A first-in-class non-cytotoxic nanocarrier based on a recombinant human ferritin boosts targeted therapy, chemotherapy and immunotherapy
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
40187454
DOI
10.1016/j.ijbiomac.2025.142843
PII: S0141-8130(25)03395-1
Knihovny.cz E-resources
- Keywords
- Human ferritin nanocarrier, Peptide grafting, cancer therapy booster,
- MeSH
- Ferritins * chemistry genetics pharmacology MeSH
- Immunotherapy * MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Nanoparticles * chemistry MeSH
- Drug Carriers * chemistry MeSH
- Antineoplastic Agents pharmacology chemistry MeSH
- Recombinant Proteins chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Ferritins * MeSH
- Drug Carriers * MeSH
- Antineoplastic Agents MeSH
- Recombinant Proteins MeSH
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 KD). 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.
Department of Biochemical Sciences Sapienza University Rome Italy
Institute of Molecular Biology and Pathology Italian National Research Council IBPM CNR Rome Italy
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