1. Tumor-Specific Delivery of 5-Fluorouracil-Incorporated Epidermal Growth Factor Receptor-Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models.
- Author
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Mahajan UM, Li Q, Alnatsha A, Maas J, Orth M, Maier SH, Peterhansl J, Regel I, Sendler M, Wagh PR, Mishra N, Xue Y, Allawadhi P, Beyer G, Kühn JP, Marshall T, Appel B, Lämmerhirt F, Belka C, Müller S, Weiss FU, Lauber K, Lerch MM, and Mayerle J
- Subjects
- Animals, Antimetabolites, Antineoplastic metabolism, Aptamers, Nucleotide metabolism, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Cell Line, Tumor, Cell Proliferation drug effects, Drug Resistance, Neoplasm, Endocytosis, ErbB Receptors genetics, Female, Fluorouracil metabolism, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Organoids, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, SELEX Aptamer Technique, Tumor Burden drug effects, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Mice, Antimetabolites, Antineoplastic administration & dosage, Aptamers, Nucleotide administration & dosage, Carcinoma, Pancreatic Ductal drug therapy, Drug Delivery Systems, ErbB Receptors metabolism, Fluorouracil administration & dosage, Pancreatic Neoplasms drug therapy
- Abstract
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 clathrin-dependent 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-Trp53flox/+ ;Ptf1a-Cre [KPC]), in an orthotopic cell line-derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1nu ), 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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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