In Situ Formation of Fibronectin-Enriched Protein Corona on Epigenetic Nanocarrier for Enhanced Synthetic Lethal Therapy.
Adv Sci (Weinh)
; 11(19): e2307940, 2024 May.
Article
em En
| MEDLINE
| ID: mdl-38482976
ABSTRACT
PARP inhibitors (PARPi)-based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5-azacytidine (AZA)-conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self-assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR-proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD-1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC).
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fibronectinas
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Carcinoma Pulmonar de Células não Pequenas
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Nanopartículas
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Neoplasias Pulmonares
Limite:
Animals
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Humans
Idioma:
En
Revista:
Adv Sci (Weinh)
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Alemanha