Mahajan, U. M., Li, Q., Alnatsha, A., Maas, J., Orth, M., Maier, S. H., Peterhansl, J., Regel, I., Sendler, M., Wagh, P. R., Mishra, N., Xue, Y., Allawadhi, P., Beyer, G., Kuhn, J. P., Marshall, T., Appel, B., Lammerhirt, F., Belka, C., Muller, S., Weiss, F. U., Lauber, K., Lerch, M. M., and Mayerle, J. (2021). Gastroenterology 161, 996-1010 e1011. doi: 10.1053/j.gastro.2021.05.055
Backgrounds and aims: Fluoropyrimidine 5-fluorouracil (5FU) increasingly represents the chemotherapeutic backbone for neoadjuvant, adjuvant and palliative treatment of pancreatic ductal adenocarcinoma (PDAC). Even in combination with other agents, 5FU efficacy remains transient and limited. One explanation for the inadequate response is insufficient and nonspecific delivery of 5FU to the tumor.
Methods: We designed, generated and characterized 5FU-incorporated SELEX-selected EGFR-targeted aptamers for tumor-specific delivery of 5FU to PDAC cells and tested their therapeutic efficacy in vitro and in vivo.
Results: 5FU-EGFR-aptamers reduced proliferation in a concentration-dependent manner in mouse and human pancreatic cancer cell lines. Time-lapsed live imaging revealed EGFR-specific uptake of aptamers via clathrin-dependent endocytosis. 5FU-aptamer treatment was equally effective in 5FU-sensitive and 5FU-refractory PDAC cell-lines. Biweekly treatment with 5FU-EGFR-aptamers reduced tumor burden in a syngeneic orthotopic transplantation model of PDAC, in an autochthonously growing genetically engineered PDAC model (LSL-KrasG12D/+, LSL-Trp53flox/+, Ptf1a-Cre (KPC)), in an orthotopic cell-line derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1nu) as well as in patient-derived organoids (PDOs). Tumor growth was significantly attenuated during 5FU-EGFR-aptamer treatment in the course of follow-up.
Conclusion: Tumor-specific targeted delivery of 5FU using EGFR-aptamers as carrier achieved high target specificity, overcame 5FU resistance, proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model as well as PDOs and therefore represents a promising backbone for pancreatic cancer chemotherapy in patients. Furthermore, our approach has the potential to target virtually any cancer entity sensitive to 5FU treatment by incorporating 5FU into a cancer-cell-targeting aptamers as delivery platform.