Endogenous Conjugation of Biomimetic Dinitrosyl Iron Complex with Protein Vehicles for Oral Delivery of Nitric Oxide to Brain and Activation of Hippocampal Neurogenesis

Cheng-Ru Wu; Yi-Da Huang; Yong-Huei Hong; Ya-Hsin Liu; Manmath Narwane; Yu-Hsiang Chang; Trinh Kieu Dinh; Hsin-Tzu Hsieh; Yi-Jen Hseuh; Ping-Ching Wu; Chih-Wen Pao; Ting-Shan Chan; I-Jui Hsu; Yunching Chen; Hung-Chi Chen; Ting-Yu Chin; Tsai-Te Lu

doi:10.1021/jacsau.1c00160

Endogenous Conjugation of Biomimetic Dinitrosyl Iron Complex with Protein Vehicles for Oral Delivery of Nitric Oxide to Brain and Activation of Hippocampal Neurogenesis

JACS Au. 2021 Jun 7;1(7):998-1013. doi: 10.1021/jacsau.1c00160. eCollection 2021 Jul 26.

Authors

Cheng-Ru Wu¹, Yi-Da Huang^{1

2}, Yong-Huei Hong¹, Ya-Hsin Liu¹, Manmath Narwane¹, Yu-Hsiang Chang¹, Trinh Kieu Dinh¹, Hsin-Tzu Hsieh¹, Yi-Jen Hseuh², Ping-Ching Wu³, Chih-Wen Pao⁴, Ting-Shan Chan⁴, I-Jui Hsu⁵, Yunching Chen¹, Hung-Chi Chen^{2

6}, Ting-Yu Chin⁷, Tsai-Te Lu¹

Affiliations

¹ Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
² Department of Ophthalmology and Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
³ Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
⁴ National Synchrotron Radiation Research Center, Hsinchu, Taiwan.
⁵ Department of Molecular Science and Engineering, Research and Development Center of Smart Textile Technology, National Taipei University of Technology, Taipei, Taiwan.
⁶ Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan, Taiwan.

Abstract

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)₂Fe(μ-SCH₂CH₂OH)₂Fe(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.