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Abstract：
OCTN2 (SLC22A5) is a Na+ -coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na+ . Computational OCTN2 docking analysis shows that the presence of Na+ is important for the formation of the energetically stable intermediate complex of transporter-Na+ -LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter-mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles.
摘要：
OCTN2（SLC22A5）是小肠中1-肉碱的Na偶联吸收转运蛋白。这项研究测试了这种转运蛋白用于口服递送封装在l-肉碱缀合的聚(乳酸-共-乙醇酸)(PLGA)纳米颗粒(LC-PLGANP)中的治疗药物的潜力,并公开了转运蛋白靶向纳米颗粒的细胞内吞作用的分子机制。l-肉碱与PLGA-NP表面的缀合增强了被包封药物的细胞摄取和肠吸收。在这两种情况下，摄取过程取决于共转运离子Na+。计算OCTN2对接分析表明，Na的存在对于转运蛋白-Na-LC-PLGANP的能量稳定中间复合物的形成很重要，这也是纳米颗粒细胞内吞的第一步。转运蛋白介导的LC-PLGANP的肠吸收通过胞吞作用/胞吞作用而不是通过传统的跨膜转运发生。通过对照和淋巴管结扎大鼠中药物的血浆外观来评估门静脉血液与淋巴途径的关系。通过淋巴系统的吸收是NP口服递送的主要途径。总之,LC-PLGANP可以有效地靶向肠细胞上的OCTN2，以增强药物的口服递送，在设计靶向转运蛋白的纳米颗粒时应注意协同运动离子的关键作用。
