期刊
HELIYON
卷 9, 期 10, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.heliyon.2023.e20770
关键词
Targeted therapy; Solid cancer; Human ferritin; Transferrin receptor (CD71); Genz-644282
The study demonstrated the effectiveness of utilizing the HFt-based drug carrier The-0504 to deliver Genz-644282 inhibitor to CD71-expressing tumors, showing promising anti-tumor activity. The drug exhibited long persistence in rat serum, allowing for reduced administration frequency without compromising therapeutic efficacy.
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 gamma H2AX. Expression increases up to 4-fold and is more persistent ascompared 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.
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