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A novel monomethylauristatin E prodrug for malignant cancer targeted therapy
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Abstracts / Journal of Controlled Release 259 (2017) e5–e195
and reduced target gene without significant toxicity, demonstrating potential gene delivery for human blood cell gene silencing.
of MMAE, Boc-lys(Ac)-PABC-MMAE, with two-wave activation to ensure its safety. Firstly, the masking group of lysine moiety undergoes deacetylation by histone deacetylase (HDAC), then lysine is removed by endogenous protease cathepsin L (CTSL) [2], finally MMAE is released after spontaneous elimination of the pamionbenzylcarbamate (PABC) (Fig. 1). Due to high expression of HDAC and CTSL in cancer cells, MMAE tends to be selectively released from the prodrug in tumor cells. In vitro studies confirmed the stronger inhibition effect to the cancer cells compared to normal cells. In cancer cells A549 and MCF-7, the cytotoxicity of the prodrug is comparable to free MMAE. While in normal cells L929 and LO2, the IC50 of the prodrug is 12 times lower than free MMAE. When the HDAC inhibitor LBH589 was employed, the prodrug exhibited obvious lower toxicity to A549 cancer cells, confirming the enzymeactive effect of the prodrug in cancer cells. The above results proved the Boc-lys(Ac)-PABC-MMAE is a promising MMAE-prodrug, and may help this drug to be applied in the clinic.
Fig. 1. Schematic illustration of monocyte-targeted siRNA delivery using anti-FcR scFv-9R.
Keywords: monocyte targeting, single chain antibody, gene silencing, inflammatory diseases Acknowledgements This work was partially supported by grants from the National Research Foundation of Korea (2014049587, 2015003019), the Brain Korea 21 plus program (22A20130011095), and the Korean Health Technology R&D project through the Ministry of Health & Welfare (HI13C-1938-010014). References [1] K. Jiang, J. Li, J. Yin, Q. Ma, B. Yan, X. Zhang, L. Wang, L. Wang, T. Liu, Y. Zhang, Targeted delivery of CXCR4-siRNA by scFv for HER2+ breast cancer therapy, Biomaterials, 59 (2015) 77-87. [2] Y. Lu, L. Liu, Y. Wang, F. Li, J. Zhang, M. Ye, H. Zhao, X. Zhang, M. Zhang, J. Zhao, siRNA delivered by EGFR-specific scFv sensitizes EGFR-TKI-resistant human lung cancer cells, Biomaterials, 76 (2016) 196-207. [3] N.V. Serbina, E.G. Pamer, Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2, Nat. Immunol. 7 (2006) 311-317.
doi:10.1016/j.jconrel.2017.03.247
A novel monomethylauristatin E prodrug for malignant cancer targeted therapy Shengcai Yanga,b, Na Shena, Wantong Songa, Zhaohui Tanga,⁎, Xuesi Chena,⁎ a Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China b State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, China ⁎Corresponding authors. E-mail addresses: [email protected] (S. Yang), [email protected] (Z. Tang), [email protected] (X. Chen) An ideal cancer therapy is to eliminate cancer cells with least damage to normal cells. Monomethyl auristatin E (MMAE), an antimitotic agent inhibiting tubulin polymerization [1], has serve toxicity to tumor cells, whereas the great toxicity also limits its clinical application. Thus, to synthesize a MMAE prodrug which releases the active MMAE in a cancer-selective manner is essential for applying MMAE in cancer therapy. Here, we prepared a prodrug
Fig. 1. Chemical structure of Boc-lys(Ac)-PABC-MMAE.
Keywords: MMAE, drug controlled release, cancer-selective, prodrug Acknowledgements This research was financially supported by National Natural Science Foundation of China (51373168). References [1] S.O. Doronina, B.E. Toki, M.Y. Torgov, B.A. Mendelsohn, C.G. Cerveny, D.F. Chace, R.L. DeBlanc, R.P. Gearing, T.D. Bovee, C.B. Siegall, J.A. Francisco, A.F. Wahl, D.L. Meyer, P.D. Senter, Development of potent monoclonal antibody auristatin conjugates for cancer therapy, Nat. Biotech. 21 (2003) 778-784. [2] N. Ueki, S. Lee, N.S. Sampson, M.J. Hayman, Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease, Nat. Commun. 4 (2013) 2735.
doi:10.1016/j.jconrel.2017.03.248
Macrocyclic drug conjugates of metronidazole-cyclodextrin for colon-targeted delivery Shijie Weia, Huimin Chua, Lisheng Xua, Zhizhong Wanga,b,⁎, Qing Huanga,b,⁎ a Department of Pharmacy, General Hospital, Ningxia Medical University, Yinchuan 750004, China b Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004, China ⁎Corresponding authors at: Department of Pharmacy, General Hospital, Ningxia Medical University, Yinchuan 750004, China. E-mail addresses: [email protected] (S. Wei), [email protected] (Z. Wang), [email protected] (Q. Huang) Metronidazole (MTZ) is recommended as one of a number of chemotherapy options for the first-line treatment of amoebic colitis.
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
and reduced target gene without significant toxicity, demonstrating potential gene delivery for human blood cell gene silencing.
of MMAE, Boc-lys(Ac)-PABC-MMAE, with two-wave activation to ensure its safety. Firstly, the masking group of lysine moiety undergoes deacetylation by histone deacetylase (HDAC), then lysine is removed by endogenous protease cathepsin L (CTSL) [2], finally MMAE is released after spontaneous elimination of the pamionbenzylcarbamate (PABC) (Fig. 1). Due to high expression of HDAC and CTSL in cancer cells, MMAE tends to be selectively released from the prodrug in tumor cells. In vitro studies confirmed the stronger inhibition effect to the cancer cells compared to normal cells. In cancer cells A549 and MCF-7, the cytotoxicity of the prodrug is comparable to free MMAE. While in normal cells L929 and LO2, the IC50 of the prodrug is 12 times lower than free MMAE. When the HDAC inhibitor LBH589 was employed, the prodrug exhibited obvious lower toxicity to A549 cancer cells, confirming the enzymeactive effect of the prodrug in cancer cells. The above results proved the Boc-lys(Ac)-PABC-MMAE is a promising MMAE-prodrug, and may help this drug to be applied in the clinic.
Fig. 1. Schematic illustration of monocyte-targeted siRNA delivery using anti-FcR scFv-9R.
Keywords: monocyte targeting, single chain antibody, gene silencing, inflammatory diseases Acknowledgements This work was partially supported by grants from the National Research Foundation of Korea (2014049587, 2015003019), the Brain Korea 21 plus program (22A20130011095), and the Korean Health Technology R&D project through the Ministry of Health & Welfare (HI13C-1938-010014). References [1] K. Jiang, J. Li, J. Yin, Q. Ma, B. Yan, X. Zhang, L. Wang, L. Wang, T. Liu, Y. Zhang, Targeted delivery of CXCR4-siRNA by scFv for HER2+ breast cancer therapy, Biomaterials, 59 (2015) 77-87. [2] Y. Lu, L. Liu, Y. Wang, F. Li, J. Zhang, M. Ye, H. Zhao, X. Zhang, M. Zhang, J. Zhao, siRNA delivered by EGFR-specific scFv sensitizes EGFR-TKI-resistant human lung cancer cells, Biomaterials, 76 (2016) 196-207. [3] N.V. Serbina, E.G. Pamer, Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2, Nat. Immunol. 7 (2006) 311-317.
doi:10.1016/j.jconrel.2017.03.247
A novel monomethylauristatin E prodrug for malignant cancer targeted therapy Shengcai Yanga,b, Na Shena, Wantong Songa, Zhaohui Tanga,⁎, Xuesi Chena,⁎ a Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China b State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, China ⁎Corresponding authors. E-mail addresses: [email protected] (S. Yang), [email protected] (Z. Tang), [email protected] (X. Chen) An ideal cancer therapy is to eliminate cancer cells with least damage to normal cells. Monomethyl auristatin E (MMAE), an antimitotic agent inhibiting tubulin polymerization [1], has serve toxicity to tumor cells, whereas the great toxicity also limits its clinical application. Thus, to synthesize a MMAE prodrug which releases the active MMAE in a cancer-selective manner is essential for applying MMAE in cancer therapy. Here, we prepared a prodrug
Fig. 1. Chemical structure of Boc-lys(Ac)-PABC-MMAE.
Keywords: MMAE, drug controlled release, cancer-selective, prodrug Acknowledgements This research was financially supported by National Natural Science Foundation of China (51373168). References [1] S.O. Doronina, B.E. Toki, M.Y. Torgov, B.A. Mendelsohn, C.G. Cerveny, D.F. Chace, R.L. DeBlanc, R.P. Gearing, T.D. Bovee, C.B. Siegall, J.A. Francisco, A.F. Wahl, D.L. Meyer, P.D. Senter, Development of potent monoclonal antibody auristatin conjugates for cancer therapy, Nat. Biotech. 21 (2003) 778-784. [2] N. Ueki, S. Lee, N.S. Sampson, M.J. Hayman, Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease, Nat. Commun. 4 (2013) 2735.
doi:10.1016/j.jconrel.2017.03.248
Macrocyclic drug conjugates of metronidazole-cyclodextrin for colon-targeted delivery Shijie Weia, Huimin Chua, Lisheng Xua, Zhizhong Wanga,b,⁎, Qing Huanga,b,⁎ a Department of Pharmacy, General Hospital, Ningxia Medical University, Yinchuan 750004, China b Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004, China ⁎Corresponding authors at: Department of Pharmacy, General Hospital, Ningxia Medical University, Yinchuan 750004, China. E-mail addresses: [email protected] (S. Wei), [email protected] (Z. Wang), [email protected] (Q. Huang) Metronidazole (MTZ) is recommended as one of a number of chemotherapy options for the first-line treatment of amoebic colitis.