Toward "CO in a Pill" : Silica-Immobilized Organic CO Prodrugs for Studying the Feasibility of Systemic Delivery of CO via In Situ Gastrointestinal CO Release
Carbon monoxide (CO), an endogenous signaling molecule, is known to exert a range of pharmacological effects, including anti-inflammation, organ protection, and antimetastasis in various animal models. We have previously shown the ability of organic prodrugs to deliver CO systemically through oral administration. As part of our efforts for the further development of these prodrugs, we are interested in minimizing the potential negative impact of the "carrier" portion of the prodrug. Along this line, we have previously published our work on using benign "carriers" and physically trapping the "carrier" portion in the gastrointestinal (GI) tract. We herein report our feasibility studies on using immobilized organic CO prodrugs for oral CO delivery while minimizing systemic exposure to the prodrug and the "carrier portion." In doing so, we immobilize a CO prodrug to silica microparticles, which are generally recognized as safe by the US FDA and known to provide large surface areas for loading and water accessibility. The latter point is essential for the hydrophobicity-driven activation of the CO prodrug. Amidation-based conjugation with silica is shown to provide 0.2 mmol/g loading degree, effective prodrug activation in buffer with comparable kinetics as the parent prodrug, and stable tethering to prevent detachment. One representative silica conjugate, SICO-101, is shown to exhibit anti-inflammation activity in LPS-challenged RAW264.7 cells and to deliver CO systemically in mice through oral administration and GI CO release. We envision this strategy as a general approach for oral CO delivery to treat systemic and GI-specific inflammatory conditions.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Molecular pharmaceutics - 20(2023), 3 vom: 06. März, Seite 1850-1856 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Xiaoxiao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.03.2023 Date Revised 24.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.molpharmaceut.2c01104 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM353090980 |
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| 520 | |a Carbon monoxide (CO), an endogenous signaling molecule, is known to exert a range of pharmacological effects, including anti-inflammation, organ protection, and antimetastasis in various animal models. We have previously shown the ability of organic prodrugs to deliver CO systemically through oral administration. As part of our efforts for the further development of these prodrugs, we are interested in minimizing the potential negative impact of the "carrier" portion of the prodrug. Along this line, we have previously published our work on using benign "carriers" and physically trapping the "carrier" portion in the gastrointestinal (GI) tract. We herein report our feasibility studies on using immobilized organic CO prodrugs for oral CO delivery while minimizing systemic exposure to the prodrug and the "carrier portion." In doing so, we immobilize a CO prodrug to silica microparticles, which are generally recognized as safe by the US FDA and known to provide large surface areas for loading and water accessibility. The latter point is essential for the hydrophobicity-driven activation of the CO prodrug. Amidation-based conjugation with silica is shown to provide 0.2 mmol/g loading degree, effective prodrug activation in buffer with comparable kinetics as the parent prodrug, and stable tethering to prevent detachment. One representative silica conjugate, SICO-101, is shown to exhibit anti-inflammation activity in LPS-challenged RAW264.7 cells and to deliver CO systemically in mice through oral administration and GI CO release. We envision this strategy as a general approach for oral CO delivery to treat systemic and GI-specific inflammatory conditions | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CO prodrug | |
| 650 | 4 | |a anti-inflammation | |
| 650 | 4 | |a carbon monoxide | |
| 650 | 4 | |a gaseous signaling molecule | |
| 650 | 4 | |a oral administration | |
| 650 | 4 | |a silica gel immobilization | |
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| 700 | 1 | |a Wang, Minjia |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Anifowose, Abiodun |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Chalet |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Binghe |e verfasserin |4 aut | |
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