Wang Shijing, Zhao Yan, Yao Fei, Wei Pengxue, Ma Lan, Zhang Shaochong
Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, 18 Zetian Road, Futian District, Shenzhen 518040, China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, Nanshan District, Shenzhen 518055, China.
Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Guangqiao Road, Guangming District, Shenzhen 518107, China.
Biomed Pharmacother. 2024 May;174:116437. doi: 10.1016/j.biopha.2024.116437. Epub 2024 Mar 24.
Retinoblastoma (RB) is a type of pediatric solid tumor in the fundus. The lack of precision therapies combined with the difficulty of delivering small interfering RNA (siRNA) into the eyes means that there is currently no nucleic acid-based therapy for RB in clinical practice. Here, we reported on anti-GD2 and glutathione-responsive spherical nucleic acids (SNAs), loaded with siRNA and the inhibitor NVP-CGM097, which jointly blocked the oncogenic factor n in RB cells (Y79 and WERI-RB-1). The SNAs were formed through the self-assembly of bifunctional cholesterol amphiphiles containing aptamers that specifically targeted GD2-positive RB cells, allowing for the formation of an SNA with a dense DNA shell. The aptamer/siRNA component functioned both as a carrier and a payload, enhancing the specific recognition and delivery of both components and constituting an active agent for MDM2 regulation. Following SNA endocytosis by RB cells, siRNA and NVP-CGM097 were released from the SNA particles by glutathione, which synergistically blocked the MDM2-p53 pathway, increasing p53 protein content and inducing cell apoptosis. This study showed a potent antitumor effect following intravitreal injection of SNAs in Y79 tumor-bearing mice through clinical manifestation and tumor pathological analysis. In hematological analysis and hepatotoxicity assays, SNAs were safer for mice than melphalan, the favored drug for treating RB in clinical practice. Our results illustrated the potential of intravitreally injected SNAs as a precision medicine for treating RB.
视网膜母细胞瘤（RB）是一种发生于眼底的儿童实体瘤。由于缺乏精准治疗方法，且难以将小干扰RNA（siRNA）递送至眼内，目前临床上尚无基于核酸的RB治疗方法。在此，我们报道了一种抗GD2且对谷胱甘肽有反应的球形核酸（SNA），其负载了siRNA和抑制剂NVP-CGM097，二者共同阻断RB细胞（Y79和WERI-RB-1）中的致癌因子n。SNA通过含有适配体的双功能胆固醇两亲分子自组装形成，这些适配体特异性靶向GD2阳性的RB细胞，从而形成具有致密DNA外壳的SNA。适配体/siRNA组分既作为载体又作为有效载荷，增强了两种组分的特异性识别和递送，并构成了调节MDM2的活性剂。RB细胞内吞SNA后，谷胱甘肽使siRNA和NVP-CGM097从SNA颗粒中释放出来，二者协同阻断MDM2-p53通路，增加p53蛋白含量并诱导细胞凋亡。通过临床表现和肿瘤病理分析，本研究显示在Y79荷瘤小鼠玻璃体内注射SNA后具有显著的抗肿瘤作用。在血液学分析和肝毒性试验中，SNA对小鼠而言比临床上治疗RB常用的药物美法仑更安全。我们的结果说明了玻璃体内注射SNA作为治疗RB的精准药物的潜力。
