The role of the interaction with cell-surface glycosaminoglycans (GAGs) during in vivo HSV infection is currently unknown. The rationale of the current investigation was to improve the anticancer efficacy of systemically administered retargeted oHSVs (ReHVs) by decreasing their binding to GAGs, including those of endothelial cells, blood cells, and off-tumor tissues. As a proof-of-principle approach, we deleted seven amino acids critical for interacting with GAGs from the glycoprotein C (gC) of R-337 ReHV. The modification in the resulting R-399 recombinant prolonged the half-life in the blood of systemically administered R-399 and enhanced its biodistribution to tumor-positive lungs and to the tumor-negative liver. Ultimately, it greatly increased the R-399 efficacy against metastatic-like lung tumors upon IV administration but not against subcutaneous tumors upon IT administration. These results provide evidence that the increased efficacy seen upon R-399 systemic administration correlated with the slower clearance from the circulation. To our knowledge, this is the first in vivo evidence that the partial impairment of the gC interaction with GAGs resulted in a prolonged half-life of circulating ReHV, an increase in the amount of ReHV taken up by tissues and tumors, and, ultimately, an enhanced anticancer efficacy of systemically administered ReHV.
在体内单纯疱疹病毒（HSV）感染过程中，与细胞表面糖胺聚糖（GAGs）相互作用的具体功能目前尚不明确。本研究旨在通过降低系统性给药的靶向改造单纯疱疹病毒（ReHVs）与GAGs的结合能力——包括与内皮细胞、血细胞以及非肿瘤组织中的GAGs结合——从而提升其抗癌疗效。作为原理验证，我们从R-337 ReHV的糖蛋白C（gC）中删除了七个对GAGs相互作用至关重要的氨基酸。这一改造使得重组病毒R-399在系统性给药后血液中的半衰期延长，并增强了其在肿瘤阳性肺部及肿瘤阴性肝脏中的生物分布。最终，该改造显著提高了R-399经静脉给药对转移样肺肿瘤的疗效，但未增强其经瘤内给药对皮下肿瘤的效果。这些结果表明，R-399系统性给药后疗效的提升与其在循环中清除速度的减缓相关。据我们所知，这是首次在体内证实：部分破坏gC与GAGs的相互作用可延长循环中ReHV的半衰期，增加组织和肿瘤对ReHV的摄取量，并最终增强系统性给药ReHV的抗癌疗效。
肿瘤(癌症)患者之家