Advances in screening hyperthermic nanomedicines in 3D tumor models.

Hyperthermic nanomedicines are particularly relevant for tackling human cancer, providing a valuable alternative to conventional therapeutics. The early-stage preclinical performance evaluation of such anti-cancer treatments is conventionally performed in flat 2D cell cultures that do not mimic the volumetric heat transfer occurring in human tumors. Recently, improvements in bioengineered 3D in vitro models have unlocked the opportunity to recapitulate major tumor microenvironment hallmarks and generate highly informative readouts that can contribute to accelerating the discovery and validation of efficient hyperthermic treatments. Leveraging on this, herein we aim to showcase the potential of engineered physiomimetic 3D tumor models for evaluating the preclinical efficacy of hyperthermic nanomedicines, featuring the main advantages and design considerations under diverse testing scenarios. The most recent applications of 3D tumor models for screening photo- and/or magnetic nanomedicines will be discussed, either as standalone systems or in combinatorial approaches with other anti-cancer therapeutics. We envision that breakthroughs toward developing multi-functional 3D platforms for hyperthermia onset and follow-up will contribute to a more expedited discovery of top-performing hyperthermic therapies in a preclinical setting before their in vivo screening.

Ex-situ magnetic activated carbon for the adsorption of three pharmaceuticals with distinct physicochemical properties from real wastewater.

Pharmaceuticals are able to evade conventional wastewater treatments and therefore, are recurrently found in the environment with proven potential to cause harm to human and wildlife. Adsorption onto activated carbon (AC) is a promising complement. However, AC production from non-renewable resources and its difficult after-use recuperation are prohibitive. Hence, a waste-based magnetic activated carbon (MAC) was produced from paper mill sludge, via an ex-situ synthesis, for the adsorptive removal of carbamazepine (CBZ), sulfamethoxazole (SMX) and ibuprofen (IBU) from ultrapure water and wastewater. The MAC was obtained through the promotion of electrostatic interactions between magnetic and activated carbon particles in a water suspension at controlled pH between the points of zero charge of both surfaces. The optimized condition (MACX3) presented remarkable properties regarding specific surface area (SBET=795 m2 g-1) and saturation magnetization (MS=19 emu g-1). Kinetic and equilibrium adsorption studies were performed under batch conditions. Adsorption equilibrium was reached in up to 30 min for all pharmaceuticals in both matrices, proving the low dependence on the adsorbate and the broad applicability of MACX3 in pharmaceutical adsorption. Regarding equilibrium experiments, high Langmuir maximum adsorption capacities (qm) were achieved in ultrapure water (up to 711 ± 40 µmol g-1). Equilibrium studies in wastewater revealed a decay in qm when compared to ultrapure water: 28% for CBZ (468 ± 20 µmol g-1 (111 ± 5 mg g-1)), 78% for SMX (145 ± 10 µmol g-1 (37 ± 3 mg g-1)) and 62% for IBU (273 ± 8 µmol g-1 (56 ± 2 mg g-1)), attributed to the wastewater pH, which dictates the speciation of the pharmaceuticals and controls electrostatic interactions between pharmaceuticals and MAC, and to competition effects by organic matter. It was demonstrated the promising applicability of a waste-based ex-situ MAC, rapidly retrievable from water, as an alternative tertiary wastewater treatment for pharmaceuticals removal.

Efficient Brownian oscillators and nanoheaters based on gallium-doped ε-Fe2O3.

Wireless actuation at the nanoscale is vital in many contexts, and magnetic fields acting on nanoparticles (NPs) are among the most effective tools when actuation concerns linear forces. However, effective tools to apply torques at the nanoscale are still missing, because NPs where the magnetic moment is strongly coupled to the lattice agglomerate due to their high magnetic moment. Here, we show that gallium-doped ε-iron oxide NPs have small interparticle magnetic interactions and huge lattice-coupling for efficiently applying torques at the nanoscale. In this view, they are expected to be useful tools to efficiently apply mechanical forces to induce cellular apoptosis and to discern between mechanical and thermal contributions to cellular apoptosis currently under debate.

Screening of dual chemo-photothermal cellular nanotherapies in organotypic breast cancer 3D spheroids.

Living therapeutics approaches that exploit mesenchymal stem cells (MSCs) as nanomedicine carriers are highly attractive due to MSCs native tropism toward the 3D tumor microenvironment. However, a streamlined pre-clinical evaluation of nano-in-cell anti-cancer therapies remains limited by the lack of in vitro testing platforms for screening MSCs-3D microtumor interactions. Herein we generated dense breast cancer mono and heterotypic 3D micro-spheroids for evaluating MSCs-solid tumors interactions and screen advanced nano-in-MSCs therapies. Breast cancer monotypic and heterotypic models comprising cancer cells and cancer associated fibroblasts (CAFs) were self-assembled under controlled conditions using the liquid overlay technique. The resulting microtumors exhibited high compactness, reproducible morphology and necrotic regions, similarly to native solid tumors. For evaluating tumoritropic therapies in organotypic tumor-stroma 3D models, theranostic polydopamine nanoparticles loaded with indocyanine green-doxorubicin combinations (PDA-ICG-DOX) were synthesized and administered to human bone-marrow derived MSCs (hBM-MSCs). The dual-loaded PDA nano-platforms were efficiently internalized, exhibited highly efficient NIR-light responsivity and assured MSCs viability up to 3 days. The administration of PDA-ICG-DOX nano-in-MSC tumoritropic units to microtumor models was performed in ultra-low adhesion surfaces for simulating in vitro the stem cell-tumor interactions observed in the in vivo scenario. Bioimaging analysis revealed hBM-MSCs adhesion to 3D cancer cells mass and MSCs-chemo-photothermal nanotherapeutics exhibited higher anti-tumor potential when compared to their standalone chemotherapy treated 3D tumor counterparts. Overall, the proposed methodology is suitable for evaluating MSCs-microtumors individualized interactions and enables a rapid high-throughput screening of tumoritropic therapies bioperformance.

In situ functionalization of a cellulosic-based activated carbon with magnetic iron oxides for the removal of carbamazepine from wastewater.

The main goal of this work was to produce an easily recoverable waste-based magnetic activated carbon (MAC) for an efficient removal of the antiepileptic pharmaceutical carbamazepine (CBZ) from wastewater. For this purpose, the synthesis procedure was optimized and a material (MAC4) providing immediate recuperation from solution, remarkable adsorptive performance and relevant properties (specific surface area of 551 m2 g-1 and saturation magnetization of 39.84 emu g-1) was selected for further CBZ kinetic and equilibrium adsorption studies. MAC4 presented fast CBZ adsorption rates and short equilibrium times (< 30-45 min) in both ultrapure water and wastewater. Equilibrium studies showed that MAC4 attained maximum adsorption capacities (qm) of 68 ± 4 mg g-1 in ultrapure water and 60 ± 3 mg g-1 in wastewater, suggesting no significant interference of the aqueous matrix in the adsorption process. Overall, this work provides evidence of potential application of a waste-based MAC in the tertiary treatment of wastewaters. Graphical abstract.

Monitoring Proteolytic Activity in Real Time: A New World of Opportunities for Biosensors.

Proteases play a pivotal role in several biological processes, from digestion, cell proliferation, and differentiation to fertility. Deregulation of protease metabolism can result in several pathological conditions (i.e., cancer, neurodegenerative disorders, and others). Therefore, monitoring proteolytic activity in real time could have a fundamental role in the early diagnosis of these diseases. Herein, the main approaches used to develop biosensors for monitoring proteolytic activity are reviewed. A comparison of the advantages and disadvantages of each approach is provided along with a discussion of their importance and promising opportunities for the early diagnosis of severe diseases. This new era of biosensors can be characterized by the ability to control and monitor biological processes, ultimately improving the potential of personalized medicine.

Magnetic hyperthermia with ε-Fe2O3 nanoparticles.

Biocompatibility restrictions have limited the use of magnetic nanoparticles for magnetic hyperthermia therapy to iron oxides, namely magnetite (Fe3O4) and maghemite (γ-Fe2O3). However, there is yet another magnetic iron oxide phase that has not been considered so far, in spite of its unique magnetic properties: ε-Fe2O3. Indeed, whereas Fe3O4 and γ-Fe2O3 have a relatively low magnetic coercivity, ε-Fe2O3 exhibits a giant coercivity. In this report, the heating power of ε-Fe2O3 nanoparticles in comparison with γ-Fe2O3 nanoparticles of similar size (∼20 nm) was measured in a wide range of field frequencies and amplitudes, in uncoated and polymer-coated samples. It was found that ε-Fe2O3 nanoparticles primarily heat in the low-frequency regime (20-100 kHz) in media whose viscosity is similar to that of cell cytoplasm. In contrast, γ-Fe2O3 nanoparticles heat more effectively in the high frequency range (400-900 kHz). Cell culture experiments exhibited no toxicity in a wide range of nanoparticle concentrations and a high internalization rate. In conclusion, the performance of ε-Fe2O3 nanoparticles is slightly inferior to that of γ-Fe2O3 nanoparticles in human magnetic hyperthermia applications. However, these ε-Fe2O3 nanoparticles open the way for switchable magnetic heating owing to their distinct response to frequency.

Density Gradient Selection of Colloidal Silver Nanotriangles for Assembling Dye-Particle Plasmophores.

A simple method based on sucrose density gradient centrifugation is proposed here for the fractionation of colloidal silver nanotriangles. This method afforded particle fractions with surface plasmon resonances, spanning from red to infrared spectral ranges that could be used to tune optical properties for plasmonic applications. This feature was exemplified by selecting silver nanotriangle samples with spectral overlap with Atto-655 dye's absorption and emission in order to assemble dye-particle plasmophores. The emission brightness of an individual plasmophore, as characterized by fluorescence correlation spectroscopy, is at least 1000-fold more intense than that of a single Atto-655 dye label, which renders them as promising platforms for the development of fluorescence-based nanosensors.

Integrated Optical Mach-Zehnder Interferometer Based on Organic-Inorganic Hybrids for Photonics-on-a-Chip Biosensing Applications.

The development of portable low-cost integrated optics-based biosensors for photonics-on-a-chip devices for real-time diagnosis are of great interest, offering significant advantages over current analytical methods. We report the fabrication and characterization of an optical sensor based on a Mach-Zehnder interferometer to monitor the growing concentration of bacteria in a liquid medium. The device pattern was imprinted on transparent self-patternable organic-inorganic di-ureasil hybrid films by direct UV-laser, reducing the complexity and cost production compared with lithographic techniques or three-dimensional (3D) patterning using femtosecond lasers. The sensor performance was evaluated using, as an illustrative example, E. coli cell growth in an aqueous medium. The measured sensitivity (2 × 10-4 RIU) and limit of detection (LOD = 2 × 10-4) are among the best values known for low-refractive index contrast sensors. Furthermore, the di-ureasil hybrid used to produce this biosensor has additional advantages, such as mechanical flexibility, thermal stability, and low insertion losses due to fiber-device refractive index mismatch (~1.49). Therefore, the proposed sensor constitutes a direct, compact, fast, and cost-effective solution for monitoring the concentration of lived-cells.

Nano-Localized Thermal Analysis and Mapping of Surface and Sub-Surface Thermal Properties Using Scanning Thermal Microscopy (SThM).

Determining and acting on thermo-physical properties at the nanoscale is essential for understanding/managing heat distribution in micro/nanostructured materials and miniaturized devices. Adequate thermal nano-characterization techniques are required to address thermal issues compromising device performance. Scanning thermal microscopy (SThM) is a probing and acting technique based on atomic force microscopy using a nano-probe designed to act as a thermometer and resistive heater, achieving high spatial resolution. Enabling direct observation and mapping of thermal properties such as thermal conductivity, SThM is becoming a powerful tool with a critical role in several fields, from material science to device thermal management. We present an overview of the different thermal probes, followed by the contribution of SThM in three currently significant research topics. First, in thermal conductivity contrast studies of graphene monolayers deposited on different substrates, SThM proves itself a reliable technique to clarify the intriguing thermal properties of graphene, which is considered an important contributor to improve the performance of downscaled devices and materials. Second, SThM's ability to perform sub-surface imaging is highlighted by thermal conductivity contrast analysis of polymeric composites. Finally, an approach to induce and study local structural transitions in ferromagnetic shape memory alloy Ni-Mn-Ga thin films using localized nano-thermal analysis is presented.

Influence of the surface termination on the light emission of crystalline silicon nanoparticles.

The light emission properties of silicon crystalline nanoparticles (SiNPs) have been investigated using steady-state and time-resolved photoluminescence measurements carried out at 12 K and at room temperature. To enable a comparative study of the role of surface terminal groups on the optical properties, we investigated SiNPs-H ensembles with the same mean NP diameter but differing on the surface termination, namely organic-functionalized with 1-dodecene (SiNPs-C12) and H-terminated (SiNPs-H). We show that although the spectral dependence of the light emission is rather unaffected by surface termination, characterized by a single broad band peaking at ∼1.64 eV, both the exciton recombination lifetimes and quantum yields display a pronounced dependence on the surface termination. Exciton lifetimes and quantum yields are found to be significantly lower in SiNPs-H compared SiNPs-C12. This difference is due to distinct non-radiative recombination probabilities resulting from inter-NP exciton migration, which in SiNPs-C12 is inhibited by the energy barriers imposed by the bulky surface groups. The surface groups of organic-terminated SiPs are responsible for the inhibition of inter-NP exciton transfer, yielding a higher quantum yield compared to SiNPs-H. The surface oxidation of SiNPs-C12 leads to the appearance of a phenomenon of an exciton transference from to the Si core to oxide-related states that contribute to light emission. These excitons recombine radiatively, explaining why the emission quantum of the organic-terminated SiNPs is the same after surface oxidation of SiNPs-C12.

Contact angles and wettability of ionic liquids on polar and non-polar surfaces.

Many applications involving ionic liquids (ILs) require the knowledge of their interfacial behaviour, such as wettability and adhesion. In this context, herein, two approaches were combined aiming at understanding the impact of the IL chemical structures on their wettability on both polar and non-polar surfaces, namely: (i) the experimental determination of the contact angles of a broad range of ILs (covering a wide number of anions of variable polarity, cations, and cation alkyl side chain lengths) on polar and non-polar solid substrates (glass, Al-plate, and poly-(tetrafluoroethylene) (PTFE)); and (ii) the correlation of the experimental contact angles with the cation-anion pair interaction energies generated by the Conductor-like Screening Model for Real Solvents (COSMO-RS). The combined results reveal that the hydrogen-bond basicity of ILs, and thus the IL anion, plays a major role through their wettability on both polar and non-polar surfaces. The increase of the IL hydrogen-bond accepting ability leads to an improved wettability of more polar surfaces (lower contact angles) while the opposite trend is observed on non-polar surfaces. The cation nature and alkyl side chain lengths have however a smaller impact on the wetting ability of ILs. Linear correlations were found between the experimental contact angles and the cation-anion hydrogen-bonding and cation ring energies, estimated using COSMO-RS, suggesting that these features primarily control the wetting ability of ILs. Furthermore, two-descriptor correlations are proposed here to predict the contact angles of a wide variety of ILs on glass, Al-plate, and PTFE surfaces. A new extended list is provided for the contact angles of ILs on three surfaces, which can be used as a priori information to choose appropriate ILs before a given application.

Joining time-resolved thermometry and magnetic-induced heating in a single nanoparticle unveils intriguing thermal properties.

Whereas efficient and sensitive nanoheaters and nanothermometers are demanding tools in modern bio- and nanomedicine, joining both features in a single nanoparticle still remains a real challenge, despite the recent progress achieved, most of it within the last year. Here we demonstrate a successful realization of this challenge. The heating is magnetically induced, the temperature readout is optical, and the ratiometric thermometric probes are dual-emissive Eu(3+)/Tb(3+) lanthanide complexes. The low thermometer heat capacitance (0.021·K(-1)) and heater/thermometer resistance (1 K·W(-1)), the high temperature sensitivity (5.8%·K(-1) at 296 K) and uncertainty (0.5 K), the physiological working temperature range (295-315 K), the readout reproducibility (>99.5%), and the fast time response (0.250 s) make the heater/thermometer nanoplatform proposed here unique. Cells were incubated with the nanoparticles, and fluorescence microscopy permits the mapping of the intracellular local temperature using the pixel-by-pixel ratio of the Eu(3+)/Tb(3+) intensities. Time-resolved thermometry under an ac magnetic field evidences the failure of using macroscopic thermal parameters to describe heat diffusion at the nanoscale.

Ratiometric highly sensitive luminescent nanothermometers working in the room temperature range. Applications to heat propagation in nanofluids.

There is an increasing demand for accurate, non-invasive and self-reference temperature measurements as technology progresses into the nanoscale. This is particularly so in micro- and nanofluidics where the comprehension of heat transfer and thermal conductivity mechanisms can play a crucial role in areas as diverse as energy transfer and cell physiology. Here we present two luminescent ratiometric nanothermometers based on a magnetic core coated with an organosilica shell co-doped with Eu(3+) and Tb(3+) chelates. The design of the hybrid host and chelate ligands permits the working of the nanothermometers in a nanofluid at 293-320 K with an emission quantum yield of 0.38 ± 0.04, a maximum relative sensitivity of 1.5% K(-1) at 293 K and a spatio-temporal resolution (constrained by the experimental setup) of 64 × 10(-6) m/150 × 10(-3) s (to move out of 0.4 K--the temperature uncertainty). The heat propagation velocity in the nanofluid, (2.2 ± 0.1) × 10(-3) m s(-1), was determined at 294 K using the nanothermometers' Eu(3+)/Tb(3+) steady-state spectra. There is no precedent of such an experimental measurement in a thermographic nanofluid, where the propagation velocity is measured from the same nanoparticles used to measure the temperature.

Magnetically responsive dry fluids.

Ferrofluids and dry magnetic particles are two separate classes of magnetic materials with specific niche applications, mainly due to their distinct viscosity and interparticle distances. For practical applications, the stability of these two properties is highly desirable but hard to achieve. Conceptually, a possible solution to this problem would be encapsulating the magnetic particles but keeping them free to rotate inside a capsule with constant interparticle distances and thus shielded from changes in the viscosity of the surrounding media. Here we present an example of such materials by the encapsulation of magnetic ferrofluids into highly hydrophobic silica, leading to the formation of dry ferrofluids, i.e., a material behaving macroscopically as a dry powder but locally as a ferrofluid where magnetic nanoparticles are free to rotate in the liquid.

Synthesis of cobalt aluminate nanopigments by a non-aqueous sol-gel route.

Here we report the chemical synthesis of cobalt aluminum oxide (CoAl2O4) nanoparticles by a non-aqueous sol-gel route. The one-pot procedure is carried out at mild temperatures (in the 150 to 300 °C range), and consists of the reaction between cobalt acetate and aluminium isopropoxide in benzyl alcohol. The resulting CoAl2O4 nanoparticles show an unusually low average size, between 2.5 and 6.2 nm, which can be controlled by the synthesis temperature. The colorimetric properties of the nanoparticles are also determined by the synthesis temperature and the characteristic blue color of CoAl2O4 pigments is achieved in samples prepared at T ≥ 200 °C. The nanoparticles are antiferromagnetically ordered below ∼27 K with an uncompensated configuration. The uncompensated moment shows the typical features of strongly interacting superparamagnetic nanoparticles and spin-glass systems.

Organic-Inorganic Eu(3+)/Tb(3+) codoped hybrid films for temperature mapping in integrated circuits.

The continuous decrease on the geometric size of electronic devices and integrated circuits generates higher local power densities and localized heating problems that cannot be characterized by conventional thermographic techniques. Here, a self-referencing intensity-based molecular thermometer involving a di-ureasil organic-inorganic hybrid thin film co-doped with Eu(3+) and Tb(3+) tris (ß-diketonate) chelates is used to obtain the temperature map of a FR4 printed wiring board with spatio-temporal resolutions of 0.42 µm/4.8 ms.

Thermometry at the nanoscale.

Non-invasive precise thermometers working at the nanoscale with high spatial resolution, where the conventional methods are ineffective, have emerged over the last couple of years as a very active field of research. This has been strongly stimulated by the numerous challenging requests arising from nanotechnology and biomedicine. This critical review offers a general overview of recent examples of luminescent and non-luminescent thermometers working at nanometric scale. Luminescent thermometers encompass organic dyes, QDs and Ln(3+)ions as thermal probes, as well as more complex thermometric systems formed by polymer and organic-inorganic hybrid matrices encapsulating these emitting centres. Non-luminescent thermometers comprise of scanning thermal microscopy, nanolithography thermometry, carbon nanotube thermometry and biomaterials thermometry. Emphasis has been put on ratiometric examples reporting spatial resolution lower than 1 micron, as, for instance, intracellular thermometers based on organic dyes, thermoresponsive polymers, mesoporous silica NPs, QDs, and Ln(3+)-based up-converting NPs and ß-diketonate complexes. Finally, we discuss the challenges and opportunities in the development for highly sensitive ratiometric thermometers operating at the physiological temperature range with submicron spatial resolution.

A single-source route for the synthesis of metal oxide nanoparticles using vegetable oil solvents.

We report a general method for the synthesis of metal oxide colloidal nanocrystals in sunflower oil using single-source precursors. In this research, iron oxide nanocrystals have been synthesized and characterized though this method can be extended to the synthesis of other common metal oxides such as ZnO and also to other types of vegetable oils as solvents. Using this method, nanoparticles with average diameters of 7 nm and 3 nm were obtained respectively for iron oxide and zinc oxide. The magnetic iron oxide phase was identified using powder XRD, surface enhanced Raman spectroscopy and magnetic measurements as maghemite as the main component. The magnetic measurements demonstrate the superparamagnetic behavior of the iron oxide nanoparticles. This synthetic approach is an interesting way to synthesize metal oxide nanocrystals in eco-friendly solvents of natural origin.

Magnetic and relaxation properties of multifunctional polymer-based nanostructured bioferrofluids as MRI contrast agents.

A series of maghemite/polymer composite ferrofluids with variable magnetic core size, which show a good efficiency as MRI contrast agents, are presented. These ferrofluids are biocompatible and can be proposed as possible platforms for multifunctional biomedical applications, as they contain anchoring groups for biofunctionalization, can incorporate fluorescent dyes, and have shown low cellular toxicity. The magnetic properties of the ferrofluids have been determined by means of magnetization and ac susceptibility measurements as a function of temperature and frequency. The NMR dispersion profiles show that the low frequency behavior of the longitudinal relaxivity r(1) is well described by the heuristic model of (1)H nuclear relaxation induced by superparamagnetic nanoparticles proposed by Roch and co-workers. The contrast efficiency parameter, i.e., the nuclear transverse relaxivity r(2), for samples with d > 10 nm assumes values comparable with or better than the ones of commercial samples, the best results obtained in particles with the biggest magnetic core, d = 15 nm. The contrast efficiency results are confirmed by in vitro MRI experiments at ν = 8.5 MHz, thus allowing us to propose a set of optimal microstructural parameters for multifunctional ferrofluids to be used in MRI medical diagnosis.