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Nanoparticle‐mediated delivery of tetrahydrobiopterin increases nitric oxide synthesis in diabetes
Author(s) -
Meininger Cynthia,
Rao Kavitha,
Vasir Jaspreet,
Dimitrijevic Sanja,
Bittenbinder David,
Li Xilong,
Kelly Katherine,
Wu Guoyao,
Labhasetwar Vinod
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.857.1
Subject(s) - tetrahydrobiopterin , nitric oxide , chemistry , bioavailability , nitric oxide synthase , high performance liquid chromatography , pharmacology , endothelial dysfunction , chromatography , endocrinology , medicine , organic chemistry
A deficiency of tetrahydrobiopterin (BH4), a critical cofactor for endothelial cell (EC) nitric oxide (NO) synthase, may be a common cause of vascular dysfunction in many diseases. Our goal was to augment BH4 levels in ECs in order to increase NO bioavailability and improve vascular function in streptozotocin‐induced diabetic rats. We encapsulated BH4 in biodegradable poly(D,L‐lactide‐co‐glycolide) nanoparticles (NPs) using an emulsion‐solvent evaporation method. Concentrations of BH4 in ECs and vessels were calculated using a reversed phase high‐performance liquid chromatography (HPLC) method after oxidation of samples under acidic and alkaline conditions, while nitrite levels were measured using an HPLC method developed in our lab. NO‐dependent relaxation of vessels was assessed by measuring the response to increasing concentrations of acetylcholine. NPs were taken up by ECs in a time‐and dose‐dependent fashion. BH4 levels in ECs and NO synthesis were increased after uptake of BH4‐loaded NPs. Importantly, BH4‐loaded NPs increased endothelium‐dependent vasodilatory responses of vessels from diabetic rats, demonstrating the ability of NP‐mediated BH4 delivery to restore vascular function. These studies support the feasibility of utilizing biodegradable NPs to deliver therapeutic agents to ECs to attenuate dysfunction associated with vascular disease. (Supported by NIH grant #HL093689).