Aptamer-Drug Conjugates-loaded Bacteria for Pancreatic Cancer Synergistic Therapy
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 an approach to synergistic therapy that utilizes the penetrative capability of bacteria and the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 via 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 hours 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. Overall design: First, bacteria act as microbial stealth bombers aimed at the tumor microenvironment (TME) through the aptamer's guidance system to deliver a potent drug payload, but also as protective shields for ApDC, effectively mitigating the risk of renal clearance and nuclease degradation. Second, owing to the bacterial predilection for the hypoxic TME and their innate tissue-penetrating capabilities, ApDC can navigate the otherwise formidable tumor stroma, ensuring precise drug delivery to the innermost tumor regions and achieving efficacious tumor cell killing. Moreover, leveraging the binding affinity of the nucleic acid aptamer Sgc8c to pancreatic cancer cells, these drug-loaded bacteria can proficiently transport the medication to the tumor site, thereby enhancing the therapeutic effect. Simultaneously, the proliferation of bacteria acts as a catalyst for an immune response, thereby facilitating a targeted combination therapy against tumors. This strategy effectively leverages the strengths of both ApDC-targeted therapy and bacterial therapy, presenting a promising strategy for the treatment of pancreatic cancer.