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

Abstract

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 (T opt = 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.

Urchin-like Fe3O4@Bi2S3 Nanospheres Enable the Destruction of Biofilm and Efficiently Antibacterial Activities

“…To evaluate the magnetic hyperthermia properties of Fe 3 O 4 and Fe 3 O 4 @Bi 2 S 3 nanospheres, the Fe 3 O 4 and Fe 3 O 4 @Bi 2 S 3 solutions (2 mL) with different concentrations were placed into a 5 mL insulated cryopreservation tube and placed inside the middle of the copper coil to apply an alternating magnetic field (AMF) (390 kHz, 18 A). The specific absorption rate (SAR) was employed to evaluate the magnetic hyperthermia efficiency captured per unit time . Infrared thermographic images showed that the Fe 3 O 4 and Fe 3 O 4 @Bi 2 S 3 groups emerged with a significant magnetothermal heating effect compared to the PBS group (Figure a) within 600 s of AMF.…”

Molecular Insights into the One-Carbon Loss Oxidation of Indole-3-acetic Acid

“…Previously, plant-derived HRP and human myeloperoxidase (MPO) were observed to promote the oxidation of IAA into IAld. This prompted us to utilize the HRP or MPO genes as queries to search for functionally similar enzymes from the L.…”

“…The precise microbial enzymes involved in IAA processing as well as their structure and activities have yet to be described. An early study has shown that plant peroxidases can catalyze the oxidation reaction of IAA to IAld with molecular oxygen . Interestingly, plant peroxidases and bacterial DyPs share some common substrates.…”

Designer Nanoreactors for Bioorthogonal Catalysis

“…Besides the catalytic metals, thermophilic enzymes can also be interfaced with magnetic NPs to induce non-native biochemical reactions. For example, Torres-Herrero et al synthesized a hybrid nanosystem containing three components: horseradish peroxidase (HRP) as a therapeutic enzyme and magnetic NP clusters as AMF-induced local heaters inside the silica container to employ for directed-enzyme-prodrug-therapy …”