title: Enhanced delivery of liposomes to lung tumor through targeting interleukin-4 receptor on both tumor cells and tumor endothelial cells.
abstract: A growing body of evidence suggests that pathological lesions express tissue-specific molecular targets or biomarkers within the tissue. Interleukin-4 receptor (IL-4R) is overexpressed in many types of cancer cells, including lung cancer. Here we investigated the properties of IL-4R-binding peptide-1 (IL4RPep-1), a CRKRLDRNC peptide, and its ability to target the delivery of liposomes to lung tumor. IL4RPep-1 preferentially bound to H226 lung tumor cells which express higher levers of IL-4R compared to H460 lung tumor cells which express less IL-4R. Mutational analysis revealed that C1, R2, and R4 residues of IL4RPep-1 were the key binding determinants. IL4RPep-1-labeled liposomes containing doxorubicin were more efficiently internalized in H226 cells and effectively delivered doxorubicin into the cells compared to unlabeled liposomes. In vivo fluorescence imaging of nude mice subcutaneously xenotransplanted with H226 tumor cells indicated that IL4RPep-1-labeled liposomes accumulate more efficiently in the tumor and inhibit tumor growth more effectively compared to unlabeled liposomes. Interestingly, expression of IL-4R was high in vascular endothelial cells of tumor, while little was detected in vascular endothelial cells of control organs including the liver. IL-4R expression in cultured human vascular endothelial cells was also up-regulated when activated by a pro-inflammatory cytokine tumor necrosis factor-α. Moreover, the up-regulation of IL-4R expression was observed in primary human lung cancer tissues. These results indicate that IL-4R-targeting nanocarriers may be a useful strategy to enhance drug delivery through the recognition of IL-4R in both tumor cells and tumor endothelial cells.
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea; CMRI, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Lianhua
authors.initials: L
authors.lastname: Chi
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Moon-Hee
authors.initials: MH
authors.lastname: Na
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea; CMRI, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Jung
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea; CMRI, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Sri Murugan Poongkavithai
authors.initials: SM
authors.lastname: Vadevoo
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea; CMRI, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Cheong-Wun
authors.initials: CW
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea; CMRI, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Guruprasath
authors.initials: G
authors.lastname: Padmanaban
authors.affiliation: Department of Pathology, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Tae-In
authors.initials: TI
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Park
authors.affiliation: Dongsan Medical Center, Daegu, Republic of Korea.
authors.forename: Ilseon
authors.initials: I
authors.lastname: Hwang
authors.affiliation: Dongsan Medical Center, Daegu, Republic of Korea.
authors.forename: Keon Uk
authors.initials: KU
authors.lastname: Park
authors.affiliation: Industrial Technology Research Institute, HsinChu, Taiwan.
authors.forename: Frank
authors.initials: F
authors.lastname: Liang
authors.affiliation: Industrial Technology Research Institute, HsinChu, Taiwan.
authors.forename: Maggie
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Bio and Brain engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Jiho
authors.initials: J
authors.lastname: Park
authors.affiliation: Biomedical Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea; CMRI, Kyungpook National University, Daegu, Republic of Korea. Electronic address: leebh@knu.ac.kr.
authors.forename: Byung-Heon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D019948:Receptors, Interleukin-4 / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D009842:Oligopeptides; D019948:Receptors, Interleukin-4; D004317:Doxorubicin
keywords: IL-4 receptor; Liposomes; Lung tumor; Targeted drug delivery