Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
J Control Release. 2016 Aug 28;236:79-89. doi: 10.1016/j.jconrel.2016.06.033. Epub 2016 Jun 26.
While interferon alpha (IFNα) is used in several viral and cancer contexts, its efficacy against ovarian cancer (OC) is far from being incontrovertibly demonstrated and, more importantly, is hindered by heavy systemic side effects. To overcome these issues, here we propose a strategy that allows a targeted delivery of the cytokine, by conjugating IFNα2a with an aldehyde-modified form of hyaluronic acid (HA). The resulting HA-IFNα2a bioconjugate was biochemically and biologically characterized. The conjugation with HA did not substantially modified both the antiviral function and the anti-proliferative activity of the cytokine. Moreover, the induction of STAT1 phosphorylation and of a specific gene expression signature in different targets was retained. In vivo optical imaging biodistribution showed that the i.p.-injected HA-IFNα2a persisted into the peritoneal cavity longer than IFNα2a without being toxic for intraperitoneal organs, thus potentially enhancing the loco-regional therapeutic effect. Indeed, in OC xenograft mouse models bioconjugate significantly improved survival as compared to the free cytokine. Overall, HA-IFNα2a bioconjugate disclosed an improved anticancer efficacy, and can be envisaged as a promising loco-regional treatment for OC.
干扰素 alpha（IFNα）在几种病毒和癌症环境中得到应用，但它在卵巢癌（OC）方面的疗效远未得到无可争议的证明，更重要的是，其严重的全身副作用使其受到阻碍。为了克服这些问题，我们提出了一种策略，通过将 IFNα2a 与醛修饰形式的透明质酸（HA）缀合，实现细胞因子的靶向递送。对所得的 HA-IFNα2a 生物缀合物进行了生化和生物学表征。HA 的缀合并未实质上改变细胞因子的抗病毒功能和抗增殖活性。此外，在不同靶标中保留了 STAT1 磷酸化和特定基因表达特征的诱导。体内光学成像生物分布显示，与 IFNα2a 相比，腹腔内注射的 HA-IFNα2a 在腹腔内的持续时间更长，而对腹腔内器官没有毒性，从而有可能增强局部治疗效果。实际上，在 OC 异种移植小鼠模型中，与游离细胞因子相比，生物缀合物显著提高了生存率。总体而言，HA-IFNα2a 生物缀合物显示出了改进的抗癌疗效，可被视为 OC 的一种有前途的局部治疗方法。
