Magnetic hybrid Pd/Fe-oxide nanoparticles meet the demands for ablative thermo-brachytherapy.

OBJECTIVE: To investigate the potential of hybrid Pd/Fe-oxide magnetic nanoparticles designed for thermo-brachytherapy of breast cancer, considering their specific loss power (SLP) and clinical constraints in the applied magnetic field. METHODS: Hybrid nanoparticles consisting of palladium-core and iron oxide shell of increasing thickness, were suspended in water and their SLPs were measured at varying magnetic fields (12-26 mT peak) and frequencies (50-730 kHz) with a commercial alternating magnetic field generator (magneTherm™ Digital, nanoTherics Ltd.). RESULTS: Validation of the heating device used in this study with commercial HyperMag-C nanoparticles showed a small deviation (±4%) over a period of 1 year, confirming the reliability of the method. The integration of dual thermometers, one in the center and one at the bottom of the sample vial, allowed monitoring of homogeneity of the sample suspensions. SLPs measurements on a series of nanoparticles of increasing sizes showed the highest heating for the diameter of 21 nm (SLP = 225 W/g) at the applied frequencies of 346 and 730 kHz. No heating was observed for the nanoparticles with the size <14 nm, confirming the importance of the size-parameter. The heating ability of the best performing Pd/Fe-oxide-21 was calculated to be sufficient to ablate tumors with a radius ±4 and 12 mm using 10 and 1 mg/mL nanoparticle concentration, respectively. CONCLUSIONS: Nanoparticles consisting of non-magnetic palladium-core and magnetic iron oxide shell are suitable for magnetic hyperthermia/thermal ablation under clinically safe conditions of 346 kHz and 19.1 mT, with minimal eddy current effects in combination with maximum SLP.

Design and Validation of Experimental Setup for Cell Spheroid Radiofrequency-Induced Heating.

While hyperthermia has been shown to induce a variety of cytotoxic and sensitizing effects on cancer tissues, the thermal dose-effect relationship is still not well quantified, and it is still unclear how it can be optimally combined with other treatment modalities. Additionally, it is speculated that different methods of applying hyperthermia, such as water bath heating or electromagnetic energy, may have an effect on the resulting biological mechanisms involved in cell death or in sensitizing tumor cells to other oncological treatments. In order to further quantify and characterize hyperthermia treatments on a cellular level, in vitro experiments shifted towards the use of 3D cell spheroids. These are in fact considered a more representative model of the cell environment when compared to 2D cell cultures. In order to perform radiofrequency (RF)-induced heating in vitro, we have recently developed a dedicated electromagnetic field applicator. In this study, using this applicator, we designed and validated an experimental setup which can heat 3D cell spheroids in a conical polypropylene vial, thus providing a reliable instrument for investigating hyperthermia effects at the cellular scale.

Feasibility Study on the Radiation Dose by Radioactive Magnetic Core-Shell Nanoparticles for Open-Source Brachytherapy.

BACKGROUND: Treatment of early-stage breast cancer currently includes surgical removal of the tumor and (partial) breast irradiation of the tumor site performed at fractionated dose. Although highly effective, this treatment is exhaustive for both patient and clinic. In this study, the theoretical potential of an alternative treatment combining thermal ablation with low dose rate (LDR) brachytherapy using radioactive magnetic nanoparticles (RMNPs) containing 103-palladium was researched. METHODS: The radiation dose characteristics and emission spectra of a single RMNP were calculated, and dose distributions of a commercial brachytherapy seed and an RMNP brachytherapy seed were simulated using Geant4 Monte Carlo toolkit. RESULTS: It was found that the RMNP seeds deliver a therapeutic dose similar to currently used commercial seed, while the dose distribution shows a spherical fall off compared to the more inhomogeneous dose distribution of the commercial seed. Changes in shell thickness only changed the dose profile between 2 × 10-4 mm and 3 × 10-4 mm radial distance to the RMNP, not effecting long-range dose. CONCLUSION: The dose distribution of the RMNP seed is comparable with current commercial brachytherapy seeds, while anisotropy of the dose distribution is reduced. Because this reduces the dependency of the dose distribution on the orientation of the seed, their surgical placement is easier. This supports the feasibility of the clinical application of the proposed novel treatment modality.

From Structure to Function: Understanding Synthetic Conditions in Relation to Magnetic Properties of Hybrid Pd/Fe-Oxide Nanoparticles.

Heterostructured magnetic nanoparticles show great potential for numerous applications in biomedicine due to their ability to express multiple functionalities in a single structure. Magnetic properties are generally determined by the morphological characteristics of nanoparticles, such as the size/shape, and composition of the nanocrystals. These in turn are highly dependent on the synthetic conditions applied. Additionally, incorporation of a non-magnetic heterometal influences the final magnetic behavior. Therefore, construction of multifunctional hybrid nanoparticles with preserved magnetic properties represents a certain nanotechnological challenge. Here, we focus on palladium/iron oxide nanoparticles designed for combined brachytherapy, the internal form of radiotherapy, and MRI-guided hyperthermia of tumors. The choice of palladium forming the nanoparticle core is envisioned for the eventual radiolabeling with 103Pd to enable the combination of hyperthermia with brachytherapy, the latter being beyond the scope of the present study. At this stage, we investigated the synthetic mechanisms and their effects on the final magnetic properties of the hybrid nanoparticles. Thermal decomposition was applied for the synthesis of Pd/Fe-oxide nanoparticles via both, one-pot and seed-mediated processes. The latter method was found to provide better control over morphology of the nanoparticles and was therefore examined closely by varying reaction conditions. This resulted in several batches of Pd/Fe-oxide nanoparticles, whose magnetic properties were evaluated, revealing the most relevant synthetic parameters leading to promising performance in hyperthermia and MRI.

On the Versatility of Nanozeolite Linde Type L for Biomedical Applications: Zirconium-89 Radiolabeling and In Vivo Positron Emission Tomography Study.

Porous materials, such as zeolites, have great potential for biomedical applications, thanks to their ability to accommodate positively charged metal-ions and their facile surface functionalization. Although the latter aspect is important to endow the nanoparticles with chemical/colloidal stability and desired biological properties, the possibility for simple ion-exchange enables easy switching between imaging modalities and/or combination with therapy, depending on the envisioned application. In this study, the nanozeolite Linde type L (LTL) with already confirmed magnetic resonance imaging properties, generated by the paramagnetic gadolinium (GdIII) in the inner cavities, was successfully radiolabeled with a positron emission tomography (PET)-tracer zirconium-89 (89Zr). Thereby, exploiting 89Zr-chloride resulted in a slightly higher radiolabeling in the inner cavities compared to the commonly used 89Zr-oxalate, which apparently remained on the surface of LTL. Intravenous injection of PEGylated 89Zr/GdIII-LTL in healthy mice allowed for PET-computed tomography evaluation, revealing initial lung uptake followed by gradual migration of LTL to the liver and spleen. Ex vivo biodistribution confirmed the in vivo stability and integrity of the proposed multimodal probe by demonstrating the original metal/Si ratio being preserved in the organs. These findings reveal beneficial biological behavior of the nanozeolite LTL and hence open the door for follow-up theranostic studies by exploiting the immense variety of metal-based radioisotopes.

Polysaccharide-Based Theranostic Systems for Combined Imaging and Cancer Therapy: Recent Advances and Challenges.

Designing novel systems for efficient cancer treatment and improving the quality of life for patients is a prime requirement in the healthcare sector. In this regard, theranostics have recently emerged as a unique platform, which combines the benefits of both diagnosis and therapeutics delivery. Theranostics have the desired contrast agent and the drugs combined in a single carrier, thus providing the opportunity for real-time imaging to monitor the therapy results. This helps in reducing the hazards related to treatment overdose or underdose and gives the possibility of personalized therapy. Polysaccharides, as natural biomolecules, have been widely explored to develop theranostics, as they act as a matrix for simultaneously loading both contrast agents and drugs for their utility in drug delivery and imaging. Additionally, their remarkable physicochemical attributes (biodegradability, satisfactory safety profile, abundance, and diversity in functionality and charge) can be tuned via postmodification, which offers numerous possibilities to develop theranostics with desired characteristics. Hence, we provide an overview of recent advances in polysaccharide matrix-based theranostics for drug delivery combined with magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computed tomography, and ultrasound imaging. Herein, we also summarize the toxicity assessment of polysaccharides, associated contrast agents, and nanotoxicity along with the challenges and future research directions.

Towards Enhanced MRI Performance of Tumor-Specific Dimeric Phenylboronic Contrast Agents.

It is known that phenylboronic acid (PBA) can target tumor tissues by binding to sialic acid, a substrate overexpressed by cancer cells. This capability has previously been explored in the design of targeting diagnostic probes such as Gd- and 68Ga-DOTA-EN-PBA, two contrast agents for magnetic resonance imaging (MRI) and positron emission tomography (PET), respectively, whose potential has already been demonstrated through in vivo experiments. In addition to its high resolution, the intrinsic low sensitivity of MRI stimulates the search for more effective contrast agents, which, in the case of small-molecular probes, basically narrows down to either increased tumbling time of the entire molecule or elevated local concentration of the paramagnetic ions, both strategies resulting in enhanced relaxivity, and consequently, a higher MRI contrast. The latter strategy can be achieved by the design of multimeric GdIII complexes. Based on the monomeric PBA-containing probes described recently, herein, we report the synthesis and characterization of the dimeric analogues (GdIII-DOTA-EN)2-PBA and (GdIII-DOTA-EN)2F2PBA. The presence of two Gd ions in one molecule clearly contributes to the improved biological performance, as demonstrated by the relaxometric study and cell-binding investigations.

Nuclear Waste and Biocatalysis: A Sustainable Liaison?

It is well-known that energy-rich radiation induces water splitting, eventually yielding hydrogen peroxide. Synthetic applications, however, are scarce and to the best of our knowledge, the combination of radioactivity with enzyme-catalysis has not been considered yet. Peroxygenases utilize H2O2 as an oxidant to promote highly selective oxyfunctionalization reactions but are also irreversibly inactivated in the presence of too high H2O2 concentrations. Therefore, there is a need for efficient in situ H2O2 generation methods. Here, we show that radiolytic water splitting can be used to promote specific biocatalytic oxyfunctionalization reactions. Parameters influencing the efficiency of the reaction and current limitations are shown. Particularly, oxidative inactivation of the biocatalyst by hydroxyl radicals influences the robustness of the overall reaction. Radical scavengers can alleviate this issue, but eventually, physical separation of the enzymes from the ionizing radiation will be necessary to achieve robust reaction schemes. We demonstrate that nuclear waste can also be used to drive selective, peroxygenase-catalyzed oxyfunctionalization reactions, challenging our view on nuclear waste in terms of sustainability.

Solid-phase synthesis and evaluation of tumour-targeting phenylboronate-based MRI contrast agents.

Paramagnetic macrocycles functionalized with phenylboronic moieties have proven to be interesting for MRI applications based on their ability to recognize cancer cells and generate local contrast. However, full use of the potential of this class of compounds is hampered by laborious and inefficient synthetic and, especially, purification procedures. The amphiphilic character of water-soluble phenylboronates renders them difficult compounds to be prepared through conventional solution synthesis due to the tendency to aggregate and form adducts with other nucleophiles. The new strategy described herein exploits the advantage of solid-phase synthesis with the application of DEAM-PS resin for anchorage and the subsequent simplified derivatization of boronates. GdDOTA-EN-PBA and its fluorinated analogue GdDOTA-EN-F2PBA were synthesized in a much easier, faster and economically convenient way to achieve good yields and purity. Furthermore, the effect of electron-withdrawing fluorine atoms on the aromatic ring of the latter compound was investigated by comparing the physico-chemical properties of both compounds as well as their binding affinity towards melanoma cancer cells.

Mesoscopic FRET Antenna Materials by Self-Assembling Iridium(III) Complexes and BODIPY Dyes.

This study presents a new design of light-harvesting antenna materials using two dyes organised into mesoporous silica: an iridium(III) complex and a BODIPY-derived surfactant that undergo Förster resonance energy transfer (FRET), acting, respectively, as donor and acceptor. The chemical structure of each dye determines the position taken within the micellar templates used for the synthesis of the silica host, which maintains mesopore order as shown by TEM imaging. Steady-state and time-resolved UV-visible spectroscopy revealed that incorporation of the iridium complex into the silica shields it from oxygen-induced quenching and allows a degree of control over the donor-acceptor distance, yielding FRET efficiencies from 24 to 76 % and tuneable emission ranges. Such silica-based antennae show promising properties for the realisation of polychromatic sensitisers for photovoltaics and photocatalysis.

Tumor Targeting via Sialic Acid: [68Ga]DOTA-en-pba as a New Tool for Molecular Imaging of Cancer with PET.

PURPOSE: The aim of this study was to demonstrate the potential of Ga-68-labeled macrocycle (DOTA-en-pba) conjugated with phenylboronic vector for tumor recognition by positron emission tomography (PET), based on targeting of the overexpressed sialic acid (Sia). PROCEDURES: The imaging reporter DOTA-en-pba was synthesized and labeled with Ga-68 at high efficiency. Cell binding assay on Mel-C and B16-F10 melanoma cells was used to evaluate melanin production and Sia overexpression to determine the best model for demonstrating the capability of [68Ga]DOTA-en-pba to recognize tumors. The in vivo PET imaging was done with B16-F10 tumor-bearing SCID mice injected with [68Ga]DOTA-en-pba intravenously. Tumor, blood, and urine metabolites were assessed to evaluate the presence of a targeting agent. RESULTS: The affinity of [68Ga]DOTA-en-pba to Sia was demonstrated on B16-F10 melanoma cells, after the production of melanin as well as Sia overexpression was proved to be up to four times higher in this cell line compared to that in Mel-C cells. Biodistribution studies in B16-F10 tumor-bearing SCID mice showed blood clearance at the time points studied, while uptake in the tumor peaked at 60 min post-injection (6.36 ± 2.41 % ID/g). The acquired PET images were in accordance with the ex vivo biodistribution results. Metabolite assessment on tumor, blood, and urine samples showed that [68Ga]DOTA-en-pba remains unmetabolized up to at least 60 min post-injection. CONCLUSIONS: Our work is the first attempt for in vivo imaging of cancer by targeting overexpression of sialic acid on cancer cells with a radiotracer in PET.

Luminescence Properties of Self-Aggregating TbIII-DOTA-Functionalized Calix[4]arenes.

Self-aggregating calix[4]arenes carrying four DOTA ligands on the upper rim for stable complexation of paramagnetic GdIII-ions have already been proposed as MRI probes. In this work, we investigate the luminescence properties of TbIII-DOTA-calix[4]arene-4OPr containing four propyl-groups and compare them with those of the analog substituted with a phthalimide chromophore (TbIII-DOTA-calix[4]arene-3OPr-OPhth). We show that, given its four aromatic rings, the calix[4]arene core acts as an effective sensitizer of Tb-centered luminescence. Substituents on the lower rim can modulate the aggregation behavior, which in turn determines the luminescence properties of the compounds. In solid state, the quantum yield of the phthalimide derivative is almost three times as high as that of the propyl-functionalized analog demonstrating a beneficial role of the chromophore on Tb-luminescence. In solution, however, the effect of the phthalimide group vanishes, which we attribute to the large distance between the chromophore and the lanthanide, situated on the opposite rims of the calix[4]arene. Both quantum yields and luminescence lifetimes show clear concentration dependence in solution, related to the strong impact of aggregation on the luminescence behavior. We also evidence the variability in the values of the critical micelle concentration depending on the experimental technique. Such luminescent calix[4]arene platforms accommodating stable lanthanide complexes can be considered valuable building blocks for the design of dual MR/optical imaging probes.

Surface PEG Grafting Density Determines Magnetic Relaxation Properties of Gd-Loaded Porous Nanoparticles for MR Imaging Applications.

Surface PEGylation of nanoparticles designed for biomedical applications is a common and straightforward way to stabilize the materials for in vivo administration and to increase their circulation time. This strategy becomes less trivial when MRI active porous nanomaterials are concerned as their function relies on water/proton-exchange between the pores and bulk water. Here we present a comprehensive study on the effects of PEGylation on the relaxometric properties of nanozeolite LTL (dimensions of 20 × 40 nm) ion-exchanged with paramagnetic GdIII ions. We evidence that as long as the surface grafting density of the PEG chains does not exceed the "mushroom" regime (conjugation of up to 6.2 wt % of PEG), Gd-LTL retains a remarkable longitudinal relaxivity (38 s-1 mM-1 at 7 T and 25 °C) as well as the pH-dependence of the longitudinal and transverse relaxation times. At higher PEG content, the more compact PEG layer (brush regime) limits proton/water diffusion and exchange between the interior of LTL and the bulk, with detrimental consequences on relaxivity. Furthermore, PEGylation of Gd-LTL dramatically decreases the leakage of toxic GdIII ions in biological media and in the presence of competing anions, which together with minimal cytotoxicity renders these materials promising probes for MRI applications.

Nanoparticles of lanthanide oxysulfate/oxysulfide for improved oxygen storage/release.

Lanthanide oxysulfates have the ability to store and release large volumes of oxygen under oxidizing/reducing conditions, rendering them interesting as automotive catalysts. Herein we demonstrate a remarkable improvement of both processes by utilization of nanoparticles compared to the bulk materials. A further improvement of the catalytic activity was achieved by cost-effective doping with 1.9 wt% of Ni.

Controllable Hydrocarbon Formation from the Electrochemical Reduction of CO2 over Cu Nanowire Arrays.

In this work, the effect of Cu nanowire morphology on the selective electrocatalytic reduction of CO2 is presented. Cu nanowire arrays were prepared through a two-step synthesis of Cu(OH)2 and CuO nanowire arrays on Cu foil substrates and a subsequent electrochemical reduction of the CuO nanowire arrays to Cu nanowire arrays. By this simple synthesis method, Cu nanowire array electrodes with different length and density were able to be controllably synthesized. We show that the selectivity for hydrocarbons (ethylene, n-propanol, ethane, and ethanol) on Cu nanowire array electrodes at a fixed potential can be tuned by systematically altering the Cu nanowire length and density. The nanowire morphology effect is linked to the increased local pH in the Cu nanowire arrays and a reaction scheme detailing the local pH-induced formation of C2  products is also presented by a preferred CO dimerization pathway.

Fate of Organic Functionalities Conjugated to Theranostic Nanoparticles upon Their Activation.

Neutron activation is widely applied for the preparation of radioactive isotopes to be used in imaging and/or therapy. The type of diagnostic/therapeutic agents varies from small chelates coordinating radioactive metal ions to complex nanoparticulate systems. Design of these agents often relies on conjugation of certain organic functionalities that determine their pharmacokinetics, biodistribution, targeting, and cell-penetrating abilities, or simply on tagging them with an optical label. The conjugation chemistry at the surface of nanoparticles and their final purification often require laborious procedures that become even more troublesome when radioactive materials are involved. This study represents a thorough investigation on the effects of neutron activation on the organic moieties of functionalized nanoparticles, with special focus on (166)Ho2O3 particles conjugated with PEG-fluorescein and PEG-polyarginine motives. Spectroscopic and thermogravimetric analyses demonstrate only a limited degradation of PEG-fluorescein upon irradiation of the particles up to 10 h using a thermal neutron flux of 5 × 10(16) m(-2) s(-1). Cell experiments show that the polyarginine-based mechanisms of membrane penetration remain unaltered after exposure of the functionalized particles to the mixed field of neutrons and gammas present during activation. This confirms that radiation damage on the PEG-polyarginines is minimal. Intrinsic radiations from (166)Ho do not seem to affect the integrity of conjugated organic material. These findings open up a new perspective to simplify the procedures for the preparation of functionalized metal-based nanosystems that need to be activated by neutron irradiation in order to be applied for diagnostic and/or therapeutic purposes.

Selective electrochemical reduction of CO2 to CO on CuO-derived Cu nanowires.

In this work, we report a new synthesis method to prepare a Cu nanowire electrocatalyst for selective CO2 reduction at room temperature and atmospheric pressure. Cu nanowire array electrodes were prepared through a two-step synthesis of Cu(OH)2 and CuO nanowire arrays on Cu foil substrates and a subsequent electrochemical reduction of the CuO nanowire arrays. The Cu nanowire arrays are able to electrochemically reduce CO2 to CO with a faradaic efficiency of ∼50% at a moderate overpotential of 490 mV, which is significantly higher than that of polycrystalline Cu foil catalysts at identical conditions. The improved faradaic efficiency for the reduction of CO2 to CO is ascribed to the enhanced stabilization for the CO2˙(-) intermediate on the high surface area Cu nanowire arrays.

Nanozeolite-LTL with Gd(III) deposited in the large and Eu(III) in the small cavities as a magnetic resonance optical imaging probe.

The immense structural diversity of more than 200 known zeolites is the basis for the wide variety of applications of these fascinating materials ranging from catalysis and molecular filtration to agricultural uses. Despite this versatility, the potential of zeolites in medical imaging has not yet been much exploited. In this work a novel strategy is presented to selectively deposit different ions into distinct framework locations of zeolite-LTL (Linde type L) and it is demonstrated that the carefully ion-exchanged Gd/Eu-containing nanocrystals acquire exceptional magnetic properties in combination with enhanced luminescence. This smart exploitation of the framework structure yields the highest relaxivity density (13.7 s(-1) L g(-1) at 60 MHz and 25 °C) reported so far for alumosilicates, rendering these materials promising candidates for the design of dual magnetic resonance/optical imaging probes, as demonstrated in preliminary phantom studies.

Gadolinium oxysulfide nanoparticles as multimodal imaging agents for T2-weighted MR, X-ray tomography and photoluminescence.

We have synthesized gadolinium oxysulfide nanoparticles (NPs) doped with other lanthanides (Eu(3+), Er(3+), Yb(3+)) via a hydroxycarbonate precursor precipitation route followed by a sulfuration process under a H2S-Ar atmosphere at 750 °C in order to propose new multimodal nanoplatforms for Magnetic Resonance (MR), X-ray and photoluminescence imaging. Gd2O2S:Eu(3+) NPs strongly absorb near UV (≈ 300-400 nm) and re-emit strong red light (624 nm). They can be easily internalized by cancer cells, and imaged by epifluorescence microscopy under excitation in the NUV (365 nm). They are not cytotoxic for living cells up to 100 µg mL(-1). Consequently, they are well adapted for in vitro imaging on cell cultures. Gd2O2S:Eu(3+) NPs also show strong transverse relaxivity and strong X-ray absorption allowing their use as contrast agents for T2-weighted MRI and X-ray tomography. Our study shows that Gd2O2S:Eu(3+) NPs are considerably better than commercial Ferumoxtran-10 NPs as negative contrast agents for MRI. Upconversion emission of Gd2O2S:Er; Yb (1; 8%) NPs under infrared excitation (λ(ex) = 980 nm) shows mainly red emission (≈ 650-680 nm). Consequently, they are more specifically designed for in vivo deep fluorescence imaging, because both excitation and emission are located inside the "transparency window" of biological tissues (650-1200 nm). Magnetic relaxivity and X-ray absorption behaviors of Gd2O2S:Er; Yb NPs are almost similar to Gd2O2S:Eu(3+) NPs.

Supramolecular "leeks" of a fluorinated hybrid amphiphile that self-assembles into a disordered columnar phase.

We report on the formation of unprecedented "leek"-shaped aggregates of an anionic fluoroalkyl sulfonate surfactant (FS) and the supramolecular assembly of these aggregates into a disordered columnar phase (CS). The leeks are formed by wrapping of 2-4 FS-water bilayers of thickness 26-28 Å into 10-20 nm thick and >100 nm long structures, in the concentration regime of 63-70 wt % FS. A lamellar (Lα) lyotropic liquid-crystalline (LLC) phase forms at higher concentration, between 70 and 84 wt %. In the two LLC phases, the FS molecules were organized in an interdigitated or tilted fashion, or a combination of the two. Such a unique supramolecular self-assembly of amphiphiles has not been predicted nor observed before. This self-assembly behavior could be of interest to various fields like microencapsulation, nanomedicine, and membrane protein crystallization.