Study on Combined Systemic Delivery of siRNA Specific to Tumor Mediated by Atelocollagen and Cisplatin against Prostate Cancer
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摘要: 目的 通过去端肽胶原向异体移植肿瘤递送siRNA，探讨去端肽胶原介导法联合顺铂在前列腺癌中的疗效及安全性。 方法 以Bcl-xL mRNA为靶点构建特异siRNA，提取去端肽胶原，制备siRNA/去端肽胶原复合物；以前列腺细胞系PC-3种植裸鼠为研究对象，随机分为腹腔局部瘤内注射组及静脉全身注射组，并将两组裸鼠随机注射Bcl-xL siRNA+顺铂或Bcl-xL siRNA/去端肽胶原复合物+顺铂进行治疗，观察不同治疗组裸鼠肿瘤体积的变化，并同时监测不同组裸鼠肝功能及肾功能在治疗前后的改变。 结果 当采用瘤内注射时，Bcl-xL siRNA/去端肽胶原蛋白与单独使用Bcl-xL siRNA相比，可显著抑制肿瘤生长（P<0.001），并可增加顺铂的敏感度；当采用全身静脉给药时，Bcl-xL siRNA/去端肽胶原复合物，也可显著抑制肿瘤的生长（P<0.001），与顺铂联合治疗抑瘤效果更为明显；并且无论瘤内或静脉注射，Bcl-xL siRNA/去端肽胶原蛋白使用前后，小鼠肝、肾功能变化均无统计学差别。 结论 去端肽胶原介导递送siRNA可提高顺铂治疗前列腺癌的疗效，去端肽胶原介导递送siRNA联合顺铂是安全和可行的治疗方案。Abstract: Objective To investigated the therapeutic efficacy and the security of atelocollagen-mediated method combined with cisplatin in prostate cancer through delivering siRNA to cancer xenograft by atelocollagen. Bcl-xL siRNA, combined with cisplatin(CDDP) and mediated by atelocollagen, in a pregrown solid xenograft derived from prostate cancer. Methods The nude mice with xenograft from PC-3 cells were randomly divided into four treatment groups: two groups for local intraperitoneal tumour injection and the other two groups for systemic intravenous injection. Four siRNAs targeting human Bcl-xL mRNA were designed and compounded with atelocollagen. Then the compound of Bcl-xL siRNA/atelocollagen/CDDP or Bcl-xL siRNA/ CDDP were randomly injected into the treatment groups.At regular intervals,the tumor volumes, liver enzyme and renal function in different groups of mice were measured and evaluated. Results In intratumoral treatment groups,when compared with the injection of Bcl-xL siRNA, Bcl-xL expressions in the PC-3 xenograft were effectively downregulated and tumor growth was inhibited by local injection of Bcl-xL siRNA/atelocollagen (P<0.001).In intravenous treatment groups, Bcl-xL siRNA/atelocollagen also effectively inhibited tumor growth when compared with the injection of Bcl-xL siRNA (P<0.001).And there were no significantly statistical differences or severe side effects such as liver or renal damage before or after Bcl-xL siRNA/atelocollagen in both groups. Conclusion Our results indicate that systemic delivery of siRNA combined with cisplatin via atelocollagen, which specifically targets tumors, is safe and feasible for prostate cancer therapy.
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Key words:
- siRNA /
- Prostate cancer /
- Atelocollagen /
- Cisplatin
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[1] Fire A, Xu S, Montgomery MK, et al.Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans[J].Nature,1998,391 (6669):806-11. [2] Elbashir SM, Harborth J, Lendeckel W, et al. Duplexesof 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells[J].Nature,2001,411(6836):494-8. [3] Reischl D, Zimmer A. Drug delivery of siRNA therapeutics: potentials and limits of nanosystems[J].Nanomedicine,2008,5(1):8-20. [4] Kawakami S, Hashida M. Targeted delivery systems of small interfering RNA by systemic administration[J]. Drug Metab Pharmacokinet,2007,22(3):142-51. [5] McCaffrey AP,Meuse L,Pham TT,et al.RNA interference in adult mice[J].Nature,2002,418(6893):38-9. [6] Santel A,Aleku M,Keil O,et al. RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy[J]. Gene Ther,2006,13(18):1360-70. [7] Urban-Klein B, Werth S, Abuharbeid S,et al.RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo[J].Gene Ther,2005,12(5):461-6. [8] Juliano R, Alam MR,Dixit V,et al.Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides[J]. Nucleic Acids Res,2008,36(12):4158-71. [9] Ochiya T, Takahama Y, Nagahara S, et al. New delivery system for plasmid DNA in vivo using atelocollagen as a carrier material: the Minipellet[J]. Nat Med,1999,5(6):707-10. [10] Hanai K, Takeshita F, Honma K,et al. Atelocollagen-mediated systemic DDS for nucleic acid medicines[J].Ann N Y Acad Sci,2006,1082:9-17. [11] Takeshita F, Minakuchi Y, Nagahara S, et al. Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo[J]. Proc Natl Acad Sci U S A ,2005,102(34):12177-82. [12] Zhang L,Zhao H,Sun A,et al.Early down-regulation of Bcl-xL expression during megakaryocytic differentiation of thrombopoietin-induced CD34+ bone marrow cells in essential thrombocythemia[J].Haematologica,2004,89(10):1196-206. [13] Komuro I,Yasuda T,Iwamoto A,et al.Catalase plays a critical role in the CSF-independent survival of human macrophages via regulation of the expression of Bcl-2 family[J].J Biol Chen,2005,280(50):41137-45. [14] Jemal A,Bray F,Center MM,et al.Global cancer statistics[J]. CA Cancer J Clin, 2011,61(2):69-90.
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