Design, synthesis, & biological evaluation of nanoparticle drug delivery systems.
Faraji-AH; Vlasova-II; Konduru-NV; Feng-W; Kagan-VE; Wipf-P
Toxicologist 2009 Mar; 108(1):182
The prevalence of nanotechnology in medicine has grown exponentially in recent years; moreover, intense exploration into the toxicology of nanomaterials has paralleled this growth. It is known that inorganic nanoparticles - such as those made from silica - catalyze the production of damaging free radicals. This undesirable toxicity limits the medical applications of inorganic nanoparticles. However, functionalization of the reactive nanoparticle surface may mask the potential for free radical generation. Free radical scavengers - in particular, 2,2,6,6-tetramethylpiperidine- N-oxyl (TEMPO) - may be covalently attached to nanoparticles via an acid-labile oxazoline moiety, which selectively hydrolyzes to release the antioxidant payload upon lysosomal incorporation. This new release strategy may increase the biocompatibility of inorganic nanoparticles via reduction of oxidative stress pathways. As an extension, the oxazoline release mechanism may be utilized to deliver a myriad of small molecule drugs, as it is amenable to drug attachment via peptide coupling and esterification. Silica nanoparticles were prepared and their surfaces were functionalized with the oxazoline-TEMPO antioxidant release system. In addition, the nanoparticles were conjugated to fluorescein, thus permitting to monitor subcellular localization via fluorescence microscopy. The nanoparticles were coated with phosphatidylserine to allow for efficient uptake. Macrophages (RAW264.7) were incubated with these nanoparticles; rapid and extensive uptake was seen within 0.5-1 hours. The nanoparticles concentrated in lysosomes and mitochondria, with a significant reduction in superoxide generation. In summary, the toxicity associated with inorganic nanoparticles may be mitigated by surface modification with small molecule antioxidants, thus increasing their biocompatibility and prevalence in medicine and drug delivery.
Absorption-rates; Antioxidants; Antioxidation; Biological-effects; Biological-factors; Chemical-hypersensitivity; Chemical-reactions; Drug-interaction; Exposure-assessment; Exposure-levels; Exposure-methods; Inorganic-compounds; Molecular-biology; Medical-research; Medical-treatment; Statistical-analysis; Nanotechnology
The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland
University of Pittsburgh at Pittsburgh