The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Cancer Res. 2010 Dec 1;70(23):9549-53. doi: 10.1158/0008-5472.CAN-10-1760. Epub 2010 Jul 29.
The convergence of phage-displayed peptide libraries and recombinant viral vectors launched a promising new direction in targeted viral gene therapeutics, but the translation of targeting peptides to functional cancer therapeutic agents has been challenging. Here, we report progress in developing a successful strategy to optimize targeted viral infection through adenovirus-displayed, semirandom peptide libraries. A phage-derived peptide targeting the prostate-specific membrane antigen (PSMA) was genetically incorporated into the adenoviral capsid Fiber protein and flanked by random peptide cassettes. The resulting adenovirus library was biopanned against PSMA-expressing cells and tumors to identify a PSMA-retargeted adenovirus. While the initial peptide alone could not target viral infection, the selected virus preferentially infects PSMA-expressing cells through the targeting peptide and infects LNCaP tumors after intravenous injection. Our results indicate that virus-displayed, semirandom peptide libraries can be used to optimize targeting infection. This approach represents a novel principle for developing targeted agents in a variety of disease models.
噬菌体展示肽文库和重组病毒载体的融合为靶向病毒基因治疗开辟了一个有前途的新方向，但将靶向肽转化为功能性癌症治疗剂一直具有挑战性。在这里，我们报告了在开发通过腺病毒展示的半随机肽文库来优化靶向病毒感染的成功策略方面的进展。一种针对前列腺特异性膜抗原 (PSMA) 的噬菌体衍生肽被基因整合到腺病毒衣壳纤维蛋白中，并被随机肽盒侧翼。由此产生的腺病毒文库针对表达 PSMA 的细胞和肿瘤进行生物淘选，以鉴定出一种针对 PSMA 的重定向腺病毒。虽然最初的肽本身不能靶向病毒感染，但所选病毒通过靶向肽优先感染表达 PSMA 的细胞，并在静脉注射后感染 LNCaP 肿瘤。我们的结果表明，病毒展示的半随机肽文库可用于优化靶向感染。这种方法为在各种疾病模型中开发靶向药物提供了一个新的原则。
