The Synergy of Bacteria and Nucleic Acid Drugs: A New Breakthrough in Pancreatic Cancer with ApDC and VNP20009

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), has long been a formidable challenge in cancer research. With a high mortality rate and limited effectiveness of traditional therapies, we have continually searched for innovative strategies to offer hope to patients. Our focus turned to the promising field of nucleic acid aptamer drug conjugates (ApDC) as a novel, targeted therapeutic approach.

The Story of ApDC: Why We Chose It for Pancreatic Cancer

Our journey began with aptamers—small, single-stranded DNA or RNA molecules with strong targeting abilities, capable of recognizing and binding to specific proteins on the surface of cancer cells. In the case of pancreatic cancer, the PTK7 protein is an ideal target, and we selected the Sgc8c aptamer for its ability to precisely bind to these cancer cells. To boost therapeutic efficacy, we conjugated the potent chemotherapy drug monomethyl auristatin E (MMAE) with the aptamer, creating a nucleic acid aptamer drug conjugate (ApDC). This discovery was exciting, especially because there are currently no FDA-approved ADC drugs for pancreatic cancer, leaving a significant gap in treatment options.

We realized that ApDC offers unique advantages over traditional antibody-drug conjugates (ADC). Specifically, ApDCs have superior tissue penetration and are easier to modify compared to antibody-based ADCs. These properties make them particularly suited for pancreatic cancer, where the dense stroma often limits the effectiveness of larger molecules like antibodies. With Sgc8c’s ability to target PTK7, we believe this strategy is designed to meet the specific challenges of pancreatic cancer treatment.

Although ApDCs seem flawless in design, we quickly encountered the problem of limited stability in vivo. Extending its stability within the body became our top priority.

VNP20009: Injecting New Energy into ApDC

In our search for a solution, we turned to VNP20009, a genetically modified attenuated strain of Salmonella. This facultative anaerobic bacterium has a preference for hypoxic environments, making it an ideal candidate for targeting the tumor microenvironment of pancreatic cancer. Even more importantly, VNP20009 can penetrate the dense stroma of pancreatic tumors, making it the perfect vehicle to deliver ApDC to the tumor site.

 Using a simple click chemistry reaction, we conjugated a large amount of ApDC onto the surface of the bacteria. The bacteria not only create a protective “steric shield” around the ApDC, improving its stability in vivo, but also serve as a “delivery vehicle,” helping it penetrate the physical barriers of the tumor and effectively release the drug inside. Moreover, VNP20009 triggers a localized inflammatory response, attracting immune cells to the tumor, further enhancing the anti-tumor immune response.

This combination significantly improved the stability of ApDC, extending its serum half-life to 48 hours. Even more exciting, in animal models, the synergy between the bacteria and ApDC resulted in a substantial increase in drug concentration within the tumor and significantly higher tumor cell death rates.

Fig 1. Schematic illustrating the construction of functionalized bacteria and the mechanism against pancreatic tumors.

Challenges and Breakthroughs: The Path of Research

The path of scientific research is never smooth. In the early stages of our experiments, we encountered many challenges, especially in safely and effectively delivering both the bacteria and the drug. Each failure pushed us to think more deeply about how to balance the safety of the bacteria with the efficacy of the drug.

One of the main challenges was managing the potential toxicity of using live bacterial vectors while ensuring ApDC’s therapeutic effects. We had to repeatedly adjust bacterial concentrations and dosing regimens, continually optimizing the system until we found the right balance. After numerous trials and modifications, we finally identified the ideal concentration and delivery method that allowed for safe transport of ApDC to the tumor while addressing the unique challenges of the pancreatic cancer microenvironment.

Looking Ahead: The Boundless Potential of ApDC

Our research not only highlights the tremendous potential of ApDC in targeted cancer therapy but also showcases how VNP20009 enhances its efficacy through synergy. The complexity of pancreatic cancer makes it difficult for current therapies to succeed, but we believe that as this new therapeutic approach is further refined, it could offer new hope to patients.

The future of cancer treatment may very well lie in dual therapies, combining advanced molecular drugs like ApDC with innovative delivery systems such as VNP20009. By simultaneously addressing the issues of drug stability and tumor penetration, this strategy promises a more effective and less toxic treatment option for pancreatic cancer.

Every step forward in science is filled with unknowns and challenges, but we are confident that this innovative strategy not only provides a new treatment option for pancreatic cancer but also paves the way for future breakthroughs in cancer therapy.