The strawberry-derived permeation enhancer pelargonidin enables oral protein delivery.
The strawberry-derived permeation enhancer pelargonidin enables oral protein delivery.
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DOI：
10.1073/pnas.2207829119
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发表时间：
2022-08-16
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
据报道，数百万患者由于针头恐惧症或疼痛而跳过治疗注射，这导致疾病结果较差。尽管简单且无痛的蛋白质治疗剂口服给药将避免患者的犹豫和痛苦，但这是不可能的，因为肠对包括蛋白质在内的大分子是不可渗透的。在这里，我们证明了草莓色素天竺葵素可逆地透化肠上皮衬里，并使有效的口服蛋白质递送，而不会诱导炎症或组织损伤小鼠。虽然患者通常更喜欢口服药物递送而不是注射，但胃肠道的低渗透性使得这种方法对于大多数生物大分子来说是不可能的。一种潜在的解决方案是大分子，包括治疗性蛋白质或核酸，与肠渗透增强剂的共递送;然而，增强剂的使用在临床上受到围绕长期给药的适度功效和毒性问题的限制。在这里，我们假设胃肠道耐受性良好的植物性食物可能含有能够使口服大分子吸收而不会引起不良反应的化合物。在测试了100多种水果、蔬菜和草药后，我们发现草莓及其红色素天竺葵素是有效的、耐受性良好的肠道通透性增强剂。在小鼠中，包含天竺葵素和lU/kg剂量的胰岛素的口服胶囊制剂降低血糖水平超过4小时，相对于皮下注射，生物活性超过100%。作用在2小时内是可逆的，并与肌动蛋白和紧密连接重排。此外，每天给小鼠服用天竺葵素1个月，没有发现可检测到的副作用，包括体重减轻、组织损伤或炎症反应。这些数据表明，天竺葵素是一种非常有效的口服蛋白质摄取的增强剂，对于常规药物使用可能是安全的。
Millions of patients have reported skipping therapeutic injections due to needle phobia or pain, which leads to poorer disease outcomes. Although simple and painless oral administration of protein therapeutics would circumvent patient hesitancy and suffering, it has not been possible because the intestine is not permeable to macromolecules, including protein. Here, we demonstrate that the strawberry pigment pelargonidin reversibly permeabilizes the epithelial lining of the intestines and enables efficient oral protein delivery without inducing inflammation or tissue damage in mice. Although patients generally prefer oral drug delivery to injections, low permeability of the gastrointestinal tract makes this method impossible for most biomacromolecules. One potential solution is codelivery of macromolecules, including therapeutic proteins or nucleic acids, with intestinal permeation enhancers; however, enhancer use has been limited clinically by modest efficacy and toxicity concerns surrounding long-term administration. Here, we hypothesized that plant-based foods, which are well tolerated by the gastrointestinal tract, may contain compounds that enable oral macromolecular absorption without causing adverse effects. Upon testing more than 100 fruits, vegetables, and herbs, we identified strawberry and its red pigment, pelargonidin, as potent, well-tolerated enhancers of intestinal permeability. In mice, an oral capsule formulation comprising pelargonidin and a 1 U/kg dose of insulin reduced blood glucose levels for over 4 h, with bioactivity exceeding 100% relative to subcutaneous injection. Effects were reversible within 2 h and associated with actin and tight junction rearrangement. Furthermore, daily dosing of mice with pelargonidin for 1 mo resulted in no detectable side effects, including weight loss, tissue damage, or inflammatory responses. These data suggest that pelargonidin is an exceptionally effective enhancer of oral protein uptake that may be safe for routine pharmaceutical use.
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影响因子：
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