Transporter occluded-state conformation-induced endocytosis: Amino acid transporter ATB0,+-mediated tumor targeting of liposomes for docetaxel delivery for hepatocarcinoma therapy.
Rapidly proliferating tumor cells upregulate specific amino acid transporters, which hold great potential for tumor-selective drug delivery. Published reports have focused primarily on blocking these transporters as a means of starving the tumor cells of amino acids, but their potential in drug delivery remains understudied. In the present study, we developed liposomes functionalized with lysine and polyoxyethylene stearate conjugate (LPS) to interact with ATB0,+, an amino acid transporter overexpressed in hepatocarcinoma and the liver cancer cell line HepG2. The LPS modified liposomes (LPS-Lips) were ~100nm in size and exhibited high drug encapsulation efficiency as 94.7%. The uptake of LPS-Lips in HepG2 cells was dependent on Na+and Cl-. Molecular dynamic simulation showed that a sustained occluded state of the transporter upon binding to co-transported ions was formed and LPS-Lips triggered the cellular internalization of liposomes. We loaded these LPS-Lips with docetaxel and evaluated the potential of ATB0,+-mediated endocytosis of the drug-loaded LPS-Lips in HepG2 cells in vitro and in syngeneic mouse transplants in vivo. Compared with unmodified liposomes, which did not interact with ATB0,+, LPS-Lips exhibited the ability to deliver docetaxel more efficiently into tumor cells with consequent greater antitumor efficacy and less systemic toxicity. These studies provide first evidences that ATB0,+can be used as a novel and effective target for drug delivery system in tumor cells using chemically modified liposomes for loading with chemotherapeutics and targeting them for the transporter-mediated endocytosis. As ATB0,+is highly upregulated in several cancers, this approach holds potential for tumor-selective delivery of drugs to treat these cancer types.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China.
Qiuhua
Q
Luo
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China.
Ping
P
Gong
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China.
Mengchi
M
Sun
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China.
Longfa
L
Kou
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Vadivel
V
Ganapathy
Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Yongkui
Y
Jing
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China. Electronic address: hezhgui_student@aliyun.com.
Zhonggui
Z
He
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China; Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang, 110016, China. Electronic address: sunjin0529@aliyun.com.
Jin
J
Sun
D026962:Amino Acid Transport System ASC / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D000077143:Docetaxel; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes; D008113:Liver Neoplasms / Q000188:drug therapy*; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity
D026962:Amino Acid Transport System ASC; D000970:Antineoplastic Agents; D008081:Liposomes; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human; D043823:Taxoids; C526284:polyoxyethylene 40 stearate; D000077143:Docetaxel; D011092:Polyethylene Glycols; D008239:Lysine
ATB(0,+); Cancer therapy; Liposomes; Transporter-mediated endocytosis; Tumor-selective drug delivery