Nonadditive Effects of Repetitive Administration of Lipoplexes in Immunocompetent Mice.
Nonadditive Effects of Repetitive Administration of Lipoplexes in Immunocompetent Mice.
复制标题
DOI：
10.1016/j.xphs.2016.11.013
复制
发表时间：
2017-03
影响因子：
3.8
通讯作者：
Anchordoquy TJ
中科院分区：
文献类型：
--
作者：
Betker JL;Anchordoquy TJ
重复给药通常用于维持治疗药物水平，但先前的研究已经记录了在这些条件下某些基于脂质的递送系统的加速血液清除。为了评估重复给药的效果，将非PEG化的脂质复合物（+/− = 0.5）以3天的间隔通过尾静脉注射给予携带4 T1肿瘤的免疫活性Balb/c小鼠四次。本研究测量了重复给予非靶向脂质复合物对清除率、细胞因子/趋化因子应答、质粒分布、报告基因表达和肝毒性的影响。我们没有观察到不应期或在首次给药和随后注射该lipoplex制剂之间的血液清除率的统计学显著差异，这与不存在细胞因子/趋化因子应答一致。然而，我们确实看到对质粒积累和表达的显著影响;与单次注射后相比，4次注射后肿瘤质粒水平和表达分别提高了26倍和10倍。此外，体内成像表明，与肿瘤中相对恒定的表达相反，其他器官中的表达在每次给药后72小时迅速减少。总之，这些发现表明，通过采用重复给药可以显著增强向肿瘤的基因递送。
Repetitive administration is routinely used to maintain therapeutic drug levels, but previous studies have documented an accelerated blood clearance of some lipid-based delivery systems under these conditions. To assess the effect of repetitive administration, non-PEGylated lipoplexes (+/− = 0.5) were administered four times via tail vein injection at 3-day intervals to immunocompetent Balb/c mice bearing 4T1 tumors. This study measured the effect of repeat administration of non-targeted lipoplexes on clearance, cytokine/chemokine response, plasmid distribution, reporter gene expression, and liver toxicity. We do not observe a refractory period or a statistically significant difference in blood clearance between the first administration and subsequent injections of this lipoplex formulation, consistent with the absence of a cytokine/chemokine response. However, we do see a significant effect on both plasmid accumulation and expression; an enhancement of 26-fold and 10-fold in tumor plasmid levels and expression, respectively, after 4 injections as compared to that after a single injection. In addition, in vivo imaging suggests that expression in other organs had diminished rapidly 72 h after each administration, in contrast to relatively constant expression in the tumor. Taken together, the findings indicate that gene delivery to tumors can be dramatically enhanced by employing repetitive administration.
登录
查看更多内容
影响因子：
4.9
作者：
Betker, Jamie L.;Anchordoquy, Thomas J.
通讯作者：
Anchordoquy, Thomas J.
影响因子：
10.8
作者：
Ishida, T;Ichihara, M;Kiwada, H
通讯作者：
Kiwada, H
影响因子：
12.4
作者：
Abrams, Marc T.;Koser, Martin L.;Sepp-Lorenzino, Laura
通讯作者：
Sepp-Lorenzino, Laura
影响因子：
5.1
作者：
Brunner, S;Sauer, T;Wagner, E
通讯作者：
Wagner, E
影响因子：
10.8
作者：
Abu Lila, Amr S.;Doi, Yusuke;Kiwada, Hiroshi
通讯作者：
Kiwada, Hiroshi