Magnetic Drug Targeting: Preclinical in Vivo Studies, Mathematical Modeling, and Extrapolation to Humans.

A sound theoretical rationale for the design of a magnetic nanocarrier capable of magnetic capture in vivo after intravenous administration could help elucidate the parameters necessary for in vivo magnetic tumor targeting. In this work, we utilized our long-circulating polymeric magnetic nanocarriers, encapsulating increasing amounts of superparamagnetic iron oxide nanoparticles (SPIONs) in a biocompatible oil carrier, to study the effects of SPION loading and of applied magnetic field strength on magnetic tumor targeting in CT26 tumor-bearing mice. Under controlled conditions, the in vivo magnetic targeting was quantified and found to be directly proportional to SPION loading and magnetic field strength. Highest SPION loading, however, resulted in a reduced blood circulation time and a plateauing of the magnetic targeting. Mathematical modeling was undertaken to compute the in vivo magnetic, viscoelastic, convective, and diffusive forces acting on the nanocapsules (NCs) in accordance with the Nacev-Shapiro construct, and this was then used to extrapolate to the expected behavior in humans. The model predicted that in the latter case, the NCs and magnetic forces applied here would have been sufficient to achieve successful targeting in humans. Lastly, an in vivo murine tumor growth delay study was performed using docetaxel (DTX)-encapsulated NCs. Magnetic targeting was found to offer enhanced therapeutic efficacy and improve mice survival compared to passive targeting at drug doses of ca. 5-8 mg of DTX/kg. This is, to our knowledge, the first study that truly bridges the gap between preclinical experiments and clinical translation in the field of magnetic drug targeting.

A Framework to Account for Sedimentation and Diffusion in Particle-Cell Interactions.

In vitro experiments provide a solid basis for understanding the interactions between particles and biological systems. An important confounding variable for these studies is the difference between the amount of particles administered and that which reaches the surface of cells. Here, we engineer a hydrogel-based nanoparticle system and combine in situ characterization techniques, 3D-printed cell cultures, and computational modeling to evaluate and study particle-cell interactions of advanced particle systems. The framework presented demonstrates how sedimentation and diffusion can explain differences in particle-cell association, and provides a means to account for these effects. Finally, using in silico modeling, we predict the proportion of particles that reaches the cell surface using common experimental conditions for a wide range of inorganic and organic micro- and nanoparticles. This work can assist in the understanding and control of sedimentation and diffusion when investigating cellular interactions of engineered particles.

Melamine-Formaldehyde Microcapsules: Micro- and Nanostructural Characterization with Electron Microscopy.

A systematic study has been carried out to compare the surface morphology, shell thickness, mechanical properties, and binding behavior of melamine-formaldehyde microcapsules of 5-30 µm diameter size with various amounts of core content by using scanning and transmission electron microscopy including electron tomography, in situ nanomechanical tensile testing, and electron energy-loss spectroscopy. It is found that porosities are present on the outside surface of the capsule shell, but not on the inner surface of the shell. Nanomechanical tensile tests on the capsule shells reveal that Young's modulus of the shell material is higher than that of bulk melamine-formaldehyde and that the shells exhibit a larger fracture strain compared with the bulk. Core-loss elemental analysis of microcapsules embedded in epoxy indicates that during the curing process, the microcapsule-matrix interface remains uniform and the epoxy matrix penetrates into the surface micro-porosities of the capsule shells.

Formation and thermal stability of gold-silica nanohybrids: insight into the mechanism and morphology by electron tomography.

Gold-silica hybrids are appealing in different fields of applications like catalysis, sensorics, drug delivery, and biotechnology. In most cases, the morphology and distribution of the heterounits play significant roles in their functional behavior. Methods of synthesizing these hybrids, with variable ordering of the heterounits, are replete; however, a complete characterization in three dimensions could not be achieved yet. A simple route to the synthesis of Au-decorated SiO2 spheres is demonstrated and a study on the 3D ordering of the heterounits by scanning transmission electron microscopy (STEM) tomography is presented-at the final stage, intermediate stages of formation, and after heating the hybrid. The final hybrid evolves from a soft self-assembled structure of Au nanoparticles. The hybrid shows good thermal stability up to 400 °C, beyond which the Au particles start migrating inside the SiO2 matrix. This study provides an insight in the formation mechanism and thermal stability of the structures which are crucial factors for designing and applying such hybrids in fields of catalysis and biotechnology. As the method is general, it can be applied to make similar hybrids based on SiO2 by tuning the reaction chemistry as needed.

Analysis of changes in air pollution quality and impact of COVID-19 on environmental health in Iran: application of interpolation models and spatial autocorrelation.

In the global COVID-19 epidemic, humans are faced with a new challenge. The concept of quarantine as a preventive measure has changed human activities in all aspects of life. This challenge has led to changes in the environment as well. The air quality index is one of the immediate concrete parameters. In this study, the actual potential of quarantine effects on the air quality index and related variables in Tehran, the capital of Iran, is assessed, where, first, the data on the pollutant reference concentration for all measuring stations in Tehran, from February 19 to April 19, from 2017 to 2020, are monitored and evaluated. This study investigated the hourly concentrations of six particulate matters (PM), including PM2.5, PM10, and air contaminants such as nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO). Changes in pollution rate during the study period can be due to reduced urban traffic, small industrial activities, and dust mites of urban and industrial origins. Although pollution has declined in most regions during the COVID-19 quarantine period, the PM2.5 rate has not decreased significantly, which might be of natural origins such as dust. Next, the air quality index for the stations is calculated, and then, the interpolation is made by evaluating the root mean square (RMS) of different models. The local and global Moran index indicates that the changes and the air quality index in the study area are clustered and have a high spatial autocorrelation. The results indicate that although the bad air quality is reduced due to quarantine, major changes are needed in urban management to provide favorable conditions. Contaminants can play a role in transmitting COVID-19 as a carrier of the virus. It is suggested that due to the rise in COVID-19 and temperature in Iran, in future studies, the effect of increased temperature on COVID-19 can be assessed.

GenX is not always a better fluorinated organic compound than PFOA: A critical review on aqueous phase treatability by adsorption and its associated cost.

Hexafluoropropylene oxide dimer acid (GenX) has been marketed as a substitute for perfluorooctanoic acid (PFOA) to reduce environmental and health risks. GenX and PFOA have been detected in various natural water sources, and adsorption is recognized as a typical treatment process for PFOA removal. In this paper, comparisons of GenX and PFOA adsorption are evaluated, including adsorption potential, adsorption mechanisms, and associated costs. A detailed literature review suggests that anion-exchange resins are more effective in removing GenX than activated carbon. GenX removal efficiency through activated carbon (30%) is lower than that of PFOA (80-95%), while GenX and PFOA removal efficiencies by anion exchange resins are similar (99%). Unconventional adsorbents, such as ionic fluorogels and covalent organic frameworks can effectively remove GenX from water. The review reveals that GenX adsorption is more challenging, requiring almost 4 times the treatment cost of its predecessor, PFOA. Annual operation and maintenance costs for GenX adsorption (initial concentration of GenX and PFOA = 0.2 µg.L-1) by GAC for treating 10,000 m3 per day is almost US$1,000,000 per year, but only around US$240,000 per year for PFOA. Desorption of GenX in the presence of PFOA highlights GenX's inferior treatability by adsorption. It is believed that GenX is a more environmentally friendly compound than PFOA, but this environmental friendliness comes with the price.

Interplay of Interfacial Layers and Blend Composition To Reduce Thermal Degradation of Polymer Solar Cells at High Temperature.

The thermal stability of printed polymer solar cells at elevated temperatures needs to be improved to achieve high-throughput fabrication including annealing steps as well as long-term stability. During device processing, thermal annealing impacts both the organic photoactive layer, and the two interfacial layers make detailed studies of degradation mechanism delicate. A recently identified thermally stable poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]]:[6,6]-phenyl-C71-butyric acid methyl ester (PTB7:PC70BM) blend as photoactive layer in combination with poly(3,4-ethylenedioxythiophene) polystyrene sulfonate as hole extraction layer is used here to focus on the impact of electron extraction layer (EEL) on the thermal stability of solar cells. Solar cells processed with densely packed ZnO nanoparticle layers still show 92% of the initial efficiency after constant annealing during 1 day at 140 °C, whereas partially covering ZnO layers as well as an evaporated calcium layer leads to performance losses of up to 30%. This demonstrates that the nature and morphology of EELs highly influence the thermal stability of the device. We extend our study to thermally unstable PTB7:[6,6]-phenyl-C61-butyric acid methyl ester (PC60BM) blends to highlight the impact of ZnO on the device degradation during annealing. Importantly, only 12% loss in photocurrent density is observed after annealing at 140 °C during 1 day when using closely packed ZnO. This is in stark contrast to literature and addressed here to the use of a stable double-sided confinement during thermal annealing. The underlying mechanism of the inhibition of photocurrent losses is revealed by electron microscopy imaging and spatially resolved spectroscopy. We found that the double-sided confinement suppresses extensive fullerene diffusion during the annealing step, but with still an increase in size and distance of the enriched donor and acceptor domains inside the photoactive layer by an average factor of 5. The later result in combination with comparably small photocurrent density losses indicates the existence of an efficient transport of minority charge carriers inside the donor and acceptor enriched phases in PTB7:PC60BM blends.

Engineering hepatitis B virus core particles for targeting HER2 receptors in vitro and in vivo.

Hepatitis B Virus core (HBc) particles have been studied for their potential as drug delivery vehicles for cancer therapy. HBc particles are hollow nano-particles of 30-34 nm diameter and 7 nm thick envelopes, consisting of 180-240 units of 21 kDa core monomers. They have the capacity to assemble/dis-assemble in a controlled manner allowing encapsulation of various drugs and other biomolecules. Moreover, other functional motifs, i.e. receptors, receptor binding sequences, peptides and proteins can be expressed. This study focuses on the development of genetically modified HBc particles to specifically recognise and target human epidermal growth factor receptor-2 (HER2)-expressing cancer cells, in vitro and in vivo, for future cancer therapy. The non-specific binding capacity of wild type HBc particles was reduced by genetic deletion of the sequence encoding arginine-rich domains. A specific HER2-targeting was achieved by expressing the ZHER2 affibodies on the HBc particles surface. In vitro studies showed specific uptake of ZHER2-ΔHBc particles in HER2 expressing cancer cells. In vivo studies confirmed positive uptake of ZHER2-ΔHBc particles in HER2-expressing tumours, compared to non-targeted ΔHBc particles in intraperitoneal tumour-bearing mice models. The present results highlight the potential of these nanocarriers in targeting HER2-positive metastatic abdominal cancer following intra-peritoneal administration.

Silver Ions Direct Twin-Plane Formation during the Overgrowth of Single-Crystal Gold Nanoparticles.

It is commonly agreed that the crystalline structure of seeds dictates the crystallinity of final nanoparticles in a seeded-growth process. Although the formation of monocrystalline particles does require the use of single-crystal seeds, twin planes may stem from either single- or polycrystalline seeds. However, experimental control over twin-plane formation remains difficult to achieve synthetically. Here, we show that a careful interplay between kinetics and selective surface passivation offers a unique handle over the emergence of twin planes (in decahedra and triangles) during the growth over single-crystalline gold nanoparticles of quasi-spherical shape. Twinning can be suppressed under conditions of slow kinetics in the presence of silver ions, yielding single-crystalline particles with high-index facets.

Triple-Modal Imaging of Magnetically-Targeted Nanocapsules in Solid Tumours In Vivo.

Triple-modal imaging magnetic nanocapsules, encapsulating hydrophobic superparamagnetic iron oxide nanoparticles, are formulated and used to magnetically target solid tumours after intravenous administration in tumour-bearing mice. The engineered magnetic polymeric nanocapsules m-NCs are ~200 nm in size with negative Zeta potential and shown to be spherical in shape. The loading efficiency of superparamagnetic iron oxide nanoparticles in the m-NC was ~100%. Up to ~3- and ~2.2-fold increase in tumour uptake at 1 and 24 h was achieved, when a static magnetic field was applied to the tumour for 1 hour. m-NCs, with multiple imaging probes (e.g. indocyanine green, superparamagnetic iron oxide nanoparticles and indium-111), were capable of triple-modal imaging (fluorescence/magnetic resonance/nuclear imaging) in vivo. Using triple-modal imaging is to overcome the intrinsic limitations of single modality imaging and provides complementary information on the spatial distribution of the nanocarrier within the tumour. The significant findings of this study could open up new research perspectives in using novel magnetically-responsive nanomaterials in magnetic-drug targeting combined with multi-modal imaging.

Plasmonic nanodiamonds: targeted core-shell type nanoparticles for cancer cell thermoablation.

Targeted biocompatible nanostructures with controlled plasmonic and morphological parameters are promising materials for cancer treatment based on selective thermal ablation of cells. Here, core-shell plasmonic nanodiamonds consisting of a silica-encapsulated diamond nanocrystal coated in a gold shell are designed and synthesized. The architecture of particles is analyzed and confirmed in detail using electron tomography. The particles are biocompatibilized using a PEG polymer terminated with bioorthogonally reactive alkyne groups. Azide-modified transferrin is attached to these particles, and their high colloidal stability and successful targeting to cancer cells overexpressing the transferrin receptor are demonstrated. The particles are nontoxic to the cells and they are readily internalized upon binding to the transferrin receptor. The high plasmonic cross section of the particles in the near-infrared region is utilized to quantitatively ablate the cancer cells with a short, one-minute irradiation by a pulse 750-nm laser.

A protecting group approach toward synthesis of Au-silica Janus nanostars.

The concept of protecting groups, widely used in organic chemistry, has been applied for the synthesis of Au-silica Janus stars, in which gold branches protrude from one half of Au-silica Janus spheres. This configuration opens up new possibilities to apply the plasmonic properties of gold nanostars, as well as a variety of chemical functionalizations on the silica component.

Quantitative electron tomography: the effect of the three-dimensional point spread function.

The intensity levels in a three-dimensional (3D) reconstruction, obtained by electron tomography, can be influenced by several experimental imperfections. Such artifacts will hamper a quantitative interpretation of the results. In this paper, we will correct for artificial intensity variations by determining the 3D point spread function (PSF) of a tomographic reconstruction based on high angle annular dark field scanning transmission electron microscopy. The large tails of the PSF cause an underestimation of the intensity of smaller particles, which in turn hampers an accurate radius estimate. Here, the error introduced by the PSF is quantified and corrected a posteriori.