Iron Oxide Nanoflowers @ CuS Hybrids for Cancer Tri-Therapy: Interplay of Photothermal Therapy, Magnetic Hyperthermia and Photodynamic Therapy

Abstract

Innovative synthesis routes revolutionized nanomaterial combination and design possibilities resulting in a new generation of fine-tuned nanoparticles featuring exquisite shape and constitution control. However, there is still room for improvement when it comes to the development of multi-functional nanoparticle agents merging a plurality of therapeutic functions to tackle tumors simultaneously by synergic mechanisms. Herein, we report the design of an optimized nanohybrid for cancer tri-therapy featuring a maghemite (γ-Fe2O3) nanoflower-like multicore nanoparticle conceived for efficient magnetic hyperthermia (MHT) and a spiky copper sulfide shell (IONF@CuS) with a high near-infrared (NIR) absorption coefficient suitable for photothermal (PTT) and photodynamic therapy (PDT). Methods: Spiky-like IONF@CuS nanohybrids were obtained through a straightforward and scalable water-based template sacrificial synthesis, which allows the shell shape control by tuning polyvinylpyrrolidone (PVP) concentration. A comprehensive characterization of nanohybrid size, shape and structural properties was carried out by combining complementary TEM, SEM, HR-TEM, EELS, XRD and NTA. The all-in-one therapeutic multi-functionality was assessed on cancer cells and on tumor-bearing nude mice. Results: Tests carried out on IONF@CuS nanohybrid aqueous dispersion demonstrated their impressive efficiency to convert light (conversion coefficient = 42 ± 6 %) and magnetic stimulation (SAR ~ 350 W g -1 ) into heat as well as to induce concurrent reactive oxygen species (ROS) formation upon laser irradiation. Such capabilities were further confirmed in cellular environment by in vitro tests and at the organism level by in vivo tests in a murine tumor model. Notably, complete tumor regression was obtained for the PTT mode at low Cu concentration. Overall, these results allowed determining windows of applicability for each therapy individually or in combination. Conclusions: Altogether, the obtained data evidence the successful synthesis of a unique tri-therapeutic nanoparticle featuring highly relevant assets for clinical translation such as reduced nanoparticle administered dose, reduced laser power exposure, reduced magnetic field frequency, and the possibility of serial heating cycles and therapy monitoring by photoacoustic (PA) and magnetic resonance imaging (MRI). Furthermore, the integration of the dual heating capability (MHT + PTT) with the PDT insult offers a unique asset to tackle tumors by multiple cytotoxic strategies in order to improve the therapeutic outcome in a broader spectrum of clinical conditions.

The Role of Magnetic Nanoparticles in Cancer Nanotheranostics

“…The polyol mixture can be composed by poly(ethylene glycol) (PEG) and diethylene glycol (DEG) or N-methyldiethanolamine (NMDEA), among others, and performed at lower pressure conditions, being the reaction conditions and the selected solvents the variables of this method that can affect the obtained NP characteristics. Curcio and co-workers [31] performed the synthesis of water-soluble iron oxide nanoflowers (IONFs) using polyol synthesis, in which ferrous and ferric chloride solutions in a 2:1 molar ratio were dissolved in a liquid mixture of DEG and NMDEA in a 1:1 volume ratio and stirred for 1 h. NaOH was used as the base, that was added to a separate polyol mixture of the same composition, mixed with the iron oxide solution and stirred for another 3 h. The thermal treatment was further performed, under an increasing temperature to 220 • C for 50 min, followed by 2.5 h stirring and room temperature cooling. The sediment (containing the obtained NPs) was subjected to magnetic separation, washing (using ethanol-ethyl acetate in a 1:1 volume ratio; a 10% nitric acid treatment at 80 • C for 45 min; washing with acetone-diethyl ether solution) and final redispersion in water [31].…”

“…However, the incident infrared light penetration capacity is regarded as the most relevant of the technique limitations. Thus, the combination of both thermal therapies in a single MNP constitutes a beneficial merged therapeutic tool, that not only responds to the externally applied magnetic field, but also to the incident light [31].…”

“…A nanohybrid system composed of a multicore IONPs and a copper sulfide shell was produced using the polyol method and described as an optimized nanotheranostics platform with MRI and MHT responsive core, and PTT and PDT responsive shell. The integrated tri-modal thermal therapy nanoplatform conjugates an interesting system of cumulative heating capacity, that can provide a beneficial low dose approach in cancer nanotheranostics [31].…”

“…therapy nanoplatform conjugates an interesting system of cumulative heating capacity, that can provide a beneficial low dose approach in cancer nanotheranostics [31].…”

Injectable Nonmagnetic Liquid Metal for Eddy‐Thermal Ablation of Tumors under Alternating Magnetic Field

“…Mice in groups 3 and 4 were put into the magnetic coils for 10 min with a low field intensity (H appl × f appl = 2 × 10 9 A m −1 s −1 ), which was much lower than those reported in literature for in vivo MH study using magnetic nanoparticles (H appl × f appl > 5 × 10 9 A m −1 s −1 ). [6,23] During AMF exposure, the temperature changes of tumors were monitored by using an infrared thermal camera. The temperature of tumor tissues with LM injection increased significantly when exposed to the AMF (more than 50 °C within 5 min), while no temperature change was observed for tumors after injection with PBS under the same AMF treatment ( Figure 3B,C).…”