Remote activation of enzyme nanohybrids for cancer prodrug therapy controlled by magnetic heating

Torres-Herrero, B. ; Armenia, I. ; Alleva, M. ; Asín, L. ; Correa, S. ; Ortiz, C. ; Fernández-Afonso, Y. ; Gutiérrez, L. (Universidad de Zaragoza) ; Martínez De la Fuente, J. ; Betancor, L. ; Grazú, V.

Resumen: Herein, we have developed nanohybrids (nHs) to remotely activate a therapeutic enzyme for its use in Directed Enzyme Prodrug Therapy (DEPT). The coencapsulation of magnetic nanoparticles (MNPs) with horseradish peroxidase (HRP) using biomimetic silica as an entrapment matrix was optimized to obtain nanosized hybrids (∼150 nm) for remote activation of the therapeutic enzyme. HRP converts indole-3-acetic acid (3IAA) into peroxylated radicals, whereas MNPs respond to alternating magnetic fields (AMFs) becoming local hotspots. The AMF application triggered an increase in the bioconversion rate of HRP matching the activity displayed at the optimal temperature of the nHs (Topt = 50 °C) without altering the temperature of the reaction media. This showed that enzyme nanoactuation is possible with MNPs even if they are not covalently bound. After an extensive physicochemical/magnetic characterization, the spatial location of each component of the nH was deciphered, and an insulating role of the silica matrix was suggested as critical for introducing remote control over HRP. In vitro assays, using a human pancreatic cancer cell line (MIA PaCa-2), showed that only upon exposure to AMF and in the presence of the prodrug, the enzyme-loaded nHs triggered cell death. Moreover, in vivo experiments showed higher reductions in the tumor volume growth in those animals treated with nHs in the presence of 3IAA when exposed to AMF. Thus, this work demonstrates the feasibility of developing a spatiotemporally controlled DEPT strategy to overcome unwanted off-target effects.

Idioma: Inglés

DOI: 10.1021/acsnano.3c01599

Año: 2023

Publicado en: ACS NANO 17, 13 (2023), 12358-12373
ISSN: 1936-0851

Factor impacto JCR: 15.8 (2023)

Categ. JCR: CHEMISTRY, PHYSICAL rank: 14 / 178 = 0.079 (2023) - Q1 - T1
Categ. JCR: NANOSCIENCE & NANOTECHNOLOGY rank: 11 / 141 = 0.078 (2023) - Q1 - T1
Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 15 / 231 = 0.065 (2023) - Q1 - T1
Categ. JCR: MATERIALS SCIENCE, MULTIDISCIPLINARY rank: 27 / 439 = 0.062 (2023) - Q1 - T1

Factor impacto CITESCORE: 26.0 - Engineering (all) (Q1) - Materials Science (all) (Q1) - Physics and Astronomy (all) (Q1)

Factor impacto SCIMAGO: 4.593 - Engineering (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Nanoscience and Nanotechnology (Q1) - Materials Science (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E15-20R
Financiación: info:eu-repo/grantAgreement/EC/H2020/829162/EU/Redesigning biocatalysis: Thermal-tuning of one-pot multienzymatic cascades by nanoactuation/HOTZYMES
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CB16-01/00263
Financiación: info:eu-repo/grantAgreement/ES/MCIU/FPU19-01311
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2020-118485RB-I00

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Química Analítica (Dpto. Química Analítica)