Abstract
Abstract Background and Objective: The NF-kB/Rel family of transcription factors is involved in the development of cancer. This family is constitutively activated in many human pancreatic cancers and pancreatic cell lines. DHMEQ inhibits NF-κB activity by preventing nuclear translocation and has been shown anti-tumor effect. However, because of its hydrophobic property, DHMEQ has to be administered intraperitoneally or subcutaneously every day. Therefore, it is necessary to develop effective drug delivery system (DDS) of DHMEQ for clinical application. In this study, we have used PMBN polymer, which forms a stable polymer aggregate in water that can enhance the solubility of hydrophobic substance such as DHMEQ. The active ester group of PMBN can be replaced by proteins such as anti-epidermal growth factor receptor (EGFR) antibody. It is expected that a selective increased accumulation of PMBN-DHMEQ antibody conjugate could lead to a reduction of its dose and/or numbers of administration. The aim of this study is that investigate active enhancement of anti-cancer effect by DHMEQ using PMBN. Methods: The human pancreas adenocarcinoma cell lines, AsPC-1, BxPC-3, MIAPaCa-2, which showed high expression level of EGFR were used in vitro study. DHMEQ, PMBN and mouse monoclonal anti-human EGFR antibody (528) were mixed at the weight ratio of 1:25:5 and sonicated to prepare PMBN-DHMEQ antibody conjugate in advance. Control DHMEQ was dissolved in 0.5% chrolomethylcellulose (CMC-DHMEQ). The effect of cell growth inhibition by each preparation was evaluated by WST assay in vitro. AsPC-1 cells which expressing Gaussia luciferase (AsPC-1-Luc) was used to investigate anti-tumor effect in vivo. 5×105 of AsPC-1-Luc was injected into nice portal vein to develop liver metastases model of pancreatic cancer. Mice were given PMBN-DHMEQ antibody conjugate (intravenously) or CMC-DHMEQ (intraperitoneally) every three days at a dose of 12mg/kg DHMEQ. Metastases level of each group was compared by measuring luciferase activity of mice whole liver homogenate using Renilla Luciferase Assay System (Promega). Result: PMBN-DHMEQ antibody conjugate showed higher cell growth inhibition than CMC-DHMEQ in vitro WST assay. Also it showed stronger growth inhibition effect than CMC-DHMEQ in vivo. Quantitative luciferase assay showed that PMBN-DHMEQ antibody conjugate have 49.2 times higher effect compare to CMC-DHMEQ. Conclusion: Our results demonstrate that the PMBN-DHMEQ-anti-EGFR antibody conjugate can efficiently decrease cancer development of cells overexpressing EGFR by an active enhancement effect. This result suggest that increased accumulation of PMBN-DHMEQ anti-EGFR antibody conjugate increased tumor concentration of DHMEQ and the therapeutic response. PMBN-mediated DDS, which in turn reduce its dose and/or numbers of administration of DHMEQ. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3223. doi:10.1158/1538-7445.AM2011-3223
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