Modular Drug-Loaded Nanocapsules with Metal Dome Layers as a Platform for Obtaining Synergistic Therapeutic Biological Activities.

Multifunctional drug-loaded polymer-metal nanocapsules have attracted increasing attention in drug delivery due to their multifunctional potential endowed by drug activity and response to physicochemical stimuli. Current chemical synthesis methods of polymer/metal capsules require specific optimization of the different components to produce particles with precise properties, being particularly complex for Janus structures combining polymers and ferromagnetic and highly reactive metals. With the aim to generate tunable synergistic nanotherapeutic actuation with enhanced drug effects, here we demonstrate a versatile hybrid chemical/physical fabrication strategy to incorporate different functional metals with tailored magnetic, optical, or chemical properties on solid drug-loaded polymer nanoparticles. As archetypical examples, we present poly(lactic-co-glycolic acid) (PLGA) nanoparticles (diameters 100-150 nm) loaded with paclitaxel, indocyanine green, or erythromycin that are half-capped by either Fe, Au, or Cu layers, respectively, with application in three biomedical models. The Fe coating on paclitaxel-loaded nanocapsules permitted efficient magnetic enhancement of the cancer spheroid assembly, with 40% reduction of the cross-section area after 24 h, as well as a higher paclitaxel effect. In addition, the Fe-PLGA nanocapsules enabled external contactless manipulation of multicellular cancer spheroids with a speed of 150 µm/s. The Au-coated and indocyanine green-loaded nanocapsules demonstrated theranostic potential and enhanced anticancer activity in vitro and in vivo due to noninvasive fluorescence imaging with long penetration near-infrared (NIR) light and simultaneous photothermal-photodynamic actuation, showing a 3.5-fold reduction in the tumor volume growth with only 5 min of NIR illumination. Finally, the Cu-coated erythromycin-loaded nanocapsules exhibited enhanced antibacterial activity with a 2.5-fold reduction in the MIC50 concentration with respect to the free or encapsulated drug. Altogether, this technology can extend a nearly unlimited combination of metals, polymers, and drugs, thus enabling the integration of magnetic, optical, and electrochemical properties in drug-loaded nanoparticles to externally control and improve a wide range of biomedical applications.

Efficient Tumor Eradication at Ultralow Drug Concentration via Externally Controlled and Boosted Metallic Iron Magnetoplasmonic Nanocapsules.

With the aim to locally enhance the efficacy of cancer nanotherapies, here we present metal iron based magnetoplasmonic drug-loaded nanocapsules (MAPSULES), merging powerful external magnetic concentration in the tumor and efficient photothermal actuation to locally boost the drug therapeutic action at ultralow drug concentrations. The MAPSULES are composed of paclitaxel-loaded polylactic-co-glycolic acid (PLGA) nanoparticles partially coated by a nanodome shape iron/silica semishell. The iron semishell has been designed to present a ferromagnetic vortex for incorporating a large quantity of ferromagnetic material while maintaining high colloidal stability. The large iron semishell provides very strong magnetic manipulation via magnetophoretic forces, enabling over 10-fold higher trapping efficiency in microfluidic channels than typical superparamagnetic iron oxide nanoparticles. Moreover, the iron semishell exhibits highly damped plasmonic behavior, yielding intense broadband absorbance in the near-infrared biological windows and photothermal efficiency similar to the best plasmonic nanoheaters. The in vivo therapeutic assays in a mouse xenograft tumor model show a high amplification of the therapeutic effects by combining magnetic concentration and photothermal actuation in the tumor, leading to a complete eradication of the tumors at ultralow nanoparticle and drug concentration (equivalent to only 1 mg/kg PLGA nanoparticles containing 8 µg/kg of paclitaxel, i.e., 100-500-fold lower than the therapeutic window of the free and PLGA encapsulated drug and 13-3000-fold lower than current nanotherapies combining paclitaxel and light actuation). These results highlight the strength of this externally controlled and amplified therapeutic approach, which could be applied to locally boost a wide variety of drugs for different diseases.

Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway.

The evolution of resistance by the malaria parasite to artemisinin, the key component of the combination therapy strategies that are at the core of current antimalarial treatments, calls for the urgent identification of new fast-acting antimalarials. The apicoplast organelle is a preferred target of antimalarial drugs because it contains biochemical processes absent from the human host. Fosmidomycin is the only drug in clinical trials targeting the apicoplast, where it inhibits the methyl erythritol phosphate (MEP) pathway. Here, we characterized the antiplasmodial activity of domiphen bromide (DB), another MEP pathway inhibitor with a rapid mode of action that arrests the in vitro growth of Plasmodium falciparum at the early trophozoite stage. Metabolomic analysis of the MEP pathway and Krebs cycle intermediates in 20 µM DB-treated parasites suggested a rapid activation of glycolysis with a concomitant decrease in mitochondrial activity, consistent with a rapid killing of the pathogen. These results present DB as a model compound for the development of new, potentially interesting drugs for future antimalarial combination therapies.