适体 - 药物结合物的负载细菌用于胰腺癌协同疗法
Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy
影响因子:52.70000
分区:医学1区 Top / 生化与分子生物学1区 细胞生物学1区
发表日期:2024 Oct 14
作者:
Yu Xiao, Tao Pan, Wuren Da, Yuanding Liu, Shuangya Chen, Daiquan Chen, Keying Liu, Yihan Zheng, Daolong Xie, Yuan Gao, Haiyan Xu, Yang Sun, Weihong Tan
摘要
胰腺癌是死亡率最高的最恶性肿瘤之一，目前缺乏有效的药物。适体 - 药物缀合物（APDC）作为核酸药物的一种形式，在癌症治疗中表现出巨大的潜力。然而，基于核酸的药物在体内的不稳定性和胰腺癌的血管性具有致密基质的不稳定性限制了其应用。幸运的是，VNP20009是一种转基因鼠伤寒沙门氏菌的菌株，对厌氧环境有偏爱，但具有毒性且缺乏特异性，可以作为APDC的递送工具。在这里，我们提出了一种协同的治疗方法，该方法将细菌的穿透能力与APDC的靶向和毒性作用结合在一起，通过将APDC通过直接的一步点击化学结合到VNP20009。通过这种策略，细菌通过厌氧趋化性特异性靶向胰腺癌，随后粘附在适体特异性结合驱动的肿瘤细胞上。结果表明，与游离药物组相比，该方法将APDC的血清稳定性延长至48小时，并导致肿瘤部位的药物浓度增加。此外，适体与癌细胞的靶向结合在肿瘤部位的细菌定殖增加了三倍，从而导致肿瘤细胞的死亡和T细胞浸润增加。值得注意的是，通过整合化学疗法和免疫疗法，该治疗的有效性显着增强，在各种动物模型中都表现出一致的结果。总体而言，该策略利用细菌和APDC的优势，因此为胰腺癌治疗提供了有效的协同策略。
Abstract
Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer's specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer's targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.