School of Pharmacy , University of Nottingham , Nottingham NG7 2RD , U.K.
PsiOxus Therapeutics Limited , 4-10, The Quadrant, Abingdon Science Park , Abingdon , Oxfordshire OX14 3YS , U.K.
Bioconjug Chem. 2019 Apr 17;30(4):1244-1257. doi: 10.1021/acs.bioconjchem.9b00189. Epub 2019 Mar 27.
Oncolytic viruses offer many advantages for cancer therapy when administered directly to confined solid tumors. However, the systemic delivery of these viruses is problematic because of the host immune response, undesired interactions with blood components, and inherent targeting to the liver. Efficacy of systemically administered viruses has been improved by masking viral surface proteins with polymeric materials resulting in modulation of viral pharmacokinetic profile and accumulation in tumors in vivo. Here we describe a new class of polyvalent reactive polymer based on poly( N-(2-hydroxypropyl)methacrylamide) (polyHPMA) with diazonium reactive groups and their application in the modification of the chimeric group B oncolytic virus enadenotucirev (EnAd). A series of six copolymers with different chain lengths and density of reactive groups was synthesized and used to coat EnAd. Polymer coating was found to be extremely efficient with concentrations as low as 1 mg/mL resulting in complete (>99%) ablation of neutralizing antibody binding. Coating efficiency was found to be dependent on both chain length and reactive group density. Coated viruses were found to have reduced transfection activity both in vitro and in vivo, with greater protection against neutralizing antibodies resulting in lower transgene production. However, in the presence of neutralizing antibodies, some in vivo transgene expression was maintained for coated virus compared to the uncoated control. The decrease in transgene expression was found not to be solely due to lower cellular uptake but due to reduced unpackaging of the virus within the cells and reduced replication, indicating that the polymer coating does not cause permanent inactivation of the virus. These data suggest that virus activity may be modulated by the appropriate design of coating polymers while retaining protection against neutralizing antibodies.
溶瘤病毒直接施用于局限性实体瘤时，在癌症治疗方面具有许多优势。然而，由于宿主的免疫反应、与血液成分的不期望相互作用以及对肝脏的固有靶向性，这些病毒的全身递送存在问题。通过用聚合材料对病毒表面蛋白进行掩蔽，从而改变病毒药代动力学特征并在体内积聚在肿瘤中，可提高全身给予的病毒的功效。在这里，我们描述了一类基于聚（N-（2-羟丙基）甲基丙烯酰胺）（polyHPMA）的新型多价反应性聚合物，其具有重氮反应性基团，并将其应用于嵌合 B 组溶瘤病毒 enadenotucirev（EnAd）的修饰。合成了一系列具有不同链长和反应性基团密度的六种共聚物，并将其用于包被 EnAd。研究发现，聚合物包被的效率非常高，即使浓度低至 1mg/mL，也能完全（>99%）消除中和抗体的结合。包被效率发现既依赖于链长又依赖于反应性基团密度。在体外和体内，包被病毒的转染活性均降低，对中和抗体的保护作用增强，导致转基因的产生减少。然而，在存在中和抗体的情况下，与未包被的对照相比，包被病毒在体内仍保持一些转基因表达。发现转基因表达的降低不仅是由于细胞摄取减少，还由于病毒在细胞内的未包装减少和复制减少，这表明聚合物包被不会导致病毒永久失活。这些数据表明，通过适当设计包被聚合物，可以调节病毒活性，同时保留对中和抗体的保护作用。
