Cell. 1997 Jun 27;89(7):1145-53. (PMID: 9215636)
Pharmacol Rev. 2004 Jun;56(2):185-229. (PMID: 15169927)
Curr Hypertens Rep. 2012 Dec;14(6):540-7. (PMID: 23001875)
Biochim Biophys Acta. 2016 Jul;1863(7 Pt B):1916-25. (PMID: 26828775)
Med Oncol. 2012 Jun;29(2):761-7. (PMID: 21298497)
J Biol Chem. 2006 Jul 14;281(28):19762-71. (PMID: 16679319)
J Inorg Biochem. 2016 Jun;159:159-64. (PMID: 27031494)
Med Pediatr Oncol. 2002 May;38(5):329-37. (PMID: 11979457)
J Clin Invest. 2014 Feb;124(2):617-30. (PMID: 24382354)
J Biol Chem. 1986 Mar 5;261(7):3060-7. (PMID: 3456345)
J Nucl Cardiol. 2004 Jan-Feb;11(1):71-86. (PMID: 14752475)
Cancer Res. 1983 Feb;43(2):460-72. (PMID: 6293697)
Clin Cancer Res. 2014 Sep 15;20(18):4873-81. (PMID: 24714774)
Medchemcomm. 2016 Nov 9;8(1):158-161. (PMID: 30108701)
Nucl Med Biol. 2016 Mar;43(3):191-7. (PMID: 26924499)
Exp Mol Med. 2006 Oct 31;38(5):535-45. (PMID: 17079870)
FEBS J. 2006 May;273(10):2077-99. (PMID: 16649987)
Semin Nucl Med. 2005 Jul;35(3):197-201. (PMID: 16098293)
Nature. 2009 Jul 16;460(7253):312-3. (PMID: 19606111)
Biochim Biophys Acta. 2011 Jun;1813(6):1144-52. (PMID: 21406203)
Lancet. 1978 Jun 24;1(8078):1367. (PMID: 78137)

R01 HL111163 United States HL NHLBI NIH HHS; R01 HL142297 United States HL NHLBI NIH HHS; R50 CA211466 United States CA NCI NIH HHS

0 (((ENB-3-isopropoxy-PIDMP)Ga(III)))
0 (Coordination Complexes)
80168379AG (Doxorubicin)

Date Created: 20190524 Date Completed: 20200114 Latest Revision: 20201214

20240829

PMC6532866

10.1371/journal.pone.0215579

31120912