PsiOxus Therapeutics Ltd, Milton Park, Oxfordshire, OX14 4SD, UK.
Nanomedicine (Lond). 2012 Nov;7(11):1683-95. doi: 10.2217/nnm.12.50. Epub 2012 Jun 18.
Intravenous delivery of therapeutic virus particles remains a major goal for virotherapy of metastatic cancer. Avoiding phagocytic capture and unwanted infection of nontarget cells is essential for extended plasma particle kinetics, and simply ablating one or the other does not give extended plasma circulation. Here we show that polymer coating of adenovirus type 5 (Ad5) can combine with predosing strategies or Kupffer cell ablation to achieve systemic kinetics with a half-life >60 min, allowing ready access to peripheral tumors. Accumulation of virus particles within tumor nodules is proportional to the area under the plasma concentration/time curve. Polymer coating wild-type Ad5 in this way is known to decrease hepatic toxicity, increasing the dose of virus particles that can be safely administered. Using polymer-coating technology to deliver a replicating Ad5 systemically, virus replication and transgene expression was almost totally confined to tumor tissues, giving a much improved therapeutic index compared with uncoated virus, and complete control of human HepG2 tumor xenografts.
静脉内递送治疗性病毒颗粒仍然是转移性癌症病毒治疗的主要目标。避免吞噬细胞捕获和非靶细胞的不适当感染对于延长血浆粒子动力学至关重要，仅仅消除一个或另一个并不能延长血浆循环。在这里，我们表明，腺病毒 5 型（Ad5）的聚合物涂层可以与预剂量策略或库普弗细胞消融相结合，以实现半衰期>60 分钟的全身动力学，从而可以轻松进入外周肿瘤。病毒颗粒在肿瘤结节内的积累与血浆浓度/时间曲线下面积成正比。以这种方式对野生型 Ad5 进行聚合物涂层已知会降低肝毒性，从而增加可以安全给予的病毒颗粒剂量。使用聚合物涂层技术全身性地传递复制的 Ad5 系统，病毒复制和转基因表达几乎完全局限于肿瘤组织，与未涂层病毒相比，提供了更好的治疗指数，并完全控制了人 HepG2 肿瘤异种移植物。
