Widespread in vivo efficacy of The-0504 : A conditionally-activatable nanoferritin for tumor-agnostic targeting of CD71-expressing cancers
© 2023 The Authors..
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
---|---|
Enthalten in: |
Heliyon - 9(2023), 10 vom: 07. Okt., Seite e20770 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Fracasso, Giulio [VerfasserIn] |
---|
Links: |
---|
Themen: |
Genz-644282 |
---|
Anmerkungen: |
Date Revised 21.10.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
---|
doi: |
10.1016/j.heliyon.2023.e20770 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM363529489 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM363529489 | ||
003 | DE-627 | ||
005 | 20231226093536.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1016/j.heliyon.2023.e20770 |2 doi | |
028 | 5 | 2 | |a pubmed24n1211.xml |
035 | |a (DE-627)NLM363529489 | ||
035 | |a (NLM)37860543 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Fracasso, Giulio |e verfasserin |4 aut | |
245 | 1 | 0 | |a Widespread in vivo efficacy of The-0504 |b A conditionally-activatable nanoferritin for tumor-agnostic targeting of CD71-expressing cancers |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Revised 21.10.2023 | ||
500 | |a published: Electronic-eCollection | ||
500 | |a Citation Status PubMed-not-MEDLINE | ||
520 | |a © 2023 The Authors. | ||
520 | |a 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) | ||
520 | |a 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 | ||
520 | |a 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 | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Genz-644282 | |
650 | 4 | |a Human ferritin | |
650 | 4 | |a Solid cancer | |
650 | 4 | |a Targeted therapy | |
650 | 4 | |a Transferrin receptor (CD71) | |
700 | 1 | |a Falvo, Elisabetta |e verfasserin |4 aut | |
700 | 1 | |a Tisci, Giada |e verfasserin |4 aut | |
700 | 1 | |a Sala, Gianluca |e verfasserin |4 aut | |
700 | 1 | |a Colotti, Gianni |e verfasserin |4 aut | |
700 | 1 | |a Cingarlini, Sara |e verfasserin |4 aut | |
700 | 1 | |a Tito, Claudia |e verfasserin |4 aut | |
700 | 1 | |a Bibbo, Sandra |e verfasserin |4 aut | |
700 | 1 | |a Frusteri, Cristina |e verfasserin |4 aut | |
700 | 1 | |a Tremante, Elisa |e verfasserin |4 aut | |
700 | 1 | |a Giordani, Elena |e verfasserin |4 aut | |
700 | 1 | |a Giacomini, Patrizio |e verfasserin |4 aut | |
700 | 1 | |a Ceci, Pierpaolo |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Heliyon |d 2015 |g 9(2023), 10 vom: 07. Okt., Seite e20770 |w (DE-627)NLM255913095 |x 2405-8440 |7 nnns |
773 | 1 | 8 | |g volume:9 |g year:2023 |g number:10 |g day:07 |g month:10 |g pages:e20770 |
856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.heliyon.2023.e20770 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 9 |j 2023 |e 10 |b 07 |c 10 |h e20770 |