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

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.

L-Carnitine-conjugated nanoparticles to promote permeation across blood–brain barrier and to target glioma cells for drug delivery via the novel organic cation/carnitine transporter OCTN2

“…Of them, caveolin-dependent endocytosis was preferred by LC-PLGA NPs. The difference of endocytosis mechanism between PLGA NPs and LC-PLGA NPs might be due to the conjugation of L-carnitine [30,37]. These data strongly implicate that OCTN2-mediated endocytosis are involved in the cellular uptake of LC-PLGA NPs.…”

“…It has been suggested that the interaction of ligands with targets on cell surface mostly occurs through multivalent binding [26,30,38,39]. Therefore, it is reasonable that the PEG spacer length of ligand attached to nanoparticle surface would affect the binding of ligand to the target, and thus influence the target efficiency.…”

“…LC-PLGA NPs with different PEG spacer lengths (LC-0-PLGA NPs, LC-500-PLGA NPs, LC-1000-PLGA NPs, and LC-2000-PLGA NPs) and the unmodified nanoparticles (PLGA NPs) were prepared by the solvent extraction/ evaporation method [30]. Paclitaxel as a model drug and coumarin 6/DIR as a fluorescence probe were used to monitor the drug delivery efficiency of nanoparticles.…”

Ascorbate-conjugated nanoparticles for promoted oral delivery of therapeutic drugs via sodium-dependent vitamin C transporter 1 (SVCT1)

“…This strategy involves facilitative glucose transporter 1 (GLUT1and SLC2A1), Na þ /Cl À -coupled amino acid transporter (ATB 0,þ and SLC6A14), facilitative amino acid exchanger large neutral amino acid transporter (LAT1 and SLC7A5) and so on [14][15][16][17][18][19]. What's more, in the latest progress of our research, we found that L-carnitine-conjugated nanoparticles (LC-PLGA NPs) selectively targeted to organic cation transporter 2 (OCTN2 and SLC22A5) on the enterocytes for enhancing oral delivery of drugs [20][21][22]. The results greatly encouraged us that transporter-mediated NPs with specific ligands as a formulation hold potential for the application of orally administrated therapeutics.…”

Dual targeting ofl-carnitine-conjugated nanoparticles to OCTN2 and ATB0,+to deliver chemotherapeutic agents for colon cancer therapy

“…These findings suggest that the transporter protein is not recycled following endocytosis, but instead gets degraded. The endocytic mechanisms of LC-PLGA NPs have been investigated in our previous study (Kou et al, 2017), suggesting that clathrin-mediated, caveolin-mediated endocytosis, and macropinocytosis were involved in the endocytic process. Except for caveolin-mediated endocytosis, the endosomes containing nanoparticles and transporters would get fused with lysosomes for clathrin-mediated endocytosis and macropinocytosis, resulting in drug release and transporter degradation (Kou et al, 2013).…”