Dual targeting ofl-carnitine-conjugated nanoparticles to OCTN2 and ATB^0,+to deliver chemotherapeutic agents for colon cancer therapy

Abstract

l-Carnitine, obligatory for oxidation of fatty acids, is transported into cells by the Na-coupled transporter OCTN2 and the Na/Cl-coupled transporter ATB. Here we investigated the potential of L-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) to deliver chemotherapeutic drugs into cancer cells by targeting the nanoparticles to both OCTN2 and ATB. The cellular uptake of LC-PLGA NPs in the breast cancer cell line MCF7 and the colon cancer cell line Caco-2 was increased compared to unmodified nanoparticles, but decreased in the absence of co-transporting ions (Na and/or Cl) or in the presence of competitive substrates for the two transporters. Studies with fluorescently labeled nanoparticles showed their colocalization with both OCTN2 and ATB, confirming the involvement of both transporters in the cellular uptake of LC-PLGA NPs. As the expression levels of OCTN2 and ATB are higher in colon cancer cells than in normal colon cells, LC-PLGA NPs can be used to deliver chemotherapeutic drugs selectively into cancer cells for colon cancer therapy. With 5-fluorouracil-loaded LC-PLGA NPs, we were able to demonstrate significant increases in the uptake efficiency and cytotoxicity in colon cancer cells that were positive for OCTN2 and ATB. In a 3D spheroid model of tumor growth, LC-PLGA NPs showed increased uptake and enhanced antitumor efficacy. These findings indicate that dual-targeting LC-PLGA NPs to OCTN2 and ATB has great potential to deliver chemotherapeutic drugs for colon cancer therapy. Dual targeting LC-PLGA NPs to OCTN2 and ATB0,+ can selectively deliver chemotherapeutics to colon cancer cells where both transporters are overexpressed, preventing targeting to normal cells and thus avoiding off-target side effects.

Update on SLC6A14 in lung and gastrointestinal physiology and physiopathology: focus on cystic fibrosis

“…In rats, D'Argenio et al showed that experimental colitis induced a marked decrease in SLC6A14 transcript expression in the colon [69]. Finally, Kou et al found that colon cancer cell lines overexpressed SLC6A14 compared to normal colon cells [44].…”

Molecular Entrapment in Thermophilic Ferritin for Nanoformulation in Photodynamic Therapy

“…Fluorescence of encapsulated AO was observed 125 µm (16 cell layers) deep into the tumor cross section with a steep decrease thereby. In contrast, PLGA nanoparticles in HCT116 spheroid penetration study had peak fluorescence at 30 µm . Nanoparticle formulations have been shown to have better interactions with the tumor cells aiding in the penetration of drug molecules as opposed to the passive diffusion of drugs into the tumor cells .…”

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.…”