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Combination of l‑Carnitine with Lipophilic Linkage-Donating Gemcitabine Derivatives as Intestinal Novel Organic Cation Transporter 2‑Targeting Oral Prodrugs

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posted on 24.02.2017, 00:00 by Gang Wang, Hongxiang Chen, Dongyang Zhao, Dawei Ding, Mengchi Sun, Longfa Kou, Cong Luo, Dong Zhang, Xiulin Yi, Jinhua Dong, Jian Wang, Xiaohong Liu, Zhonggui He, Jin Sun
Novel organic cation transporter 2 (OCTN2, SLC22A5) is responsible for the uptake of carnitine through the intestine and, therefore, might be a promising molecular target for designing oral prodrugs. Poor permeability and rapid metabolism have greatly restricted the oral absorption of gemcitabine. We here describe the design of intestinal OCTN2-targeting prodrugs of gemcitabine by covalent coupling of l-carnitine to its N4-amino group via different lipophilic linkages. Because of the high OCTN2 affinity, the hexane diacid-linked prodrug demonstrated significantly improved stability (3-fold), cellular permeability (15-fold), and oral bioavailability (5-fold), while causing no toxicity as compared to gemcitabine. In addition, OCTN2-targeting prodrugs can simultaneously improve the permeability, solubility, and metabolic stability of gemcitabine. In summary, we present the first evidence that OCTN2 can act as a new molecular target for oral prodrug delivery and, importantly, the linkage carbon chain length is a key factor in modifying the affinity of the substrate for OCTN2.