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.
Subject(s)
Myocardial Reperfusion Injury/diagnostic imaging , P-Selectin/metabolism , Polysaccharides/administration & dosage , Technetium/administration & dosage , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Development , Female , Male , Molecular Weight , Polysaccharides/toxicity , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/toxicity , Rats , Rats, Wistar , SwineABSTRACT
Development of an effective and potent RNA delivery system remains a challenge for the clinical application of RNA therapeutics. Herein, we describe the development of an RNA delivery platform derived from self-assembled bicontinuous cubic lyotropic liquid crystalline phases, functionalized with zinc coordinated lipids. These metallo-cubosomes were prepared from a series of novel lipidic zinc(II)-bis(dipicolylamine) (Zn2BDPA)) complexes admixed with glycerol monooleate (GMO). The zinc metallo-cubosomes showed the high affinity to siRNA through interaction between Zn2BDPA and the phosphate groups of RNA molecules. Using a combination of dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM), we demonstrated that a variety of Zn2BDPA lipid derivatives can be loaded into GMO cubosomes and the introduction of Zn2BDPA lipids effected an internal cubic phase transition of the resulting metallo-cubosomes. The findings of this study lay the foundations for the development of a new class of noncationic lipid-based encapsulation systems, metallo-cubosomes for RNA therapeutic delivery.
Subject(s)
Drug Delivery Systems , Glycerides/chemistry , Nanoparticles/chemistry , Organometallic Compounds/chemistry , Picolinic Acids/chemistry , RNA, Small Interfering/chemistry , A549 Cells , Animals , CHO Cells , Cell Survival/drug effects , Cricetulus , Dynamic Light Scattering , Gene Silencing , Humans , Microscopy, Electron, Transmission , Organometallic Compounds/chemical synthesis , Phase Transition , Picolinic Acids/chemical synthesis , Protein Binding , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/therapeutic use , Scattering, Small Angle , X-Ray DiffractionABSTRACT
Fucoidans are widespread cost-effective sulfated marine polysaccharides which have raised interest in the scientific community over last decades for their wide spectrum of bioactivities. Unsurprisingly, nanomedicine has grasped these compounds to develop innovative therapeutic and diagnostic nanosystems. The applications of fucoidans in nanomedicine as imaging agents, drug carriers or for their intrinsic properties are reviewed here after a short presentation of the main structural data and biological properties of fucoidans. The origin and the physicochemical specifications of fucoidans are summarized in order to discuss the strategy of fucoidan-containing nanosystems in Human health. Currently, there is a need for reproducible, well characterized fucoidan fractions to ensure significant progress.
