Suchergebnisse

Qing Zhou,1,* Tiehong Yang,1,* Youbei Qiao,1 Songyan Guo,1 Lin Zhu,2 Hong Wu11Department of Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, People's Republic of China; 2Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Health Science Center, Kingsville, Texas, USA*These authors contributed equally to this workAbstract: In this study, a multifunctional poly(β-L-malic acid)-based nanoconjugate with a pH-dependent charge conversional characteristic was developed for tumor-specific drug delivery. The short branched polyethylenimine-modified poly(β-L-malic acid) (PEPM) was first synthesized. Then, the fragment HAb18 F(ab′)2 and 2,3-dimethylmaleic anhydride were covalently attached to the PEPM to form the nanoconjugate, HDPEPM. In this nanoconjugate, the 2,3-dimethylmaleic anhydride, the shielding group, could shield the positive charge of the conjugate at pH 7.4, while it was selectively hydrolyzed in the tumor extracellular space (pH 6.8) to expose the previously-shielded positive charge. To study the anticancer activity, the anticancer drug, doxorubicin, was covalently attached to the nanoconjugate. The doxorubicin-loaded HDPEPM nanoconjugate was able to efficiently undergo a quick charge conversion from -11.62 mV to 9.04 mV in response to the tumor extracellular pH. The electrostatic interaction between the positively charged HDPEPM nanoconjugates and the negatively charged cell membrane significantly enhanced their cellular uptake, resulting in the enhanced anticancer activity. Also, the tumor targetability of the nanoconjugates could be further improved via the fragment HAb18 F(ab′)2 ligand–receptor-mediated tumor cell-specific endocytosis.Keywords: nanoconjugate, charge-conversional, PMLA, pH-sensitive

Purpose: To identify genes responsible for the radiosensitivity, we investigated the role of the differential gene expression profiles by comparing radioresistant H1299 with radiosensitive H460 lung cancer cell lines. Materials and methods: mRNA profiles of lung cancer cell lines were assessed using microarray, and subsequent validation was performed with qRT-PCR (Quantitative real time-polymerase chain reaction). The expression levels of differentially expressed genes were determined by Western blot and the radioresistance of lung cancer cell lines was measured by clonogenic assay. Results: From the differentially expressed apoptosis-related genes between H1299 and H460, we found Dcr3 (Decoy receptor 3, also known as TNFRSF6B; Tumour necrosis factor receptor super family member 6B) expression was significantly (P=4.38 x 10 (7)) higher in H1299 cells than H460 cells. Moreover, the Dcr3 mRNA expression level in the radioresistant cell lines (H1299, A549, DLD1, MB231, MB157) was increased in comparison to the radiosensitive cell lines (ME180, Caski, U87MG, MCF7, H460). Overexpression of Dcr3 increased the survival rate of radiosensitive H460, MCF7, and U87MG cells, and knockdown of Dcr3 abolished the radioresistance of A549 cells. The survival rate of p53 (Tumour protein 53)-deficient H1299 after gamma-irradiation was not affected by the suppression of Dcr3 expression. However, when we introduced p53 into H1299 cells, siDcr3 (siRNA of Dcr3) suppressed the radioresistance of H1299 cells by inducing p53-dependent Fas (Fas receptor, also known as TNFRSF6; Tumour necrosis factor receptor super family member 6)-mediated apoptosis pathway. Conclusion: Characterisation of gene expression profiles in two lung cancer cell lines revealed that Dcr3 expression and p53-dependent apoptosis signalling pathway regulate cellular response to ionising radiation. ; This paper was supported by a Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean Government (MOST; M20706000020- 07M0600-02010; W-Y. Park), the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs (A084022) and Brain Korea21 (BK21) Program (S-H. Jung and W-Y. Park). ; Chaudhry MA, 2008, J BIOMED SCI, V15, P557, DOI 10.1007/s11373-008-9253-z ; Toscano F, 2008, ONCOGENE, V27, P4161, DOI 10.1038/onc.2008.52 ; Aravindan N, 2008, MOL CELL BIOCHEM, V310, P167, DOI 10.1007/s11010-007-9678-0 ; Chaudhry MA, 2008, J BIOMED BIOTECHNOL, DOI 10.1155/2008/541678 ; Hayashi S, 2007, ARTHRITIS RHEUM, V56, P1067, DOI 10.1002/art.22494 ; Ogawa K, 2006, INT J ONCOL, V28, P705 ; Liu XG, 2005, CANCER RES, V65, P9169, DOI 10.1158/0008-5472.CAN-05-0939 ; Guo WF, 2005, RADIAT RES, V164, P27 ; Nix P, 2005, BRIT J CANCER, V92, P2185, DOI 10.1038/sj.bjc.6602647 ; Viktorsson K, 2005, BIOCHEM BIOPH RES CO, V331, P868, DOI 10.1016/j.bbrc.2005.03.192 ; Fukuda K, 2004, BRIT J CANCER, V91, P1543, DOI 10.1038/sj.bjc.6602187 ; Harima Y, 2004, INT J RADIAT ONCOL, V60, P237, DOI 10.1016/j.ijrobp.2004.02.047 ; Kelley SK, 2004, CURR OPIN PHARMACOL, V4, P333, DOI 10.1016/j.coph.2004.02.006 ; Dunne AL, 2003, BRIT J CANCER, V89, P2277, DOI 10.1038/sj.bjc.6601427 ; Dent P, 2003, RADIAT RES, V159, P283 ; Park WY, 2002, ONCOGENE, V21, P8521 ; Grace MB, 2002, INT J RADIAT BIOL, V78, P1011, DOI 10.1080/09553000210158056 ; Kitahara O, 2002, NEOPLASIA, V4, P295 ; Embree-Ku M, 2002, BIOL REPROD, V66, P1456, DOI 10.1095/biolreprod66.5.1456 ; Sheard MA, 2001, INT J CANCER, V96, P213 ; Hanna E, 2001, CANCER RES, V61, P2376 ; Bernhard EJ, 2000, CANCER RES, V60, P6597 ; Amundson SA, 2000, RADIAT RES, V154, P342 ; Maecker HL, 2000, CANCER RES, V60, P4638 ; Park WY, 2000, J BIOL CHEM, V275, P20847 ; Maebayashi K, 1999, INT J RADIAT ONCOL, V44, P677 ; Ashkenazi A, 1999, CURR OPIN CELL BIOL, V11, P255 ; Matsumura Y, 1997, CANCER LETT, V115, P91 ; Hsiao M, 1997, BIOCHEM BIOPH RES CO, V233, P329 ; Riva C, 1995, ORAL ONCOL, V31B, P384 ; BIARD DSF, 1994, CANCER RES, V54, P3361 ; SLICHENMYER WJ, 1993, CANCER RES, V53, P4164 ; BRACHMAN DG, 1993, CANCER RES, V53, P3667 ; LEE JM, 1993, P NATL ACAD SCI USA, V90, P5742 ; SKLAR MD, 1988, SCIENCE, V239, P645 ; 2