Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs’ physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that “hitchhike” onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future.

中文翻译：

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肠道淋巴生物学、药物递送和治疗：现状和未来方向


从历史上看，肠道淋巴管被认为是液体、免疫细胞、膳食脂质、脂溶性维生素和亲脂性药物的被动管道。20 世纪后期对肠道淋巴药物递送的研究主要集中在药物的物理化学特性上，尤其是导致肠道淋巴转运的高亲脂性。最近的发现改变了我们的传统观点，证明淋巴管在一系列生物和病理过程中（包括肠道内）是活跃的、可塑的和组织特异性的参与者。这些发现反过来又激发了对针对一系列疾病的淋巴特异性疗法的探索，以及开发更复杂的策略来主动将药物或疫苗输送到肠道淋巴液，包括一系列纳米技术、脂质前药和脂质偶联材料，这些材料“搭便车”到淋巴运输途径。随着生物制剂等新型疗法的不断发展，人们一直关注这些疗法在口服后是否通过肠道淋巴液吸收和运输。在这里，我们回顾了对健康和疾病中胃肠道淋巴系统的解剖学和生理学的理解现状，重点是与药物输送相关的方面。我们总结了当前最先进的给药方法并量化它们进入肠道淋巴系统的摄取。最后，令人兴奋的是，我们讨论了通过肠道淋巴药物递送实现显着药代动力学和治疗益处的最新例子。我们还提出了未来推进肠道淋巴输送策略开发和临床应用的方法。