• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>other >PEG Length and Chemical Linkage Controls Polyacridine Peptide DNA Polyplex Pharmacokinetics Biodistribution Metabolic Stability and In Vivo Gene Expression
【2h】

PEG Length and Chemical Linkage Controls Polyacridine Peptide DNA Polyplex Pharmacokinetics Biodistribution Metabolic Stability and In Vivo Gene Expression

机译：PEG长度和化学键控制聚Poly啶肽DNA多聚体的药代动力学生物分布代谢稳定性和体内基因表达

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The pharmacokinetics (PK), biodistribution and metabolism of non-viral gene delivery systems administered systemically are directly related to in vivo efficacy. The magnitude of luciferase expression in the liver of mice following a tail vein dose of a polyplex, composed of 1 μg of pGL3 in complex with a polyethylene glycol (PEG) polyacridine peptide, followed by a delayed hydrodynamic (HD) stimulation (1–9 h), depends on the HD stimulation delay time and the structure of the polyacridine peptide. As demonstrated in the present study, the PEG length and the type of chemical linkage joining PEG to the polyacridine peptide dramatically influence the in vivo gene transfer efficiency. To understand how PEG length, linkage and location influence gene transfer efficiency, detailed PK, biodistribution and HD-stimulated gene expression experiments were performed on polyplexes prepared with an optimized polyacridine peptide modified through a single terminal Cys or Pen (penicillamine) with a PEG chain of average length of 2, 5, 10, 20, or 30 kDa. The chemical linkage was examined by attaching PEG5kDa to the polyacridine peptide through a thiol-thiol (SS), thiol-maleimide (SM), thiol-vinylsulfone (SV), thiol-acetamide (SA), penicillamine-thiol-maleimide (PM) or penicillamine-thiol-thiol (PS). The influence of PEG location was analyzed by attaching PEG5kDa to the polyacridine peptide through a C-terminal, N-terminal, or a middle Cys residue. The results established rapid metabolism of polyplexes containing SV and SA chemical linkages leads to a decreased polyplex PK half-life and a complete loss of HD-stimulated gene expression at delay times of 5 hrs. Conversely, polyplexes containing PM, PS, and SM chemical linkages were metabolically stable, allowing robust HD-stimulated expression at delay times up to 5 hrs post polyplex administration. The location of PEG5kDa within the polyacridine peptide exerted only a minor influence on the gene transfer of polyplexes. However, varying the PEG length from 2, 5, 10, 20, or 30 kDa dramatically altered polyplex biodistribution, with a 30 kDa PEG maximally blocking liver uptake to 13% of dose, while maintaining the ability to mediate HD-stimulated gene expression. The combination of results establishes important relationships between PEGylated polyacridine peptide structure, physical properties, in vivo metabolism, PK and biodistribution resulting in an optimal PEG length and linkage that leads to robust HD-stimulated gene expression in mice.
机译：全身给药的非病毒基因递送系统的药代动力学（PK），生物分布和代谢与体内功效直接相关。尾静脉注射多聚体后，小鼠肝脏中荧光素酶的表达强度由1μgpGL3与聚乙二醇（PEG）聚ac啶肽复合而成，随后是延迟水动力（HD）刺激（1–9 h），取决于HD刺激延迟时间和聚ac啶肽的结构。如本研究所示，PEG的长度和将PEG与聚poly啶肽连接的化学键的类型极大地影响了体内基因的转移效率。为了了解PEG的长度，连接和位置如何影响基因转移效率，对通过复合物进行了详细的PK，生物分布和HD刺激的基因表达实验，这些复合物是通过优化的通过聚丙烯酰胺单末端Cys或Pen（青霉胺）修饰的聚啶肽制备的平均长度为2、5、10、20或30 kDa。通过将PEG5kDa通过巯基-巯基（SS），巯基-马来酰亚胺（SM），巯基-乙烯基砜（SV），巯基-乙酰胺（SA），青霉胺-巯基-马来酰亚胺（PM）连接到聚poly啶肽上来检查化学键或青霉胺-硫醇-硫醇（PS）。通过将PEG5kDa通过C端，N端或中间Cys残基连接到聚analyzed啶肽上来分析PEG位置的影响。结果建立了含有SV和SA化学键的多链体的快速代谢，从而导致多链体PK半衰期缩短，并在5小时的延迟时间内完全丧失了HD刺激的基因表达。相反，含有PM，PS和SM化学键的复合物在代谢上是稳定的，允许在复合物给药后长达5小时的延迟时间内强劲的HD刺激表达。 PEG5kDa在聚5啶肽内的位置对多聚体的基因转移仅产生较小的影响。但是，将PEG长度从2、5、10、20或30 kDa改变会极大地改变复合体的生物分布，其中30 kDa PEG最大程度地阻止肝脏摄取至13％的剂量，同时保持介导HD刺激基因表达的能力。结果的组合在聚乙二醇化的聚ac啶肽结构，物理性质，体内代谢，PK和生物分布之间建立了重要的关系，从而导致了最佳的PEG长度和连接，从而在小鼠中产生了稳定的HD刺激基因表达。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号