期刊
GASTROENTEROLOGY
卷 161, 期 3, 页码 996-+出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2021.05.055
关键词
5FU; Pancreatic Cancer; Targeted Delivery; Aptamers
资金
- PePPP center of excellence [MV ESF/14-BM-A55-0045/16, ESF MV V-630-S-150-2012/132/133]
- Deutsche Forschungsgemeinschaft [DFG RE3754/2-1, SFB1321/1, 329628492]
- Forderprogramm fur Forschung und Lehre (FoFoLe) [1028]
- Friedrich-Baur-Stiftung [42/17]
- Wilhelm-Sander-Stiftung [2019.083.1]
- Bundesministerium fur Bildung und Forschung [01EK1511A]
The use of EGFR aptamers as carriers for targeted delivery of 5FU to pancreatic ductal adenocarcinoma cells has shown promising results, effectively reducing tumor growth and overcoming 5FU resistance. This approach has the potential to target various cancer entities sensitive to 5FU treatment.
BACKGROUNDS & AIMS: Fluoropyrimidine c (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 systematic evolution of ligands by exponential enrichment (SELEX)-selected epidermal growth factor receptor (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 showed EGFR-specific uptake of aptamers via clathrindependent endocytosis. The 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-Kras(G12D/+);LSL-Trp53(flox/+);Ptf1a-Cre [KPC]), in an orthotopic cell line-derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1(nu)), and in patient-derived organoids. Tumor growth was significantly attenuated during 5FU-EGFR aptamer treatment in the course of follow-up. CONCLUSIONS: Tumor-specific targeted delivery of 5FU using EGFR aptamers as the carrier achieved high target specificity; overcame 5FU resistance; and proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model, and in patient-derived organoids 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 cancer cell-targeting aptamers as the delivery platform.
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