title: Aspartate-modified doxorubicin on its N-terminal increases drug accumulation in LAT1-overexpressing tumors.
abstract: L-type amino acid transporter 1 (LAT1), overexpressed on the membrane of various tumor cells, is a potential target for tumor-targeting therapy. This study aimed to develop a LAT1-mediated chemotherapeutic agent. We screened doxorubicin modified by seven different large neutral amino acids. The aspartate-modified doxorubicin (Asp-DOX) showed the highest affinity (Km = 41.423 μmol/L) to LAT1. Aspartate was attached to the N-terminal of DOX by the amide bond with a free carboxyl and a free amino group on the α-carbon atom of the Asp residue. The product Asp-DOX was characterized by HPLC/MS. In vitro, Asp-DOX exerted stronger inhibition on the cancer cells overexpressing LAT1 and the uptake of Asp-DOX was approximately 3.5-fold higher than that of DOX in HepG2 cells. Pharmacokinetic data also showed that Asp-DOX was expressed over a longer circulation time (t1/2 = 49.14 min) in the blood compared to DOX alone (t1/2 = 15.12 min). In HepG2 and HCT116 tumor-bearing mice, Asp-DOX achieved 3.1-fold and 6.4-fold accumulation of drugs in tumor tissue, respectively, than those of the unmodified DOX. More importantly, treatment of tumor-bearing mice with Asp-DOX showed a significantly stronger inhibition of tumor growth than mice treated with free DOX in HepG2 tumor models. Furthermore, after Asp modification, Asp-DOX avoided MDR mediated by P-glycoprotein. These results suggested that the Asp-DOX modified drug may provide a new treatment strategy for tumors that overexpress LAT1 and MDR1.
authors: School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.|State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Weidang
authors: W
authors: Wu
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.|Tianjin Medical University, Tianjin, China.
authors: Yan
authors: Y
authors: Dong
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Jing
authors: J
authors: Gao
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Min
authors: M
authors: Gong
authors: Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors: Xing
authors: X
authors: Zhang
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Weiling
authors: W
authors: Kong
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Yazhuo
authors: Y
authors: Li
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Yong
authors: Y
authors: Zeng
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Duanyun
authors: D
authors: Si
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Zihong
authors: Z
authors: Wei
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Xiaoyan
authors: X
authors: Ci
authors: Hefei Tianmai Biotechnology Development Co., Ltd, Hefei, China.
authors: Lixin
authors: L
authors: Jiang
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Wei
authors: W
authors: Li
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Quansheng
authors: Q
authors: Li
authors: State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
authors: Xiulin
authors: X
authors: Yi
authors: School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.|State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.|Tianjin University of Traditional Chinese Medicine, Tianjin, China.
authors: Changxiao
authors: C
authors: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D001224:Aspartic Acid / Q000737:chemistry*; D001692:Biological Transport; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000502:physiology*; D051379:Mice; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D027283:Large Neutral Amino Acid-Transporter 1; D001224:Aspartic Acid; D004317:Doxorubicin
keywords: Anticancer drugs; Asp-DOX; HepG2; LAT1; P-glycoprotein