载有适体-药物结合物的细菌用于胰腺癌协同治疗

Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy

Signal Transduction and Targeted Therapy

影响因子:52.7

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

DOI: 10.1038/s41392-024-01973-3

摘要

胰腺癌是最具侵袭性的肿瘤之一，具有最高的死亡率，目前缺乏有效的药物。作为核酸药物的一种形式，适体-药物结合物（ApDC）在癌症治疗中展现出巨大潜力。然而，核酸类药物在体内的不稳定性以及胰腺癌的缺血性且富有密集基质的特性限制了其应用。幸运的是，VNP20009是一株具有偏好厌氧环境的转基因沙门氏菌菌株，但其毒性大且缺乏特异性，可潜在作为ApDC的递送载体。在此，我们提出了一种协同治疗策略，将细菌的穿透能力与ApDC的靶向性和毒性作用相结合，通过简单的一步点击化学将ApDC与VNP20009偶联。该策略使细菌通过厌氧趋化性特异性靶向胰腺癌，并在适体的特异性结合驱动下附着于肿瘤细胞。结果表明，该方法将ApDC的血清稳定性延长至48小时，并在肿瘤部位的药物浓度高于游离药物组。此外，适体对癌细胞的靶向结合使细菌在肿瘤部位的定植增加了三倍，导致肿瘤细胞死亡增加和T细胞浸润显著增强。值得注意的是，通过整合化疗和免疫治疗，显著提升了治疗效果，并在多种动物模型中取得一致的结果。总体而言，该策略利用细菌和ApDC的优势，提出了一种有效的胰腺癌协同治疗策略。

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.