Department of Laboratory Medicine, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
J Exp Clin Cancer Res. 2019 Sep 18;38(1):408. doi: 10.1186/s13046-019-1410-x.
Replication-competent oncolytic viruses (OVs) have been proven to be a potent anticancer weapon for clinical therapy. The preexisting neutralizing antibody in patients is a big challenge for oncolytic efficacy of OVs. Graphene oxide sheets (GOS) possess excellent biological compatibility and are easy to decorate for targeted delivery.
We generated PEI-GOS-PEG-FA (Polyethyleneimine-Graphene oxide sheets-Polyethylene glycol-Folic acid). After intravenous injection, the distribution of PEI-GOS-PEG-FA in tumor-bearing mice was visualized by the IVIS Lumina XR system. Then, the oncolytic measles virus (MV-Edm) was coated with PEI-GOS-PEG-FA to form a viral-GOS complex (GOS/MV-Edm). The oncolytic effects of GOS/MV-Edm were investigated both in vitro and in vivo.
GOS/MV-Edm exhibited higher infectivity and enhanced oncolysis. In tumor-bearing mice, GOS/MV-Edm had significantly elevated viral replication within the tumor mass, and achieved an improved antitumor effect. Then, we confirmed that GOS/MV-Edm entered cancer cells via the folate receptor instead of CD46, a natural cognate receptor of MV-Edm. GOS/MV-Edm remained the infectivity in murine cells that lack CD46. Finally, we found that GOS/MV-Edm was effectively protected from neutralization in the presence of antiserum both in vitro and in vivo. In passively antiserum immunized tumor-bearing mice, the survival was remarkably improved with intravenous injection of GOS/MV-Edm.
Our findings demonstrate that GOS/MV-Edm displays significantly elevated viral replication within the tumor mass, leading to an improved antitumor effect in solid tumor mouse model. Our study provided a novel strategy to arm OVs for more efficient cancer therapy. That may become a promising therapeutic strategy for cancer patients.
复制型溶瘤病毒(OVs)已被证明是一种有效的癌症临床治疗手段。但患者体内预先存在的中和抗体是影响 OVs 溶瘤效果的一个巨大挑战。氧化石墨烯片(GOS)具有良好的生物相容性,并且易于进行靶向递送来提高治疗效果。
我们制备了聚乙烯亚胺-氧化石墨烯片-聚乙二醇-叶酸(PEI-GOS-PEG-FA)。通过静脉注射给药后,使用 IVIS Lumina XR 系统观察载药后的氧化石墨烯片在荷瘤小鼠体内的分布。然后,用 PEI-GOS-PEG-FA 包被麻疹病毒(MV-Edm)形成病毒-氧化石墨烯片复合物(GOS/MV-Edm)。我们研究了 GOS/MV-Edm 的体内外溶瘤效果。
GOS/MV-Edm 表现出更高的感染性和增强的溶瘤作用。在荷瘤小鼠中,GOS/MV-Edm 显著提高了肿瘤内病毒的复制水平,并实现了抗肿瘤效果的改善。然后,我们证实 GOS/MV-Edm 通过叶酸受体而不是 MV-Edm 的天然同源受体 CD46 进入癌细胞。在缺乏 CD46 的鼠源细胞中,GOS/MV-Edm 仍保持着感染性。最后,我们发现 GOS/MV-Edm 在体外和体内均能有效地抵抗抗血清的中和作用。在被动免疫血清的荷瘤小鼠中,静脉注射 GOS/MV-Edm 可显著提高小鼠的存活率。
我们的研究结果表明,GOS/MV-Edm 可显著提高肿瘤内病毒的复制水平,从而在实体瘤小鼠模型中产生更好的抗肿瘤效果。我们的研究为 OVs 提供了一种新的武装策略,以实现更有效的癌症治疗。这可能成为癌症患者的一种有前途的治疗策略。