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Toita R.,Innovation Center for Medical Redox Navigation | Toita R.,Osaka University | Murata M.,Innovation Center for Medical Redox Navigation | Murata M.,Kyushu University | And 5 more authors.
Bioconjugate Chemistry | Year: 2012

We described herein a human hepatocellular carcinoma (HCC) cell-targeted protein cage for which the HCC-binding peptide termed SP94 was modified at the surface of a naturally occurred heat shock protein (Hsp) cage. Six types of HCC-targeted Hsp cages were chemically synthesized using two types of heterobifunctional linker (SM(PEG)n) with different lengths and two types of SP94 peptide, which contained a unique Cys residue at the N- or C-terminus of the peptide. These Hsp cages were characterized using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-ToF MS) analyses, sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analyses, and dynamic light scattering (DLS) measurement. Fluorescence microscopic observations revealed that all the engineered protein cages bind selectively to HCC cells but not to the other cell lines tested (including normal liver cell). Moreover, the number of SP94 peptides on Hsp cages, conjugation site of SP94 peptide, and linker length between a Hsp cage and a SP94 peptide had important effects upon the binding of engineered Hsp cages to HCC cells. An engineered Hsp cage conjugated to the N-terminus of SP94 peptide via a longer linker molecule and containing high SP94 peptide levels showed greater binding toward HCC cells. Surprisingly, through optimization of these three factors, up to 10-fold greater affinity toward HCC cells was achieved. These results are critically important not only for the development of HCC cell-targeting devices using SP94 peptide, but also to create other cell-targeting materials that utilize other peptide ligands. © 2012 American Chemical Society.

Inoue T.,Labour Welfare Corporation | Inoue T.,Kyushu University | Kobayashi K.,Kyushu University | Katsuragi T.,Labour Welfare Corporation | And 6 more authors.
Diabetology International | Year: 2011

A 75-year-old woman with a history of type 2 diabetes mellitus was admitted to our hospital with symptoms of asthenia. Laboratory results demonstrated a severe inflammatory response, abnormal kidney function, and hyperglycemia. Electrocardiography revealed atrial fibrillation. The patient was treated with antibiotics and insulin injection upon admission, and laboratory data relating to inflammation, kidney, and blood glucose level gradually improved. On the 4th day of hospitalization, chest contrast-enhanced computed tomography showed the existence of masses in both atria and the right pulmonary artery. The differential diagnosis of the left atrial mass included a thrombus and a neoplasm, such as an atrial myxoma. Because surgical removal of the masses, presumed to be thrombi, was declined by the patient, anticoagulation therapy (heparin i. v. followed by warfarin) was initiated. After 12 months of anticoagulation therapy, the masses disappeared completely without systemic embolization. © 2011 The Japan Diabetes Society.

Iwasaki H.,Kyushu University | Nakano K.,Innovation Center for Medical Redox Navigation | Shinkai K.,Kyushu University | Kunisawa Y.,Innovation Center for Medical Redox Navigation | And 4 more authors.
Cancer Science | Year: 2013

Hedgehog signal is re-activated in several cancers. In this study, we examined the role of Gli3 on malignant phenotype of tumorigenicity for colorectal cancer and its relationship with p53, WNT and ERK/AKT signals. Gli3 expression was detected in HT29 and SW480 (p53-mutant) cells, but not in DLD-1 (p53-mutant) or HCT116 (p53-wild type) cells by reverse transcription-polymerase chain reaction and immunocytochemistry. Full-length Gli3 transfection increased anchor-independent growth for all cells regardless of p53 status, with upregulation of adhesion-related genes. Exogenous Sonic-Hedgehog increased activator-type of Gli3 and colony formation in Gli3-positive HT29 and SW480 cells. After implantation of Gli3-FL or mock-transfectant DLD-1 cells into SCID mice, tumor formation was highly observed in only Gli3-FL-transfectant group. In clinical specimens, Gli3 expression was detected in subsets of colorectal cancer and related with poorly-differentiated histological type, while Sonic-Hedgehog was present with high incidence. In conclusion, activator Gli3 signal augments tumorigenicity of colorectal cancer irrespective of p53 status. © 2012 Japanese Cancer Association.

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