Title:
How we can access to cancers?
～Development of cancer treatment strategies using cell signal engineering～

Yoshiki Katayama
Department of Applied Chemistry, Kyushu University
Center for Medical Redox Navigation, Kyushu University
Center for Advanced Medical Innovation, Kyushu University
Center for Molecular Systems, Kyushu University
Center for Future Chemistry, Kyushu University

Abstract:
Cancer is a leading cause of death in worldwide. However, the efficient treatment hasn’t been developed excepting surgical way for early stage cancer. Although cancer chemotherapy will be the most ideal way for the treatment, current anticancer drugs are not effective in spite of their severe adverse effects. To address this issue, DDS technologies have been expected as promising approach. For the tumor targeting DDS, passive targeting will be one of the most versatile methodologies. The strategy follows characteristics of tumor tissue such an increased extravasation in neovasculature and enhanced retention due to the underdeveloped lymph. This effect is known as EPR effect and nano-particle can be accumulated in tumor tissue during blood circulation. This can enhance the contrast of drug distribution against tumor so that the total administration can be decreased. However, we have to notice that actual accumulation of nano-cargo is just several percent of total dosage in the use of this strategy meaning insufficient protection from adverse effect due to undesired distribution of nano-cargo. Another promising strategy is active targeting which uses specific ligand against tumor to enhance the binding ability of nano-cargo into target tumor cells. Many researches have used this strategy and obtained promising results.  However, an expression level of such marker varies specially and temporally due to heterogeneity of real tumors. Therefore, the strategy may not realize a dramatic increase of tumor distribution of nano-cargo although it may increase the retention on tumor cells. Moreover, as more important issue, the strategy doesn’t prohibit the passive distribution of nano-cargo into other normal organs. In these context, it would be obvious that we need an alternative strategy to make more promising tumor DDS having more efficient antitumor ability and suppression of adverse effect. In this talk, another strategy for tumor DDS will be introduced. The methodology uses intracellular signaling (enzymatic activity) which is abnormally activated as a trigger to release gene medicine so that the medicine isn’t released in normal cells in which such abnormal signaling doesn’t present. Actually, using of protein kinase Ca as a trigger, we successfully obtained remarkable tumor cell-specific activation of gene medicine and complete suppression of metastasis. We have proposed such strategy “D-RECS” which means DDS in response to cellular signals. Basic design and some applications of such systems will be introduced. Beside such nano-cargo DDS, therapeutic antibody has become promising for tumor treatment. However, it has been suffered from its high cost and troublesome production process. Small molecules exerting similar activity of therapeutic antibody will also be introduced as a new strategy to solve current problems of therapeutic antibody.

References
1) R. Toita, J.-H. Kang, C. Kim, T. Mori, T. Niidome, Y. Katayama, Effect of peptide content on the regulation of transgene expression by protein kinase-responsive linear polyethylenimine-peptide conjugates , Colloids and Surfaces B: Biointerfaces, in press (2014)
2) J-H. Kang, T. Mori, H. Kitazaki, T. Niidome, K. Takayama, Y. Nakanishi, Y. Katayama, Kinase Activity of Protein Kinase Calpha in Serum as a Diagnostic Biomarker of Human Lung Cancer, Anticancer, 33, 485-488 (2013)
3) Y. Nakamura, C. W. Kim, A. Tsuchiya, S. Kushio, T. Nobori, K. Li, E. K. Lee, G. Xi Zhao, D. Funamoto, T. Niidome, T. Mori, Y. Katayama, Branched polyethylenimine-based PKCα-responsive gene carriers, J. Biomater. Sci.-Polym. Ed., 24, 1858-68 (2013)
4) S. Kushio, A. Tsuchiya, Y. Nakamura, T. Nobori, C. W. Kim, G. X. Zhao, T. Funamoto, E. K. Lee, K. Lee, T. Niidome, T. Mori*, Y Katayama*, Cancer-specific gene carriers responding to cancer microenvironment: acidosis and hyper-activated protein kinases, Biomed. Eng. 25,1340005-13400016(2013)
5) C. W. Kim, R. Toita, J.-H. Kang, K. Li, E. K. Lee, G. X. Zhao, D. Funamoto, T. Nobori, Y. Nakamura, T. Mori, T. Niidome, Y. Katayama, Stabilization of Cancer-specific Gene Carrier via Hydrophobic Interaction for a Clear-cut Response to Cancer Signaling, J. Controlled Release, 170, 469-476 (2013)
6) Riki Toita, Jeong-Hun Kang, Tetsuro Tomiyama, Chan Woo Kim, Shujiro Shiosaki, Takuro Niidome, Takeshi Mori, Yoshiki Katayama, Gene carrier showing all-or-none response to cancer cell signaling, J. Am. Chem. Soc., 134,1540-15417(2012)
7) Akira Tsuchiya, Yuki Naritomi, Satoshi Kushio, Jeong-Hun Kang, Masaharu Murata, Makoto Hashizume, Takeshi Mori, Takuro Niidome, Yoshiki Katayama, Improvement in the colloidal stability of protein kinase-responsive polyplexes by PEG modification, J. Biomed. Mater. Res. Part A, 100, 1136-1141 (2012)
8) Hiroyuki Tanaka, Takeshi Mori, Takuro Niidome, Yoshiki Katayama, Creating a unique environment for selecting reactive enzymes with DNA: “Sticky” binding of oligocation-grafted polymers to DNA, Bioorg. Med. Chem., 20, 1346-1353 (2012)
9) Tetsuro Tomiyama, Riki Toita, Jeong-Hun Kang, Haruka Koga, Shujiro Shiosaki, Takeshi Mori, Takuro Niidome, Yoshiki Katayama, Effect of the introduction of condroitin sulfate into polymer-peptide conjugate responding to intracellular signals, Nanoscale Res. Lett., 6, 532 (2011)
10) Shujiro Shiosaki, Masanori Kuramoto, Riki Toita, Takeshi Mori, Takuro Niidome, Yoshiki Katayama, A hydrophilic polymer grafted with a histone tail peptide represents an artificial gene regulator activated by a histone acetyltransferase, Bioorg. Med. Chem., 19, 4101-41405 (2011)
11) Akira Tsuchiya, Jeong-Hun Kang, Daisuke Asai, Takeshi Mori, Takuro Niidome, Yoshiki Katayama, Transgene regulation system responding to Rho associated coiled-coil kinase (ROCK) activation, J. Controlled Release, 155, 40-46 (2011)
12) etsuro Tomiyama, Riki Toita, Jeong-Hun Kang, Daisuke Asai, Shujiro Shiosaki, Takeshi Mori, Takuro Niidome, Yoshiki Katayama, Tumor therapy by gene regulation system responding to cellular signal, J. Controlled Release, 148, 101-105 (2010)
13) Jun Oishi, Joohee Jung, Akira Tsuchiya, Riki Toita, Jeong-Hun Kang, Takeshi Mori, Takuro Niidome, Katsuyuki Tanizawa, Shun’ichi Kuroda, Yoshiki Katayama, A gene delivery system specific for hepatoma cells and an intracellular kinase signal based on human liver-specific bionanocapsules and signal-responsive artificial polymer, Int. J. Pharm., 396, 174-178 (2010)
14) Jeong-Hun Kang, Riki Toita, Yoshiki Katayama, Bio and nanotechnological strategies for tumor-targeted gene therapy, Biotechnol. Adv. 28, 757-763 (2010)
15) Joeng-Hun Kang, Jun Oishi, Jong-Hwan Kim, Moeko Ijuin, Riki Toita, Byungdug Jun, Daisuke Asai, Takeshi Mori, Takuro Niidome, Katsuyuki Tanizawa, Shun’ichi Kuroda, Yoshiki Katayama, Hepatoma-targeted gene delivery using a tumor cell-specific gene regulation system combined with a human liver cell-specific bionanocapsule, Nanomedicine 6, 583-589 (2010)
16) Yuko Sato, Kenji Kawamura, Takuro Niidome, Yoshiki Katayama, Characterization of gene expression regulation using D-RECS polymer by enzymatic reaction for an effective design of enzyme-responsive gene regulator, J. Controlled Release, 143, 344-349 (2010)
17) Daisuke Asai, Masanori Kuramoto, Yoko Shoji, Kota Bae Kodama, Jeong-Hun Kagng, Kenji Kawamura, Hiroshi Miyoshi, Takeshi Mori, Takuro Niidome, Hideki Nakashima, Yoshiki Katayama, Specific transgene expression in HIV-infected cells using protease-cleavable transcription regulator, J. Controlled Release 141, 52-61 (2010)
18) Tetsuro Tomiyama, Jeong-Hun Kang, Riki Toita, Takuro Niidome, Yoshiki Katayama, Protein kinase Cα-responsive polymeric carrier: Its application for gene delivery into human cancers, Cancer Sci., 100, 1532-1536 (2009)
19) Riki Toita, Jeong-Hun Kang, Jong-Hwan Kim, Tetsuro Tomiyama, Takeshi Mori, Takuro Niidome, Byungdug Jun, Yoshiki Katayama, Protein kinase Cα-specific peptide substrate graft-type copolymer for cancer cell-specific gene regulation systems, J. Controlled Release, 139, 133-139 (2009)
20) Daisuke Asai, Akira Tsuchiya,Jeong-Hun Kang, Kenji Kawamura, Jun Oishi, Takeshi Mori, Takuro Niidome, Yoko Shoji, Hideki Nakashima, Yoshiki Katayama, Inflammatory cell-specific gene regulation system responding to Ikappa-B kinase beta activation, J. Gene Med., 11, 624-632 (2009)
21) Jeong-Hun Kang, Daisuke Asai, Jong-Hwan Kim, Takeshi Mori, Riki Toita, Tetsuro Tomiyama, Yoji Asami, Jun Oishi, Yuko T. Sato, Takuro Niidome, Byungdug Jun, Hideki Nakashima, Yoshiki Katayama, Design of polymeric carriers for cancer-specific gene targeting: Utilization of abnormal protein kinase Cα activation in cancer cells, J. Am. Chem. Soc., 130, 14906-14907 (2008)