In spinal cord injury (SCI), timely therapeutic intervention is critical to inhibit the post-injury rapidly progressing degeneration of spinal cord. Towards that objective, we determined the accessibility of intravenously administered biodegradable nanoparticles (NPs) as a drug delivery system to the lesion site in rat and pig contusion models of SCI. Poly (D,L-lactide co-glycolide, PLGA)-based NPs loaded with a near-infrared dye as a marker for NPs were used. To analyze and quantify localization of NPs to the lesion site, we mapped the entire spinal cord, segment-bysegment, for the signal count. Our objectives were to determine the NP dose effect and duration of retention of NPs at the lesion site, and the time window post-SCI within which NPs localize at the lesion site. We hypothesized that breakdown of the blood-spinal cord barrier following contusion injury could lead to more specific localization of NPs at the lesion site. The mapping data showed a dose-dependent increase and significantly greater localization of NPs at the lesion site than in the remaining uninjured segment of the spinal cord. Further, NPs were seen to be retained at the lesion site for more than a week. With delayed post-SCI administration, localization of NPs at the lesion site was reduced but still localize even at four weeks post-injury administration. Interestingly, in uninjured animals (sham control), greater accumulation of NPs was seen in the thoracic and lumbar enlargement regions of the spinal cord, which in animals with SCI changed to the lesion *

Titanium dioxide nanoparticles (TiONPs) are used in sunscreen products to protect the skin from the sun's ultraviolet rays. However, following exposure to sunlight, the photocatalytic activity of TiONPs can produce an excess of reactive oxygen species (ROS), causing skin cell damage, triggering an inflammatory response. In zebrafish model, we evaluated how well Pro-NP™ (biodegradable NPs containing superoxide dismutase and catalase) could protect them from TiONP-induced photo-oxidative stress. We hypothesized that the antioxidant properties of Pro-NP™ would protect zebrafish embryos from the phototoxic effects of TiONPs, improving overall survival and growth. Dechorionated embryos were treated with TiONPs alone or co-treated with Pro-NP™, and then exposed to simulated sunlight. Pro-NP™ by itself caused no toxicity; however, for embryos exposed to 100 μg/ml TiONPs, zebrafish survival was reduced to ∼40% and at 500 μg/ml to ∼10%. In contrast, at 100 μg/ml TiONP, co-treatment with Pro-NP™ increased zebrafish survival in a dose-dependent manner. Co-treatment also improved percent of embryos hatching and resulted in normal growth of zebrafish. On the other hand, embryos treated with TiONPs alone developed deformities, had reduced pigmentation, and showed severely truncated growth. Pro-NP™ afforded a greater level of protection against TiONP-induced phototoxicity than other antioxidants (vitamin E or N-acetylcysteine) commonly used in topical skin care formulations. We conclude that Pro-NP™ exert significant protective effects against TiONP-induced phototoxicity and could be developed as a safe, effective skin care product, used alone or in combination with sunscreen products to protect the skin from sun's UV radiation.

Our study presents a new method for tracking nanoparticle penetration through different layers of the skin using near-infrared dye-loaded nanoparticles (hydrodynamic diameter = 156 nm) and optical imaging. The dye-loaded nanoparticles were mixed in a topical skin cream, applied to human cadaver skin and incubated either for three or 24 h post-application, skin tissue was clipped between glass slides prior to imaging for signal intensity across the skin thickness using an optical imaging system. The data show that nanoparticles penetrate through all the layers of the skin but there is almost an exponential decay in the signal intensity from epidermis to dermis. Depending upon the incubation time, about 55%-59% of the total signal was seen in the epidermis and the remaining through dermis and hypodermis. The advantage of the method is that it allows quantitative analysis of the extent of penetration of nanoparticles through different layers of the skin without interference of any background signal from skin tissue, and without requiring extensive tissue processing. Our method could potentially be used to study the effect of nanoparticle properties and/or the use of different formulation additives on penetration of nanoparticles through different skin layers.

A deficiency of tetrahydrobiopterin (BH4), a critical cofactor for endothelial cell (EC) nitric oxide (NO) synthase, may be a common basis for vascular dysfunction in many diseases. Our goal was to modulate BH4 levels in ECs to increase NO bioavailability and improve vascular function in diabetes. We previously showed that BH4 encapsulated in poly(D,L‐lactide‐co‐glycolide) nanoparticles (NPs) and injected i.v. significantly improved vascular function in diabetic rats. In the current study, we synthesized solid lipid NPs (SLNPs) containing BH4. Our objective was to deliver BH4 to the systemic circulation via uptake and transit of SLNPs by the gastrointestinal lymphatics. SLNPs were administered via oral gavage once per day for 2 days (SLNPs) and endothelium‐dependent vessel relaxation assessed 24 hours later by measuring the response to increasing concentrations of acetylcholine. BH4 levels were determined using a reversed phase high‐performance liquid chromatography method. BH4‐loaded SLNPs taken up by cultured ECs increased cellular BH4 levels significantly, compared to vehicle/control NPs. Importantly, BH4‐loaded SLNPs increased vasodilatory responses of aortic rings taken from gavaged diabetic rats (maximal relaxation 75% vs. 55% in rats receiving control NPs). These data support the feasibility of oral NPs to deliver therapeutic agents to ECs in the general circulation via the lymphatic system. Grant Funding Source: Supported by AHA 11GRNT7930004 and NIH HL093689