Insulin Hexamer-Caged Gadolinium Ion As MRI Contrast-o-phore

Overview

Journal Chemistry

Specialty Chemistry

Date 2018 Jun 7

PMID 29873848

Authors

Steven K Taylor

Timothy H Tran

Michael Z Liu

Paul E Harris

Yanping Sun

Sachin R Jambawalikar

Liang Tong

Milan N Stojanovic

Affiliations

Soon will be listed here.

Abstract

High-relaxivity protein-complexes of Gd are being pursued as MRI contrast agents in hope that they can be used at much lower doses that would minimize toxic-side effects of Gd release from traditional contrast agents. We construct here a new type of protein-based MRI contrast agent, a proteinaceous cage based on a stable insulin hexamer in which Gd is captured inside a water filled cavity. The macromolecular structure and the large number of "free" Gd coordination sites available for water binding lead to exceptionally high relaxivities per one Gd ion. The Gd slowly diffuses out of this cage, but this diffusion can be prevented by addition of ligands that bind to the hexamer. The ligands that trigger structural changes in the hexamer, SCN , Cl and phenols, modulate relaxivities through an outside-in signaling that is allosterically transduced through the protein cage. Contrast-o-phores based on protein-caged metal ions have potential to become clinical contrast agents with environmentally-sensitive properties.

References

Pu F, Xue S, Yang J . ProCA1.GRPR: a new imaging agent in cancer detection. Biomark Med. 2016; 10(5):449-52. PMC: 5493961. DOI: 10.2217/bmm-2016-0040. View

Raymond K, Pierre V . Next generation, high relaxivity gadolinium MRI agents. Bioconjug Chem. 2005; 16(1):3-8. DOI: 10.1021/bc049817y. View

Burton D, Forsen S, Karlstrom G, Dwek R, Mclaughlin A, Wain-Hobson S . Difficulties in determining accurate molecular motion parameters from proton relaxation enhancement measurements as illustrated by the immunoglobulin G-Gd(III) system. Eur J Biochem. 1976; 71(2):519-28. DOI: 10.1111/j.1432-1033.1976.tb11140.x. View

Berwick M, Slope L, Smith C, King S, Newton S, Gillis R . Location dependent coordination chemistry and MRI relaxivity, in designed lanthanide coiled coils. Chem Sci. 2018; 7(3):2207-2216. PMC: 5968752. DOI: 10.1039/c5sc04101e. View

Hill C, Dauter Z, Dodson E, Dodson G, Dunn M . X-ray structure of an unusual Ca2+ site and the roles of Zn2+ and Ca2+ in the assembly, stability, and storage of the insulin hexamer. Biochemistry. 1991; 30(4):917-24. DOI: 10.1021/bi00218a006. View

Ciszak E, Smith G . Crystallographic evidence for dual coordination around zinc in the T3R3 human insulin hexamer. Biochemistry. 1994; 33(6):1512-7. DOI: 10.1021/bi00172a030. View

Gulani V, Calamante F, Shellock F, Kanal E, Reeder S . Gadolinium deposition in the brain: summary of evidence and recommendations. Lancet Neurol. 2017; 16(7):564-570. DOI: 10.1016/S1474-4422(17)30158-8. View

Wagner A, Diez J, Schulze-Briese C, Schluckebier G . Crystal structure of ultralente--a microcrystalline insulin suspension. Proteins. 2008; 74(4):1018-27. DOI: 10.1002/prot.22213. View

Boros E, Gale E, Caravan P . MR imaging probes: design and applications. Dalton Trans. 2014; 44(11):4804-4818. PMC: 5155710. DOI: 10.1039/c4dt02958e. View

10.

Eads C, Mulqueen P, Horrocks Jr W, Villafranca J . Comparative study of glutamine synthetase bound lanthanide(III) ions using NMR relaxation and lanthanide(III) luminescence techniques. Biochemistry. 1985; 24(5):1221-6. DOI: 10.1021/bi00326a025. View

11.

Matsumoto Y, Jasanoff A . Metalloprotein-based MRI probes. FEBS Lett. 2013; 587(8):1021-9. PMC: 3716366. DOI: 10.1016/j.febslet.2013.01.044. View

12.

Armbruster D, Pry T . Limit of blank, limit of detection and limit of quantitation. Clin Biochem Rev. 2008; 29 Suppl 1:S49-52. PMC: 2556583. View

13.

Storm M, Dunn M . The Glu(B13) carboxylates of the insulin hexamer form a cage for Cd2+ and Ca2+ ions. Biochemistry. 1985; 24(7):1749-56. DOI: 10.1021/bi00328a027. View

14.

Dunn M . Zinc-ligand interactions modulate assembly and stability of the insulin hexamer -- a review. Biometals. 2005; 18(4):295-303. DOI: 10.1007/s10534-005-3685-y. View

15.

Pierre V, Allen M, Caravan P . Contrast agents for MRI: 30+ years and where are we going?. J Biol Inorg Chem. 2014; 19(2):127-31. PMC: 4075138. DOI: 10.1007/s00775-013-1074-5. View

16.

Pu F, Qiao J, Xue S, Yang H, Patel A, Wei L . GRPR-targeted Protein Contrast Agents for Molecular Imaging of Receptor Expression in Cancers by MRI. Sci Rep. 2015; 5:16214. PMC: 4649707. DOI: 10.1038/srep16214. View

17.

Heffern M, Matosziuk L, Meade T . Lanthanide probes for bioresponsive imaging. Chem Rev. 2013; 114(8):4496-539. PMC: 3999228. DOI: 10.1021/cr400477t. View

18.

Xue S, Qiao J, Jiang J, Hubbard K, White N, Wei L . Design of ProCAs (protein-based Gd(3+) MRI contrast agents) with high dose efficiency and capability for molecular imaging of cancer biomarkers. Med Res Rev. 2014; 34(5):1070-99. DOI: 10.1002/med.21313. View

19.

Alameda G, Evelhoch J, SUDMEIER J, Birge R . Characterization of the internal calcium(II) binding sites in dissolved insulin hexamer using europium(III) fluorescence. Biochemistry. 1985; 24(7):1757-62. DOI: 10.1021/bi00328a028. View

20.

Xue S, Yang H, Qiao J, Pu F, Jiang J, Hubbard K . Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging. Proc Natl Acad Sci U S A. 2015; 112(21):6607-12. PMC: 4450423. DOI: 10.1073/pnas.1423021112. View