Journal
JACS AU
Volume 1, Issue 7, Pages 998-1013Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacsau.1c00160
Keywords
nitric oxide; dinitrosyl iron complex; protein vehicle; drug delivery; neurogenesis
Categories
Funding
- Ministry of Science and Technology, Taiwan [MOST 1052815-C-033-007-B, MOST 108-2113-M-007-011, MOST 1092628-M-007-003-MY3, MOST 109-2622-M-007-003-CC2, MOST 109-2320-B-033-001]
- National Tsing Hua University, Taiwan [109Q2711E1, 110Q2711E1, 110Q2513E1]
- Chang Gung Memorial Hospital [CMRPG3J0511, CMRPG3G0031-3]
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The study explores the reversible interaction between the pro-neurogenic gasotransmitter NO prodrug DNIC-1 and serum albumin or gastrointestinal mucin as endogenous protein vehicles, providing a potential method for oral delivery of therapeutic NO to the brain against chronic neuropathy.
Nitric oxide (NO), a pro-neurogenic and antineur-oinflammatory gasotransmitter, features the potential to develop a translational medicine against neuropathological conditions. Despite the extensive efforts made on the controlled delivery of therapeutic NO, however, an orally active NO prodrug for a treatment of chronic neuropathy was not reported yet. Inspired by the natural dinitrosyl iron unit (DNIU) [Fe(NO)(2)], in this study, a reversible and dynamic interaction between the biomimetic [(NO)(2)Fe(mu-SCH2CH2OH)(2)Fe(NO)(2)] (DNIC-1) and serum albumin (or gastrointestinal mucin) was explored to discover endogenous proteins as a vehicle for an oral delivery of NO to the brain after an oral administration of DNIC-1. On the basis of the in vitro and in vivo study, a rapid binding of DNIC-1 toward gastrointestinal mucin yielding the mucin-bound dinitrosyl iron complex (DNIC) discovers the mucoadhesive nature of DNIC-1. A reversible interconversion between mucin-bound DNIC and DNIC-1 facilitates the mucus-penetrating migration of DNIC-1 shielded in the gastrointestinal tract of the stomach and small intestine. Moreover, the NO-release reactivity of DNIC-1 induces the transient opening of the cellular tight junction and enhances its paracellular permeability across the intestinal epithelial barrier. During circulation in the bloodstream, a stoichiometric binding of DNIC-1 to the serum albumin, as another endogenous protein vehicle, stabilizes the DNIU [Fe(NO)(2)] for a subsequent transfer into the brain. With aging mice under a Western diet as a disease model for metabolic syndrome and cognitive impairment, an oral administration of DNIC-1 in a daily manner for 16 weeks activates the hippocampal neurogenesis and ameliorates the impaired cognitive ability. Taken together, these findings disclose the synergy between biomimetic DNIC-1 and endogenous protein vehicles for an oral delivery of therapeutic NO to the brain against chronic neuropathy.
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