Ion delivery using alkali halide nanoparticles for tumor therapy and osteoarthritis treatment
Todd, Trever Jonathan
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Sodium chloride and lithium fluoride nanoparticles were synthesized and evaluated for their ability to kill cancer cells and protect chondrocytes from damage in osteoarthritis models, respectively. Sodium chloride nanoparticles were fabricated by two methods and yielded crystalline cubes that are colloidally stable in non-polar organic solvents. TEM, SEM, XRD, ICP-OES, EDS, and DLS were used to characterize the particles. The particles were endowed with aqueous stability using a phospholipid coating and subsequently introduced to tumor cells or injected into animals. Toxicity was observed in vitro with a LC50 of ~64 μg/mL Na+ added from the particles. Controls of PBS, aqueous NaCl, and free phospholipid showed no increased toxicity. Notably the toxicity is dependent on the duration the particles have been in solution. Particles that are immediately added into cells after dispersion in aqueous solution are significantly more toxic than particles that have been allowed to rest in solution. After 8 hours the particles are only minimally toxic and all observable affects are absent after 24 hours. The toxicity observed with the particles was found to proceed through a necrotic pathway, with only minimal contributions from apoptosis. Lithium fluoride nanoparticles were synthesized by a precipitation reaction in a mixed solvent system of ethylene glycol and poly(ethylene glycol). The particles were coated with a silica shell to protect from rapid aqueous degradation and attack by extracellular calcium. ICP-MS found that the coated particles slowly release lithium over the course of 48 hours. When added to chondrocytes in vitro, the particles down-regulated the expression of damaging cytokines MMP-1, -3, and -13. In vivo, the particles inhibited damage to the joint area in rat osteoarthritis models comparable to injection of 10x the concentration of aqueous LiCl. It was concluded that the slow release of lithium from the relatively large nanoparticles was responsible for the increased efficiency of therapeutic effect.