1. Pharmaceutical Development and Safety Evaluation of a GMP-Grade Fucoidan for Molecular Diagnosis of Cardiovascular Diseases
- Author
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Chauvierre, Cédric, Aid-Launais, Rachida, Aerts, Joël, Chaubet, Frederic, Maire, Murielle, Chollet, Lucas, Rolland, Lydia, Bonafé, Roberta, Rossi, Silvia, Bussi, Simona, Cabella, Claudia, Dézsi, Laszlo, Fulop, Tamas, Szebeni, Janos, Chahid, Youssef, Zheng, Kang, Stroes, Erik, Le Guludec, Dominique, Rouzet, François, Letourneur, Didier, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Pharmacy, Radiology and Nuclear Medicine, Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Recherche en Imagerie Multimodalité [Paris] (UMS34 FRIM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bracco Research SpA, Bracco, Semmelweis University [Budapest, Hungary], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Service de Médecine Nucléaire [Paris 18eme], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
- Subjects
Male ,regulatory toxicology ,MESH: Rats ,Swine ,[SDV]Life Sciences [q-bio] ,Myocardial Reperfusion Injury ,Article ,MESH: Dose-Response Relationship, Drug ,Drug Development ,Polysaccharides ,molecular diagnosis ,Animals ,scintigraphy ,MESH: Animals ,Rats, Wistar ,MESH: Swine ,ComputingMilieux_MISCELLANEOUS ,MESH: Drug Development ,Dose-Response Relationship, Drug ,MESH: Molecular Weight ,GMP-grade fucoidan ,scintigraphy, regulatory toxicology, molecular diagnosis, GMP-grade fucoidan ,Technetium ,MESH: Rats, Wistar ,MESH: Male ,MESH: Myocardial Reperfusion Injury ,Rats ,Molecular Weight ,Disease Models, Animal ,P-Selectin ,[SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology ,MESH: Polysaccharides ,MESH: P-Selectin ,MESH: Technetium ,Female ,Radiopharmaceuticals ,MESH: Disease Models, Animal ,MESH: Female ,MESH: Radiopharmaceuticals - 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 &mu, g/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.
- Published
- 2019