Journal Article

Pharmaceutical Development and Safety Evaluation of a GMP-Grade Fucoidan for Molecular Diagnosis of Cardiovascular Diseases

Chollet, Lucas, Fülöp, Tamas, Chauvierre, Cédric, Cabella, Claudia, Maire, Murielle, Bussi, Simona, Zheng, Kang H., Letourneur, Didier, Aid-Launais, Rachida, Rolland, Lydia, Szebeni, Janos, Stroes, Erik S. G., Aerts, Joël, Chaubet, Frédéric, Rouzet, François, Le Guludec, Dominique, Rossi, Silvia, Dézsi, Laszlo, Bonafé, Roberta, Chahid, Youssef

2019

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Acids / Algae / Animals / Biocompatibility / Blood platelets / Cardiovascular disease / Cardiovascular diseases / Cell surface / Chloride / Disease Models, Animal / Diseases / Dose-Response Relationship, Drug / Drug Development / Endothelium / Epithelium / Evaluation / Female / Fractionation / Fucoidan / Galenic pharmacology / Good Manufacturing Practice / Heavy metals / Heparan sulfate / In vivo methods and tests / Ischemia / Life Sciences / Low molecular weights / Macromolecules / Male / Molecular Weight / Myocardial ischemia / Myocardial Reperfusion Injury / Myocardial Reperfusion Injury - diagnostic imaging / P-Selectin / P-Selectin - metabolism / Pharmaceutical sciences / Pharmaceuticals / Platelets / Polysaccharides / Polysaccharides - administration & dosage / Polysaccharides - toxicity / Radioactive tracers / Radioisotopes / Radiopharmaceuticals / Radiopharmaceuticals - administration & dosage / Radiopharmaceuticals - toxicity / Rats / Rats, Wistar / Reperfusion / Saccharides / Safety / Seaweeds / Swine / Technetium / Technetium - administration & dosage / Technetium isotopes / Toxicology