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

Abstract

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.

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

“…250 times larger than a Fe 3 O 4 nanoparticle of 20 nm. The diameter and thickness of the Fe layer have been designed to exhibit a magnetic vortex (Figure S6a), , thereby showing near zero remanence and enabling high colloidal stability, despite the large content of ferromagnetic material. This is due to the negligible magnetic dipole–dipole interactions between the coated nanocapsules in the absence of an external magnetic field.…”

“…47−49 A similar release pattern of the paclitaxel drug was also observed in our previous work for Fe-coated and uncoated polymer nanoparticles. 33 These results indicate that neither the metal layer nor the deposition process reduced the percentage and extension of the drug release (Figure 1E), thereby preserving the water hydrolysis of the polymer chains that triggers the polymer degradation. 50 In the case of the ICG-loaded nanocapsules, a similar release pattern is expected, considering that the formulation of the polymer nanocapsules loaded is identical to that in the paclitaxel or coumarin cases, which is confirmed with the observed therapeutic activity of the drug.…”

“…32 Nevertheless, the application of drug-loaded biodegradable polymer nanoparticles as templates for the development of active multiactuated nanocapsules is currently in its early stages of exploration. Interestingly, a recent work has demonstrated their potential in magnetically amplified chemo/photothermal cancer therapy, 33 indicating a promising direction for future advancements in this area. However, there is still a need to demonstrate the capacity to extend this modular nanotherapeutic concept to other drugs and metals to achieve synergistic therapeutic effects in other biomedical applications.…”

Photothermal Nanomaterials: A Powerful Light-to-Heat Converter

“…Since silica-cored Au nanoshells served as the first photothermal nanomaterials for clinical use, more and more inorganic agents with strong absorption in the NIR region, high chemical stability, adjustable water solubility, and minimal cytotoxicity have entered clinical trials. , Clinical trials have also been underway for small organic molecules due to their good biodegradability, good repeatability, and simple preparation. , Nevertheless, the major challenges for the clinical implementation of photothermal nanomaterials are the complex metabolism and excretion behaviors . The representative works on PTT with diverse photothermal nanomaterials in recent years − are summarized in Table .…”

Impact of Macrophages on the Interaction of Cetuximab-Functionalized Polyelectrolyte Capsules with EGFR-Expressing Cancer Cells

“…Designing approaches to cancer cell targeting and targeted delivery of anticancer drugs is a major challenge in modern personalized oncology. , Multilayered polymer capsules have been demonstrated to be a promising system that can be adapted for this purpose. − Traceable delivery and accumulation of polymer capsules in cancer cells can be ensured by their magnetic retention, for which purpose magnetic nanoparticles are embedded into the capsule shell. − However, this approach lacks specificity, and capsule interactions with nontarget cells diminish the efficiency of delivery. To increase the specificity of capsule interaction with target cells, the surface of the capsule can be functionalized with various recognition molecules, including folic acid; − synthetic agents, such as N6L binding nucleolin on the surface of human pancreatic carcinoma cells; short linear peptides, such as the mUNO (CSPGAK) peptide binding mouse CD206 expressed by M2 macrophages and the IPLVVPL peptide binding hepsin expressed by human breast carcinoma cells and human ovarian carcinoma cells; and antibodies (Abs) or their Fab fragments. , …”