Remote Activation of Enzyme Nanohybrids for Cancer Prodrug Therapy Controlled by Magnetic Heating

Herein, we have developed nanohybrids (nHs) to remotelyactivatea therapeutic enzyme for its use in Directed Enzyme Prodrug Therapy(DEPT). The coencapsulation of magnetic nanoparticles (MNPs) withhorseradish peroxidase (HRP) using biomimetic silica as an entrapmentmatrix was optimized to obtain nanosized hybrids (& SIM;150 nm)for remote activation of the therapeutic enzyme. HRP converts indole-3-aceticacid (3IAA) into peroxylated radicals, whereas MNPs respond to alternatingmagnetic fields (AMFs) becoming local hotspots. The AMF applicationtriggered an increase in the bioconversion rate of HRP matching theactivity displayed at the optimal temperature of the nHs (T (opt) = 50 & DEG;C) without altering the temperatureof the reaction media. This showed that enzyme nanoactuation is possiblewith MNPs even if they are not covalently bound. After an extensivephysicochemical/magnetic characterization, the spatial location ofeach component of the nH was deciphered, and an insulating role ofthe silica matrix was suggested as critical for introducing remotecontrol over HRP. In vitro assays, using a humanpancreatic cancer cell line (MIA PaCa-2), showed that only upon exposureto AMF and in the presence of the prodrug, the enzyme-loaded nHs triggeredcell death. Moreover, in vivo experiments showedhigher reductions in the tumor volume growth in those animals treatedwith nHs in the presence of 3IAA when exposed to AMF. Thus, this workdemonstrates the feasibility of developing a spatiotemporally controlledDEPT strategy to overcome unwanted off-target effects.

Automated summary

Here, researchers have developed nanohybrids (nHs) for remote activation of a therapeutic enzyme in Directed Enzyme Prodrug Therapy (DEPT). The nanosized hybrids, composed of magnetic nanoparticles (MNPs) and horseradish peroxidase (HRP) encapsulated in biomimetic silica, were optimized for efficient remote activation of the therapeutic enzyme. The application of alternating magnetic fields (AMFs) to MNPs increased the bioconversion rate of HRP, demonstrating the possibility of enzyme nanoactuation with co-encapsulated MNPs. In vitro and in vivo experiments showed that the enzyme-loaded nHs triggered cell death and significantly reduced tumor volume growth when exposed to AMFs, highlighting the potential of this spatiotemporally controlled DEPT strategy to overcome off-target effects.