Enhanced Oral NO Delivery through Bioinorganic Engineering of Acid-Sensitive Prodrug into a Transformer-like DNIC@MOF Microrod

Yong Huei Hong, Manmath Narwane, Lawrence Yu Min Liu, Yi Da Huang, Chieh Wei Chung, Yi Hong Chen, Bo Wen Liao, Yu Hsiang Chang, Cheng Ru Wu, Hsi Chien Huang, I. Jui Hsu, Ling Yun Cheng, Liang Yi Wu, Yu Lun Chueh, Yunching Chen, Chia Her Lin, Tsai Te Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

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 [Fe2(μ-SCH2CH2COOH)2(NO)4] (DNIC-2) onto MIL-88B, a metal–organic framework (MOF) consisting of biocompatible Fe3+ 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.

Original languageEnglish
Pages (from-to)3849-3863
Number of pages15
JournalACS Applied Materials and Interfaces
Volume14
Issue number3
DOIs
Publication statusPublished - 2022 Jan 26

Keywords

  • bioinorganic engineering
  • dinitrosyl iron complexes
  • metal−organic framework
  • nitric oxide
  • oral delivery

ASJC Scopus subject areas

  • General Materials Science

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