Development of pH-Sensitive Metal-Organic Framework (MOF) for Targeted Drug Delivery in Pancreatic Cancer Treatment

Background

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with a five-year survival rate of less than 5%1 . Treatment options are often ineffective due to the advanced stage at diagnosis and the aggressive nature of the disease. Chemotherapy remains a cornerstone in PDAC treatment, but its non-specific toxicity often reduces its overall effectiveness and is frequently associated with severe side effects1 . Consequently, researchers are increasingly focusing on developing newer, more targeted therapies that offer improved efficacy with reduced toxicity. Over 90% of pancreatic cancer cases are driven by mutations in the Kirsten rat sarcoma viral oncogene (KRAS), particularly the G12D, G12V, and G12R variants, which result in continuous activation of KRAS and fuel tumour growth2 . KRASG12D mutations occur in nearly 40% of PDAC. Recent advances in precision medicine have demonstrated significant potential with MRTX1133, a KRASG12D inhibitor, in preclinical studies3 . Notably, combination therapy with MRTX1133 and the chemotherapy regimen of gemcitabine/(n)ab-paclitaxel (GnP) has induced tumour regressions and substantially reduced the likelihood of relapse, leading to prolonged tumour growth inhibition3 . However, despite these promising results, there remains a critical need to develop more targeted and effective delivery systems to further optimise the efficacy of both KRAS inhibitors and standard chemotherapy, maximising therapeutic benefits while minimising side effects. Metal-organic frameworks (MOFs) offer an innovative solution due to their tunable porous structures4 , high drug-loading capacity, and ability to release therapeutic agents in response to specific environmental stimuli, such as the acidic tumour microenvironment typical in pancreatic cancer (pH 5.5- 7.0). This project proposes encapsulating the KRASG12D inhibitor MRTX1133, alongside chemotherapeutic agents like GnP, within MOFs for controlled and targeted release, potentially improving the efficacy of pancreatic cancer treatments.

Aims

The primary aim of this project is to develop a pH-sensitive MOF for targeted drug delivery in pancreatic cancer treatment, specifically targeting the KRAS mutation. Preclinical studies will utilise the KPC (KrasLSL-G12D/+; Trp53R172H/+; Pdx1-Cre) mouse model1 to evaluate the efficacy of the MOF system in delivering both the inhibitor and chemotherapeutic agents in a controlled manner, reducing off-target toxicity and enhancing therapeutic efficiency.

Training Outcomes

Technical Expertise: The student will develop a deep understanding of advanced materials synthesis and characterisation, including MOF synthesis, drug encapsulation, pH-sensitive release studies, and detailed characterisation using spectroscopic and imaging techniques. 

Preclinical Models: The student will gain hands-on experience with pancreatic cancer cell lines in vitro and genetically engineered mouse models (KPC), conducting in vivo preclinical trials, analysing tumour regression, and assessing survival outcomes. 

Interdisciplinary Collaboration: The project will involve collaboration between experts in materials chemistry, cancer biology, drug discovery and clinical oncology. The student will develop skills in interdisciplinary research, communication, and team-based problem-solving.

References

1. Dis Model Mech., 2015, 8, 1185–1200. https://doi.org/10.1242/dmm.021055 

2. JNCI, 2024, 116, 1429–1438. https://doi.org/10.1093/jnci/djae095 

3. Cancer Discovery. 2024. Online ahead of print. https://doi.org/10.1158/2159-8290.CD-24-0177 

4. J. Am. Chem. Soc., 2016, 138, 962−968. https://doi.org/10.1021/jacs.5b11720