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Abstract
The adhesion molecule P-selectin is present on the cell surface of both activated endothelium and activated platelets. The present study describes the pharmaceutical development, safety evaluation, and preclinical efficacy of a micro-dosed radiotracer. The macromolecular nanoscale assembly consisted of a natural compound made of a sulfated fucose-rich polysaccharides (fucoidan) and a radionuclide (technetium-99m) for the detection of P-selectin expression in cardiovascular diseases. After extraction and fractionation from brown seaweeds, the good manufacturing practice (GMP) production of a low molecular weight (LMW) fucoidan of 7 kDa was achieved and full physicochemical characterization was performed. The regulatory toxicology study in rats of the GMP batch of LMW fucoidan revealed no adverse effects up to 400 μg/kg (×500 higher than the expected human dose) and pseudoallergy was not seen as well. In a myocardial ischemia-reperfusion model in rats, the GMP-grade LMW fucoidan labeled with technetium-99m detected P-selectin upregulation in vivo. The present study supports the potential of using 99mTc-fucoidan as an imaging agent to detect activated endothelium in humans.
Highlights
Cardio- and neuro-vascular diseases are currently the leading cause of death world-wide, and their burden is likely to increase due to ageing of the population and the rising prevalence of metabolicMar
We report here the pharmaceutical development and preclinical evaluation of a micro-dosed radiotracer based on the macromolecular assembly at nanoscale of a natural compound extracted from brown algae (Ascophyllum nodosum) consisting of a sulfated fucose-rich polysaccharides and a radionuclide for the molecular diagnosis of cardiovascular diseases
Depolymerization and purification processes, we obtained the monographs of the raw material (API) and the good manufacturing practice (GMP) batch with a full characterization of the main constituents since the mass balance is close to 100%
Summary
Mar. Drugs 2019, 17, 699; doi:10.3390/md17120699 www.mdpi.com/journal/marinedrugs. Mar. Drugs 2019, 17, 699 disorders such as diabetes and obesity [1]. Despite the development of potent cardiovascular prevention regimens and early endovascular and surgical interventions, coronary artery disease (CAD), and stroke remains associated with high mortality and morbidity [2]. Since atherosclerosis is a silent and asymptomatic disease until its clinical sequelae, early diagnosis is mandatory to reduce cardiovascular risk and prevent irreversible damage. Molecular imaging is a promising tool based on a contrast agent designed to recognize a molecular target of interest and to bind it [3] Adhesion molecules, such as selectins, persist on the endothelial surface after ischemia has resolved. They represent a tissue ‘imprint’ of the prior ischemic event, referred to as ‘ischemic memory’ [4]
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