A first-in-class non-cytotoxic nanocarrier based on a recombinant human ferritin boosts targeted therapy, chemotherapy and immunotherapy

To address the challenge of drug accumulation and penetration at the tumor site(s), herein we describe a first-in-class nanocarrier containing 24 copies each of two bioactive peptides (BAPs) genetically fused in frame to the 24 N-termini of a human ferritin H-type construct, named THE-10. The two BAPs are specific for PD-L1 and integrin αVβ3/αVβ5 plus Neuropilin (iRGD) respectively, conferring immune checkpoint blockade and drug-internalization properties. In turn, the THE-10 backbone brings 48 BAPs contiguous for synergism, prolonged blood half-life, and release into the tumor microenvironment upon conditional cleavage of a metalloprotease-sensitive site. Predicted THE-10 multitasking activity was experimentally supported as follows. Size-exclusion chromatography and surface plasmon resonance demonstrated BAP cleavage/release and receptor binding (nanomolar K<sub>D</sub>). Live-cell/time-lapse imaging demonstrated 4-fold-increased internalization of naked therapeutic antibodies, mirrored by enhanced cytotoxicity of the corresponding Antibody-Drug Conjugate. Slight antitumor effects were observed in vivo by treating immune checkpoint-sensitive syngeneic mouse colorectal model with THE-10 alone. Drug boosting was instead considerable on colorectal and pancreatic tumor allografts when THE-10 was co-administered with both small and large chemotherapeutic agents, outperforming the original iRGD cyclic peptide. Thus, THE-10 may enhance target therapy, chemotherapy and immunotherapy altogether, e.g. it candidates as a multitasking, all-round, antineoplastic therapy booster.

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Publication Details

Journal
International Journal of Biological Macromolecules
Published
2025-04-05
DOI
https://doi.org/10.1016/j.ijbiomac.2025.142843
Citations
3
Primary Topic
Nanoparticle-Based Drug Delivery
Type
article
Field-Weighted Citation Impact
1.79
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article

A first-in-class non-cytotoxic nanocarrier based on a recombinant human ferritin boosts targeted therapy, chemotherapy and immunotherapy

Leonid Sushytskyi, Emily Capone, Alessandro Arcovito, Peter J. Makovicky et al.
3 citations
International Journal of Biological Macromolecules
Nanoparticle-Based Drug Delivery
1.79
article

A first-in-class non-cytotoxic nanocarrier based on a recombinant human ferritin boosts targeted therapy, chemotherapy and immunotherapy

Leonid Sushytskyi, Emily Capone, Alessandro Arcovito, Peter J. Makovicky, Vincenzo De Laurenzi, Pavol Lukáč, Giada Tisci, Giovanna Ziccheddu, Lenka Rajsiglová, Elena Ricciardi, Gianluca Sala, Luca E. Vannucci, Patrizio Giacomini, Elisabetta Falvo, Sandra Bibbò, Gianni Colotti, Pierpaolo Ceci, Noah Giacon
article en
3 citations

Abstract

To address the challenge of drug accumulation and penetration at the tumor site(s), herein we describe a first-in-class nanocarrier containing 24 copies each of two bioactive peptides (BAPs) genetically fused in frame to the 24 N-termini of a human ferritin H-type construct, named THE-10. The two BAPs are specific for PD-L1 and integrin αVβ3/αVβ5 plus Neuropilin (iRGD) respectively, conferring immune checkpoint blockade and drug-internalization properties. In turn, the THE-10 backbone brings 48 BAPs contiguous for synergism, prolonged blood half-life, and release into the tumor microenvironment upon conditional cleavage of a metalloprotease-sensitive site. Predicted THE-10 multitasking activity was experimentally supported as follows. Size-exclusion chromatography and surface plasmon resonance demonstrated BAP cleavage/release and receptor binding (nanomolar K<sub>D</sub>). Live-cell/time-lapse imaging demonstrated 4-fold-increased internalization of naked therapeutic antibodies, mirrored by enhanced cytotoxicity of the corresponding Antibody-Drug Conjugate. Slight antitumor effects were observed in vivo by treating immune checkpoint-sensitive syngeneic mouse colorectal model with THE-10 alone. Drug boosting was instead considerable on colorectal and pancreatic tumor allografts when THE-10 was co-administered with both small and large chemotherapeutic agents, outperforming the original iRGD cyclic peptide. Thus, THE-10 may enhance target therapy, chemotherapy and immunotherapy altogether, e.g. it candidates as a multitasking, all-round, antineoplastic therapy booster.

International Journal of Biological MacromoleculesVol. 309(Pt 1)
Università Cattolica del Sacro Cuore (IT), University of Ostrava (CZ), Charles University (CZ), Agostino Gemelli University Polyclinic (IT), University of Chieti-Pescara (IT), Vitkovice - Research and Development (Czechia) (CZ), Institute of Microbiology (BY), Institute of Molecular Biology and Pathology (IT), Czech Academy of Sciences, Institute of Microbiology (CZ), National Cancer Institute (MY), National Research Council (IT), Sapienza University of Rome (IT), University of Chemistry and Technology, Prague (CZ)
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Nanoparticle-Based Drug Delivery
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