Depolymerizing self-immolative polymeric lanthanide chelates for vascular imaging

Eric Grolman; Quinton E A Sirianni; Joy Dunmore-Buyze; Charmainne Cruje; Maria Drangova; Elizabeth R Gillies

doi:10.1016/j.actbio.2023.07.034

Depolymerizing self-immolative polymeric lanthanide chelates for vascular imaging

Acta Biomater. 2023 Oct 1:169:530-541. doi: 10.1016/j.actbio.2023.07.034. Epub 2023 Jul 27.

Authors

Eric Grolman¹, Quinton E A Sirianni², Joy Dunmore-Buyze³, Charmainne Cruje⁴, Maria Drangova⁵, Elizabeth R Gillies⁶

Affiliations

¹ School of Biomedical Engineering, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B9, Canada; Robarts Research Institute, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
² Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
³ Robarts Research Institute, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
⁴ Department of Medical Biophysics, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5C1, Canada.
⁵ School of Biomedical Engineering, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B9, Canada; Robarts Research Institute, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada; Department of Medical Biophysics, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5C1, Canada. Electronic address: mdrangova@robarts.ca.
⁶ School of Biomedical Engineering, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B9, Canada; Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada; Department of Chemical and Biochemical Engineering, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B9, Canada. Electronic address: egillie@uwo.ca.

PMID: 37507034
DOI: 10.1016/j.actbio.2023.07.034

Abstract

Medical imaging is widely used clinically and in research to understand disease progression and monitor responses to therapies. Vascular imaging enables the study of vascular disease and therapy, but exogenous contrast agents are generally needed to distinguish the vasculature from surrounding soft tissues. Lanthanide-based agents are commonly employed in MRI, but are also of growing interest for micro-CT, as the position of their k-edges allows them to provide enhanced contrast and also to be employed in dual-energy micro-CT, a technique that can distinguish contrast-enhanced blood vessels from tissues such as bone. Small molecule Gd³⁺ chelates are available, but are excreted too rapidly. At the same time, a lack of rapid clearance from the body for long-circulating agents presents toxicity concerns. To address these challenges, we describe here the use of self-immolative polymers for the development of new degradable chelates that depolymerize completely from end-to-end following the cleavage of a single end-cap from the polymer terminus. We demonstrate that tuning the end-cap allows the rate of depolymerization to be controlled, while tuning the polymer length enables the polymer to exhibit long circulation times in the blood of mice. After successfully providing one hour of blood contrast, depolymerization led to excretion of the resulting small molecule chelates into the bladder. Despite the high doses required for micro-CT, the agents were well tolerated in mice. Thus, these self-immolative polymeric chelates provide a new platform for the development of medical imaging contrast agents. STATEMENT OF SIGNIFICANCE: Vascular imaging is used clinically to diagnose and monitor vascular disease and in research to understand the progression of disease and study responses to new therapies. For techniques such as magnetic resonance imaging and x-ray computed tomography (CT), long circulating contrast agents are needed to differentiate the vasculature from surrounding tissues. However, if these agents are not rapidly excreted from the body, they can lead to toxicity. We present here a new polymeric system that can chelate hundreds of lanthanide ions for imaging contrast and can circulate for one hour in the blood, but then after end-cap cleavage breaks down completely into small molecules for excretion. The successful application of this system in micro-CT in mice is demonstrated.

Keywords: Contrast agent; Degradable; Imaging; Self-immolative; X-ray computed tomography.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chelating Agents
Contrast Media / pharmacology
Lanthanoid Series Elements*
Mice
Polymers
Tomography, X-Ray Computed
Vascular Diseases*

Substances

Lanthanoid Series Elements
Contrast Media
Chelating Agents
Polymers