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Cotransporting Ion is a Trigger for Cellular Endocytosis of Transporter‐Targeting Nanoparticles: A Case Study of High‐Efficiency SLC22A5 (OCTN2)‐Mediated Carnitine‐Conjugated Nanoparticles for Oral Delivery of Therapeutic Drugs
Author(s) -
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
Publication year - 2017
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.201700165
Subject(s) - endocytosis , transcytosis , plga , drug delivery , biophysics , chemistry , materials science , nanoparticle , nanotechnology , biochemistry , receptor , biology
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.