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.
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.
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DOI：
10.1021/acs.molpharmaceut.2c01104
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发表时间：
2023-03-06
影响因子：
4.9
通讯作者：
Wang, Binghe
中科院分区：
文献类型：
--
作者：
Yang, Xiaoxiao;Tripathi, Ravi;Wang, Minjia;Lu, Wen;Anifowose, Abiodun;Tan, Chalet;Wang, Binghe
关键词：
一氧化碳（CO）是一种内源性信号分子，已知在各种动物模型中发挥一系列药理学作用，包括抗炎、器官保护和抗转移。我们先前已经显示了有机前药通过口服给药全身递送CO的能力。作为我们进一步开发这些前药的努力的一部分，我们感兴趣的是将前药的“载体”部分的潜在负面影响最小化。沿着这条线，我们以前已经发表了我们的工作，使用良性“载体”和物理陷阱的“载体”部分在胃肠道（GI）道。我们在此报告了我们的可行性研究，使用固定的有机CO前药口服CO交付，同时尽量减少全身暴露的前药和“载体部分”。在这样做时，我们将CO前药转化为二氧化硅微粒，其通常被美国FDA认为是安全的，并且已知提供用于负载和水可及性的大表面积。后一点对于CO前药的疏水性驱动的活化至关重要。显示与二氧化硅的基于酰胺化的缀合提供0.2mmol/g的负载度、在缓冲液中具有与母体前药相当的动力学的有效前药活化以及防止分离的稳定栓系。一种代表性的二氧化硅缀合物SICO-101显示在LPS攻击的RAW 264.7细胞中表现出抗炎活性，并通过口服给药和GI CO释放在小鼠中全身递送CO。我们设想这种策略作为口服CO递送治疗全身性和GI特异性炎症性疾病的一般方法。
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.
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DOI：
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发表时间：
2017-09-01
影响因子：
4.9
作者：
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