Your browser doesn't support javascript.
loading
Widespread in vivo efficacy of The-0504: A conditionally-activatable nanoferritin for tumor-agnostic targeting of CD71-expressing cancers.
Fracasso, Giulio; Falvo, Elisabetta; Tisci, Giada; Sala, Gianluca; Colotti, Gianni; Cingarlini, Sara; Tito, Claudia; Bibbo, Sandra; Frusteri, Cristina; Tremante, Elisa; Giordani, Elena; Giacomini, Patrizio; Ceci, Pierpaolo.
Affiliation
  • Fracasso G; Department of Biomedical Sciences, University of Padua, 35131, Padua, Italy.
  • Falvo E; CNR-National Research Council of Italy, Institute of Molecular Biology and Pathology, 00185, Rome, Italy.
  • Tisci G; Department of Biochemical Sciences, Sapienza University of Rome, 00185, Rome, Italy.
  • Sala G; Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Chieti, Italy.
  • Colotti G; Center for Advanced Studies and Technology (CAST), Chieti, Italy.
  • Cingarlini S; CNR-National Research Council of Italy, Institute of Molecular Biology and Pathology, 00185, Rome, Italy.
  • Tito C; Section of Oncology, Verona University Hospital Trust, Verona, Italy.
  • Bibbo S; Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, 00185, Rome, Italy.
  • Frusteri C; Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Chieti, Italy.
  • Tremante E; Center for Advanced Studies and Technology (CAST), Chieti, Italy.
  • Giordani E; Department of Medicine, University of Verona, 37134, Verona, Italy.
  • Giacomini P; Department of Research, Advanced Diagnostics and Technological Innovation, UOC Translational Oncology Research, IRCCS National Cancer Institute Regina Elena, Via Elio Chianesi 53, 00144, Rome, Italy.
  • Ceci P; Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS National Cancer Institute Regina Elena, Via Elio Chianesi 53, 00144, Rome, Italy.
Heliyon ; 9(10): e20770, 2023 Oct.
Article in En | MEDLINE | ID: mdl-37860543
Background: Cancer is still among the leading causes of death all over the world. Improving chemotherapy and minimizing associated toxicities are major unmet medical needs. Recently, we provided a preliminary preclinical evaluation of a human ferritin (HFt)-based drug carrier (The-0504) that selectively delivers the wide-spectrum topoisomerase I inhibitor Genz-644282 to CD71-expressing tumors. The-0504 has so far been evaluated on four different human tumor xenotransplant models (breast, colorectal, pancreatic and liver cancers). Methods: Herein, we extend our studies, by: (a) testing DNA damage in vitro, (b) treating eight additional tumor xenograft models in vivo with The-0504; (c) performing pharmacokinetic (PK) studies in rats; and (d) evaluating The-0504 anti-tumor xenotransplant efficacy by optimizing its administration schedule based on PK considerations. Results: Immunofluorescence demonstrated that The-0504 induces foci expressing the DNA double-strand break marker γH2AX. Expression increases up to 4-fold and is more persistent as compared to free Genz-644282. In vivo studies confirmed a remarkable anti-tumor activity of The-0504, resulting in tumor eradication in most murine xenograft models, regardless of embryological origin (e.g. epithelial, mesenchymal or neuroendocrine), and molecular subtypes. PK studies demonstrated a long persistence of The-0504 in rat serum (half-life of about 40 h as compared to 15 h of the free drug), with a 400-fold increase in peak concentrations as compared to the free drug. On this basis, we reduced The-0504 administration frequency from twice to once per week, with no appreciable loss in therapeutic efficacy in mice. Conclusion: The results presented here confirm that The-0504 is highly active against several human tumor xenotransplants, even when administered less frequently than previously reported. The-0504 may be a good candidate for further clinical development in a tumor histotype-agnostic setting.
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Heliyon Year: 2023 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Heliyon Year: 2023 Document type: Article