Ultrafast Directional Janus Pt-Mesoporous Silica Nanomotors for Smart Drug Delivery

Abstract

Development of bioinspired nanomachines with an efficient propulsion and cargo-towing has attracted much attention in the last years due to their potential biosensing, diagnostics, and therapeutics applications. In this context, self-propelled synthetic nanomotors are promising carriers for intelligent and controlled release of therapeutic payloads. However, the implementation of this technology in real biomedical applications is still facing several challenges. Herein, we report the design, synthesis, and characterization of innovative multifunctional gated platinum-mesoporous silica nanomotors constituted of a propelling element (platinum nanodendrite face), a drug-loaded nanocontainer (mesoporous silica nanoparticle face), and a disulfide-containing oligo(ethylene glycol) chain (S-S-PEG) as a gating system. These Janus-type nanomotors present an ultrafast self-propelled motion due to the catalytic decomposition of low concentrations of hydrogen peroxide. Likewise, nanomotors exhibit a directional movement, which drives the engines toward biological targets, THP-1 cancer cells, as demonstrated using a microchip device that mimics penetration from capillary to postcapillary vessels. This fast and directional displacement facilitates the rapid cellular internalization and the on-demand specific release of a cytotoxic drug into the cytosol, due to the reduction of the disulfide bonds of the capping ensemble by intracellular glutathione levels. In the microchip device and in the absence of fuel, nanomotors are neither able to move directionally nor reach cancer cells and deliver their cargo, revealing that the fuel is required to get into inaccessible areas and to enhance nanoparticle internalization and drug release. Our proposed nanosystem shows many of the suitable characteristics for ideal biomedical destined nanomotors, such as rapid autonomous motion, versatility, and stimuli-responsive controlled drug release.

Keywords: Janus nanomotors; directional motion; drug delivery; on-command controlled release; ultrafast self-propulsion.

Scheme 1. Schematic illustration of Janus Pt-MSNs nanomotors with a catalytic self-propulsion and a glutathione-mediated drug release.

Figure 1

HR-TEM images of Janus Pt-MSNs (S₀) (A, B) and PtNds (C, D), showing the interplanar spacing of 2.3 Å in the (111) plane of PtNd crystals.

Figure 2

STEM image (A), STEM-EDX elemental mapping of Si atoms (B), O atoms (C), Pt atoms (D), and S atoms (E), and wt % composition detected (F) in S₁ Janus Pt-MSNPs.

Figure 3

Motion characterization of Janus Pt-MSN S₁ nanomotors. (A) Mean squared displacement as a function of time interval for the nanomotors at 0% (black), 0.017% (green), 0.07% (blue), 0.2% (orange), and 0.35% (red) fuel concentration. Curves were fitted using the equations shown in the figure. (B) Velocity of nanomotors at different fuel concentrations (N = 20; error bars represent the standard error of the mean velocities obtained). (C) Trajectories for 20 Janus Pt-MSN S₁ nanomotors in PBS solution (a) and 0.07% (b) and 0.35% (c) hydrogen peroxide solutions.

Figure 4

Normalized cargo release from S₁ nanomotors in static conditions determined by measuring Ru(bpy)₃Cl₂ fluorescence (at 544 nm) vs time in aqueous solution (50 mM PBS pH 7.5), using (a) nanomotors without GSH and without H₂O₂ addition, (b) 0.1% H₂O₂-propelled nanomotors without GSH addition, (c) nanomotors with 10 mM GSH addition and without H₂O₂, and (d) 0.1% H₂O₂-propelled nanomotors with 10 mM GSH addition (A). Relation between H₂O₂ (%), velocities, and normalized cargo release (%) from S₁ nanomotors (B).

Figure 5

(A) Confocal microscopy images of internalization and controlled doxorubicin release of the S₂ nanodevice in THP-1 cells at different times. THP-1 cells treated with 50 μg mL^–1 of S₂ nanomotors in the absence of fuel (a); THP-1 cells treated with 50 μg mL^–1 of S₂ in a medium containing 0.02% H₂O₂ (b). From left to right: doxorubicin fluorescence, DNA, and membrane fluorescence marker (Hoechst 3342 and WGA, respectively) and combined (merge). (B) Mean fluorescence intensity quantification in cells from confocal images at different times and with or without the addition of fuel. (C) TEM image of S₂ nanomotor (100 μg mL^–1) internalization in THP-1 cells after 6 h.

Figure 6

Three-dimensional scheme depicting the assay followed to study self-propulsion and drug release capabilities of S₂ nanomotors in THP-1 cells using a microchip device and time-lapse optical images taken from Videos SI-1 and SI-2 of confocal microscopy showing the nanomotors’ motion behavior, which includes the trajectories analyzed by the Manual Tracking plug-in of the FIJI program, before (A) and after the addition of 0.02% H₂O₂ at 40 s of the experiment (B). (Experimental conditions: 10⁸ THP-1 cells mL^–1 in wells 1 and 2, 0.02% H₂O₂ in well 3, and 100 μg mL^–1 of S₂ nanomotors in well 4).

Figure 7

Image of THP-1 cells and S₂ nanomotors (100 μg mL^–1) in the microchip device in the absence (A) and the presence (B) of H₂O₂ solution (0.02%). Analysis of doxorubicin fluorescence intensity in five defined linear regions of interest (ROI 1–5), corresponding to different THP-1 cells at 0 (black) and 30 (red) minutes of test time (ROI 1 from S₂ and ROI 5 from S₂ + H₂O₂ zoomed).