Chemical Modification with High Molecular Weight Polyethylene Glycol Reduces Transduction of Hepatocytes and Increases Efficacy of Intravenously Delivered Oncolytic Adenovirus
Chemical Modification with High Molecular Weight Polyethylene Glycol Reduces Transduction of Hepatocytes and Increases Efficacy of Intravenously Delivered Oncolytic Adenovirus
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DOI：
10.1089/hum.2009.028
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发表时间：
2009-09-01
影响因子：
4.2
通讯作者：
Barry, Michael A.
中科院分区：
文献类型：
--
作者：
Doronin, Konstantin;Shashkova, Elena V.;Barry, Michael A.
溶瘤腺病毒是在肿瘤内复制并扩散到未感染的肿瘤细胞的抗癌剂，放大初始转导的抗癌作用。我们测试了用聚乙二醇（PEG）包被病毒颗粒是否可以在全身（静脉内）施用溶瘤腺病毒血清型5（Ad 5）后减少肝细胞的转导和肝毒性。Ad 5与高分子量的20-kDa PEG结合，但不与5-kDa PEG结合，静脉注射后减少肝细胞转导和肝毒性。用20-kDa PEG进行PEG化在从枯否细胞和肝细胞中去靶向腺病毒方面与病毒预给药和华法林一样有效。裸小鼠两种异种移植肿瘤模型中病毒分布的生物发光成像表明，用20-kDa PEG进行聚乙二醇化可将肝脏感染减少19至90倍。用20-kDa PEG PEG化的载体和未PEG化的载体的肿瘤转导水平相似。单次静脉注射后的抗癌功效在大型已建立的前列腺癌异种移植物中保持在未修饰载体的水平，导致所有动物中肿瘤的完全消除和长期无肿瘤存活。单次静脉注射后，在大型肝细胞癌异种移植物中的抗癌功效增加，与未修饰的载体相比，存活期显著延长。疗效的增加与给药前和华法林预处理相当，显著延长了中位生存期。用20-kDa PEG屏蔽腺病毒可能是一种有用的方法，以改善溶瘤腺病毒全身递送至原发性和转移性肿瘤部位后的治疗窗口。
Oncolytic adenoviruses are anticancer agents that replicate within tumors and spread to uninfected tumor cells, amplifying the anticancer effect of initial transduction. We tested whether coating the viral particle with polyethylene glycol (PEG) could reduce transduction of hepatocytes and hepatotoxicity after systemic (intravenous) administration of oncolytic adenovirus serotype 5 (Ad5). Conjugating Ad5 with high molecular weight 20-kDa PEG but not with 5-kDa PEG reduced hepatocyte transduction and hepatotoxicity after intravenous injection. PEGylation with 20-kDa PEG was as efficient at detargeting adenovirus from Kupffer cells and hepatocytes as virus predosing and warfarin. Bioluminescence imaging of virus distribution in two xenograft tumor models in nude mice demonstrated that PEGylation with 20-kDa PEG reduced liver infection 19- to 90-fold. Tumor transduction levels were similar for vectors PEGylated with 20-kDa PEG and unPEGylated vectors. Anticancer efficacy after a single intravenous injection was retained at the level of unmodified vector in large established prostate carcinoma xenografts, resulting in complete elimination of tumors in all animals and long-term tumor-free survival. Anticancer efficacy after a single intravenous injection was increased in large established hepatocellular carcinoma xenografts, resulting in significant prolongation of survival as compared with unmodified vector. The increase in efficacy was comparable to that obtained with predosing and warfarin pretreatment, significantly extending the median of survival. Shielding adenovirus with 20-kDa PEG may be a useful approach to improve the therapeutic window of oncolytic adenovirus after systemic delivery to primary and metastatic tumor sites.