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,Llactidecoglycolide) 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 endotheliumdependent vessel relaxation assessed 24 hours later by measuring the response to increasing concentrations of acetylcholine. BH4 levels were determined using a reversed phase highperformance liquid chromatography method. BH4loaded SLNPs taken up by cultured ECs increased cellular BH4 levels significantly, compared to vehicle/control NPs. Importantly, BH4loaded 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
