Guoqing Wang, Min Mu, Zongliang Zhang, Yongdong Chen, Nian Yang, Kunhong Zhong, Yanfang Li, Fang Lu, Gang Guo, Aiping Tong
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引用次数: 0
摘要
胶质母细胞瘤(GBM)是侵袭性最强的原发性脑肿瘤,迫切需要有效的治疗方法。溶瘤腺病毒(OA)有望成为临床抗肿瘤疗法的潜在候选药物,包括用于治疗胶质母细胞瘤。然而,OA 的全身给药仍面临挑战,导致抗肿瘤疗效大打折扣。在本研究中,我们开发了一种创新方法,用单宁酸和Fe3+(TA-Fe3+)包裹CXCL11-armed OA,以实现OA的全身给药。我们在体外和体内评估了纳米载体保护 OA 免受宿主免疫反应清除的能力。我们评估了OA@TA-Fe3+在GBM小鼠模型中的抗肿瘤效果和安全性。OA@TA-Fe3+能有效保护病毒不被宿主免疫清除,并延长其体内循环。靶向肿瘤部位后,TA-Fe3+可溶解并释放Fe3+和OA。Fe3+诱导H2O2产生O2,缓解缺氧状态,促进OA复制,显著改变肿瘤免疫微环境,提高抗肿瘤疗效。此外,OA@TA-Fe3+的全身给药是安全的,不会引起炎症或器官损伤。我们的研究结果表明,通过全身给药工程化 OA 有助于实现有效的肿瘤溶解病毒疗法。
Systemic delivery of tannic acid-ferric-masked oncolytic adenovirus reprograms tumor microenvironment for improved therapeutic efficacy in glioblastoma
Glioblastoma (GBM) represents the most aggressive primary brain tumor, and urgently requires effective treatments. Oncolytic adenovirus (OA) shows promise as a potential candidate for clinical antitumor therapy, including in the treatment of GBM. Nevertheless, the systemic delivery of OA continues to face challenges, leading to significantly compromised antitumor efficacy. In this study, we developed an innovative approach by encapsulating CXCL11-armed OA with tannic acid and Fe3+ (TA-Fe3+) to realize the systemic delivery of OA. The nanocarrier’s ability to protect the OA from elimination by host immune response was evaluated in vitro and in vivo. We evaluated the antitumor effect and safety profile of OA@TA-Fe3+ in a GBM-bearing mice model. OA@TA-Fe3+ effectively safeguarded the virus from host immune clearance and extended its circulation in vivo. After targeting tumor sites, TA-Fe3+ could dissolve and release Fe3+ and OA. Fe3+-induced O2 production from H2O2 relieved the hypoxic state, and promoted OA replication, leading to a remarkable alteration of tumor immune microenvironment and enhancement in antitumor efficacy. Moreover, the systemic delivery of OA@TA-Fe3+ was safe without inflammation or organ damage. Our findings demonstrated the promising potential of systemically delivering the engineered OA for effective oncolytic virotherapy against GBM.
期刊介绍:
Cancer Gene Therapy is the essential gene and cellular therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene and cellular therapies for cancer. The journal publishes original laboratory and clinical research papers, case reports and review articles. Publication topics include RNAi approaches, drug resistance, hematopoietic progenitor cell gene transfer, cancer stem cells, cellular therapies, homologous recombination, ribozyme technology, antisense technology, tumor immunotherapy and tumor suppressors, translational research, cancer therapy, gene delivery systems (viral and non-viral), anti-gene therapy (antisense, siRNA & ribozymes), apoptosis; mechanisms and therapies, vaccine development, immunology and immunotherapy, DNA synthesis and repair.
Cancer Gene Therapy publishes the results of laboratory investigations, preclinical studies, and clinical trials in the field of gene transfer/gene therapy and cellular therapies as applied to cancer research. Types of articles published include original research articles; case reports; brief communications; review articles in the main fields of drug resistance/sensitivity, gene therapy, cellular therapy, tumor suppressor and anti-oncogene therapy, cytokine/tumor immunotherapy, etc.; industry perspectives; and letters to the editor.