| Autor: |
Kou, Longfa, Yao, Qing, Sun, Mengchi, Wu, Chunnuan, Wang, Jia, Luo, Qiuhua, Wang, Gang, Du, Yuqian, Fu, Qiang, Wang, Jian, He, Zhonggui, Ganapathy, Vadivel, Sun, Jin |
| Zdroj: |
Advanced Healthcare Materials; September 2017, Vol. 6 Issue: 17 |
| Abstrakt: |
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. Cotransporting ion, Na+,is found as a trigger for the proceeding of l‐carnitine‐conjugated poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (LC‐PLGA NPs) targeting to Na+‐coupled organic cation/carnitine transporter 2 (OCTN2). In this case, LC‐PLGA NPs and Na+bind to specific binding sites of OCTN2, and then initiate the conformation change from outward‐facing to occluded state to form an energetically stable intermediate complex (OCTN2‐Na+‐LC‐PLGA NPs). The complex induces membrane invagination and the following endocytosis. |
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