Mobile Magnetic Nanocatalysts for Bioorthogonal Targeted Cancer Therapy

Abstract

The use of magnetic nanorobots to activate chemotherapeutic prodrugs represents a promising alternative to current chemotherapeutic treatments. Here, a hybrid nanowire (NW) for targeted bioorthogonally driven activation of the latent chemotherapeutic prodrug 5‐fluoro‐1‐propargyl‐uracil (Pro‐5‐FU) in in vitro and in vivo cancer models is proposed. The NWs are composed of magnetic iron (Fe) and palladium (Pd), a known bioorthogonal catalyst. In vitro tests with a cancer cell line showed no significant cytotoxic effect by the NWs. In contrast, NWs combined with Pro‐5‐FU lead to a significant reduction of cell viability, similarly to the one induced by its active chemotherapeutic counterpart 5‐fluorouracil (5‐FU). The reduction in cell viability is attributed to the catalytic activation of Pro‐5‐FU into 5‐FU. To demonstrate their targeted therapeutic abilities, magnetic fields are used to attract the FePd NWs to a predefined area within a cultured cancer cell population, causing a local Pro‐5‐FU activation, and subsequent cell death in this region. As a proof of concept, NWs are injected in cancer tumor xenografts. The intraperitoneal injection of Pro‐5‐FU significantly retards tumour growth without causing significant side effects. This work presents a novel chemotherapeutic approach combining nanorobotics and bioorthogonal activation of prodrugs as an efficient alternative to conventional chemotherapy.

Catalysis Concepts in Medicinal Inorganic Chemistry

“…By placing am agnet under specific regions of aP etri dish, they could attract the magnetic catalysts in defined areas where they triggeredt he activation of the prodrug and induced cell death with spatial control.F ePd nanowires injected in tumors and intraperitoneal administration of 5FU significantly reduced tumor growth in mice models. [59] The group of Bradley proposedadiverseb ioorthogonal catalysis concept applying copper-catalyzed azide-alkyne cycloaddition (CuAAC) for the in situ synthesis of ac ytotoxic Combretastatind erivativei nt he extracellular milieu. Combretastatin A4 is at ubulin polymerization inhibitor and ah ighly cytotoxic agent against av arietyo fc ancer cell lines.…”

Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium‐Functionalized Microdevices

“…Cells were independently treated with Pd‐microdevices (1 mg mL −1 ) or 2 c (−ve controls) or in combination (activation assay) and compared to treatment with unmodified 1 (+ve control) across a range of concentrations. As expected, the devices (which are larger than cells and remain in the extracellular space) displayed no toxic effect. In contrast, the Pd‐devices/ 2 c combination led to potent antiproliferative effect in all cell lines, slightly lower than that mediated by direct treatment with 1 .…”

“…Palladium (Pd) catalysts are one of the tools of choice currently under investigation to release caged drugs in vitro and in vivo . The selection of this metal is based on its high bio‐compatibility, its versatility to adopt different shapes and sizes and its remarkable capabilities to catalyze N ‐ and O ‐dealkylation reactions on manifold types of substrates under physiological conditions .…”

Dissociative Bioorthogonal Reactions

“…[23] Metallic Pd nanoparticlesc an also remove proc groups. [24] These nanoparticles effectively deprotected proc-protected aminocoumarin, achieving 95 %c onversion within minutes in HEPES/DMSO( 95:5) with stoichiometricP d 0 .M oreover,i tw as demonstrated that Pd 0 resins [25] and ah ybrid magnetic iron and Pd nanowire [26] werea ble to deprotect propargyl groups from 5-fluorouracil.…”