Hamed Heidari

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.

Quantitative Tomography of Organic Photovoltaic Blends at the Nanoscale.

The success of semiconducting organic materials has enabled green technologies for electronics, lighting, and photovoltaics. However, when blended together, these materials have also raised novel fundamental questions with respect to electronic, optical, and thermodynamic properties. This is particularly important for organic photovoltaic cells based on the bulk heterojunction. Here, the distribution of nanoscale domains plays a crucial role depending on the specific device structure. Hence, correlation of the aforementioned properties requires 3D nanoscale imaging of materials domains, which are embedded in a multilayer device. Such visualization has so far been elusive due to lack of contrast, insufficient signal, or resolution limits. In this Letter, we introduce spectral scanning transmission electron tomography for reconstruction of entire volume plasmon spectra from rod-shaped specimens. We provide 3D structural correlations and compositional mapping at a resolution of approximately 7 nm within advanced organic photovoltaic tandem cells. Novel insights that are obtained from quantitative 3D analyses reveal that efficiency loss upon thermal annealing can be attributed to subtle, fundamental blend properties. These results are invaluable in guiding the design and optimization of future devices in plastic electronics applications and provide an empirical basis for modeling and simulation of organic solar cells.

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.

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.

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.

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.

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.