Multiscale Modeling of Nanoparticles Growth, Self-assembly and Applications in Nanomedicine

In this thesis, we use quantum and classical methods to precisely model nanoscale materials on their own and in contact with biological components (nanomedicines). Most of the studies have been performed in close collaborations with experimentalists. First, we perform multiscale modeling of materials, using quantum ab initio methods and classical atomistic molecular dynamics (MD) simulations. We study (1) the nucleation of gold nanocrystals from its aqueous solution (Au(Cl4)-), (2) the dynamics of reaction intermediates (Si(OH)4) during wet etching of silicon nanopillars, (3) a capacitive gas sensing at the interface of an ionic liquid and a gold electrode, and (4) a reversible self-assembly of azobenzene-functionalized gold nanoparticles (NPs) in toluene. Second, we use atomistic MD simulations to model the interactions of nanoscale systems (NPs, micelles) with proteins and lipid bilayers. We investigate (5) irreversible interactions of functionalized NPs with selected viruses (HPV, dengue virus), (6) interactions of predesigned NPs with an Aβ40 amyloid fibril, (7) the enhancement of an enzymatic activity on the surfaces of ligated quantum dots, (8) the effect of PEG chain length in dendron micelles (DM) on the charge-dependent DM-cellular interactions, and (9) the effect of structural properties of DMs on their target-mediated cellular interactions

Transient Clustering of Reaction Intermediates during Wet Etching of Silicon Nanostructures

Wet chemical etching is a key process in fabricating silicon (Si) nanostructures. Currently, wet etching of Si is proposed to occur through the reaction of surface Si atoms with etchant molecules, forming etch intermediates that dissolve directly into the bulk etchant solution. Here, using in situ transmission electron microscopy (TEM), we follow the nanoscale wet etch dynamics of amorphous Si (a-Si) nanopillars in real-time and show that intermediates generated during alkaline wet etching first aggregate as nanoclusters on the Si surface and then detach from the surface before dissolving in the etchant solution. Molecular dynamics simulations reveal that the molecules of etch intermediates remain weakly bound to the hydroxylated Si surface during the etching and aggregate into nanoclusters via surface diffusion instead of directly diffusing into the etchant solution. We confirmed this model experimentally by suppressing the formation of nanoclusters of etch intermediates on the Si surfaces by shielding the hydroxylated Si sites with large ions. These results suggest that the interaction of etch intermediates with etching surfaces controls the solubility of reaction intermediates and is an important parameter in fabricating densely packed clean 3D nanostructures for future generation microelectronics

Template-Free Hierarchical Self-Assembly of Iron Diselenide Nanoparticles into Mesoscale Hedgehogs

The ability of semiconductor nanoparticles (NPs) to self-assemble has been known for several decades. However, the limits of the geometrical and functional complexity for the self-assembled nanostructures made from simple often polydispersed NPs are still continuing to amaze researchers. We report here the self-assembly of primary ∼2–4 nm FeSe₂ NPs with puck-like shapes into either (a) monocrystalline nanosheets ∼5.5 nm thick and ∼1000 nm in lateral dimensions or (b) mesoscale hedgehogs ∼550 nm in diameter with spikes of ∼250 nm in length, and ∼10–15 nm in diameter, the path of the assembly is determined by the concentration of dodecanethiol (DT) in the reaction media. The nanosheets represent the constitutive part of hedgehogs. They are rolled into scrolls and assembled around a single core with distinct radial orientation forming nanoscale “needles” approximately doubling its fractal dimension of these objects. The core is assembled from primary NPs and nanoribbons. The size distribution of the mesoscale hedgehogs can be as low as 3.8%, indicating a self-limited mechanism of the assembly. Molecular dynamics simulation indicates that the primary FeSe₂ particles have mobile edge atoms and asymmetric basal surfaces. The top-bottom asymmetry of the puck-like NPs originates from the Fe-rich/Se-rich stripes on the (011) surface of the orthorhombic FeSe₂ crystal lattice, displaying 2.7 nm periodicity that is comparable to the lateral size of the primary NPs. As the concentration of DT increases, the NPs bind to additional metal sites, which increases the chemical and topographic asymmetry and switches the assembly pathways from nanosheets to hedgehogs. These results demonstrate that the self-assembly of NPs with non-biological surface ligands and without any biological templates results in morphogenesis of inorganic superstructures with complexity comparable to that of biological assemblies, for instance mimivirus. The semiconductor nature of FeSe₂ hedgehogs enables their utilizations in catalysis, drug delivery, optics, and energy storage

Poly(ethylene glycol) Corona Chain Length Controls End-Group-Dependent Cell Interactions of Dendron Micelles

To systematically investigate the relationship among surface charge, PEG chain length, and nano–bio interactions of dendron-based micelles (DMs), a series of PEGylated DMs with various end groups (−NH₂, −Ac, and −COOH) and PEG chain lengths (600 and 2000 g/mol) are prepared and tested <i>in vitro</i>. The DMs with longer PEG chains (DM_2K) do not interact with cells despite their positively charged surfaces. In sharp contrast, the DMs with shorter PEG chains (DM₆₀₀) exhibit charge-dependent cellular interactions, as observed in both <i>in vitro</i> and molecular dynamics (MD) simulation results. Furthermore, all DMs with different charges display enhanced stability for hydrophobic dye encapsulation compared to conventional linear-block copolymer-based micelles, by allowing only a minimal leakage of the dye <i>in vitro</i>. Our results demonstrate the critical roles of the PEG chain length and polymeric architecture on the terminal charge effect and the stability of micelles, which provides an important design cue for polymeric micelles

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

Alzheimer’s Diseases (AD) is the most common neurodegenerative disease, but efficient therapeutic and early diagnosis agents for this neurological disorder are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated linking a hydrophobic amyloid fibril-binding fragment with a hydrophilic azamacrocycle that can dramatically increase the binding affinity towards various amyloid β (Aβ) peptide aggregates. The developed compound exhibits uncommon fluorescence turn-on and high binding affinity for Aβ aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of the LS-4-treated brain sections reveals that LS-4 can readily penetrate the blood-brain-barrier (BBB) and bind to the Aβ oligomers in vivo, as confirmed by immunostaining with an Aβ oligomer-specific antibody. In addition, the treatment of 5xFAD mice with LS-4 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates vs. the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Furthermore, molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure can significantly enhance the electrostatic interactions with the polar residues of the Aβ peptide species. Finally, taking advantage of the strong Cu-chelating property of the azamacrocycle, we performed a series of radioimaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate a significantly larger extent in the 5xFAD mice brains vs. the WT controls. Overall, these in vitro and in vivo studies illustrate that the novel strategy to employ an amphiphilic molecule containing a hydrophilic fragment attached to a hydrophobic amyloid fibril-binding fragment can increase the binding affinity of these compounds for the soluble Aβ oligomers and can thus be used to detect and regulate the soluble Aβ species in AD

Tuning the Selectivity of Dendron Micelles Through Variations of the Poly(ethylene glycol) Corona

Engineering controllable cellular interactions into nanoscale drug delivery systems is key to enable their full potential. Here, using folic acid (FA) as a model targeting ligand and dendron micelles (DM) as a nanoparticle (NP) platform, we present a comprehensive experimental and modeling investigation of the structural properties of DMs that govern the formation of controllable, FA-mediated cellular interactions. Our experimental results demonstrate that a high level of control over the specific cell interactions of FA-targeted DMs can be achieved through modulation of the PEG corona length and the FA content. Using various molecular weight PEGs (0<i>.</i>6K, 1K, and 2K g/mol) and contents of dendron-FA conjugate incorporated into DMs (0, 5, 10, 25 wt %), the cell interactions of the targeted DMs could be controlled to exhibit minimal to >25-fold enhancement over nontargeted DMs. Molecular dynamics simulations indicated that structural characteristics, such as solvent accessible surface area of FA, local PEG density near FA, and FA mobility, account in part for the experimental differences in cellular interactions. The molecular structure that allows FA to depart from the surface of DMs to facilitate the initial cell surface binding was revealed to be the most important contributor for determining FA-mediated cellular interactions of DMs. The modular properties of DMs in controlling their specific cell interactions support the potential of DMs as a delivery platform and offer design cues for future development of targeted NPs

Highly Sensitive Capacitive Gas Sensing at Ionic Liquid–Electrode Interfaces

We have developed an ultrasensitive gas-detection method based on the measurement of a differential capacitance of electrified ionic liquid (IL) electrode interfaces in the presence and absence of adsorbed gas molecules. The observed change of differential capacitance has a local maximum at a certain potential that is unique for each type of gas, and its amplitude is related to the concentration of the gas molecules. We establish and validate this gas-sensing method by characterizing SO₂ detection at ppb levels with less than 1.8% signal from other interfering species (i.e., CO₂, O₂, NO₂, NO, SO₂, H₂O, H₂, and cyclohexane, tested at the same concentration as SO₂). This study opens a new avenue of utilizing tunable electrified IL–electrode interfaces for selective sensing of molecules with a kinetic size resolution of 0.1 Å

Confined, Oriented, and Electrically Anisotropic Graphene Wrinkles on Bacteria

Curvature-induced dipole moment and orbital rehybridization in graphene wrinkles modify its electrical properties and induces transport anisotropy. Current wrinkling processes are based on contraction of the entire substrate and do not produce confined or directed wrinkles. Here we show that selective desiccation of a bacterium under impermeable and flexible graphene <i>via</i> a flap-valve operation produces axially aligned graphene wrinkles of wavelength 32.4–34.3 nm, consistent with modified Föppl–von Kármán mechanics (confinement ∼0.7 × 4 μm²). Further, an electrophoretically oriented bacterial device with confined wrinkles aligned with van der Pauw electrodes was fabricated and exhibited an anisotropic transport barrier (Δ<i>E</i> = 1.69 meV). Theoretical models were developed to describe the wrinkle formation mechanism. The results obtained show bio-induced production of confined, well-oriented, and electrically anisotropic graphene wrinkles, which can be applied in electronics, bioelectromechanics, and strain patterning