Nitric oxide (NO),
a pro-neurogenic and antineuroinflammatory 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(μ-SCH
2
CH
2
OH)
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.
Nitric oxide (NO) is an endogenous gasotransmitter regulating alternative physiological processes in the cardiovascular system. To achieve translational application of NO, continued efforts are made on the development of orally active NO prodrugs for long-term treatment of chronic cardiovascular diseases. Herein, immobilization of NO-delivery [Fe 2 (μ-SCH 2 CH 2 COOH) 2 (NO) 4 ] (DNIC-2) onto MIL-88B, a metal−organic framework (MOF) consisting of biocompatible Fe 3+ and 1,4-benzenedicarboxylate (BDC), was performed to prepare a DNIC@MOF microrod for enhanced oral delivery of NO. In simulated gastric fluid, protonation of the BDC linker in DNIC@MOF initiates its transformation into a DNIC@tMOF microrod, which consisted of DNIC-2 well dispersed and confined within the BDC-based framework. Moreover, subsequent deprotonation of the BDC-based framework in DNIC@tMOF under simulated intestinal conditions promotes the release of DNIC-2 and NO. Of importance, this discovery of transformer-like DNIC@MOF provides a parallel insight into its stepwise transformation into DNIC@ tMOF in the stomach followed by subsequent conversion into molecular DNIC-2 in the small intestine and release of NO in the bloodstream of mice. In comparison with acid-sensitive DNIC-2, oral administration of DNIC@MOF results in a 2.2-fold increase in the oral bioavailability of NO to 65.7% in mice and an effective reduction of systolic blood pressure (SBP) to a ΔSBP of 60.9 ± 4.7 mmHg in spontaneously hypertensive rats for 12 h.
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