Neutral Nanoparticles Research Articles

Modulating interactions between ligand-coated nanoparticles and phase-separated lipid bilayers by varying the ligand density and the surface charge.

The interactions between nanoparticles and lipid bilayers are critical in applications of nanoparticles in nanomedicine, cell imaging, toxicology, and elsewhere. Here, we investigate the interactions between nanoparticles coated with neutral and/or charged ligands and phase-separated lipid bilayers using coarse-grained molecular dynamics simulation. Both penetration and adsorption processes as well as the final distribution of the nanoparticles can be readily modulated by varying the ligand density and the surface charge of the nanoparticles. Completely hydrophobic (neutral) nanoparticles with larger size initially preferentially penetrate into the liquid-disordered region of the lipid bilayer and finally transfer into the liquid-ordered region; partially hydrophilic nanoparticles with low or moderate surface charge tend to either distribute in the liquid-disordered region or be adsorbed on the surface of the lipid bilayer, while strongly hydrophilic nanoparticles with high surface charge always reside on the surface of the lipid bilayer. Interactions of the nanoparticles with the lipid bilayers are affected by the surface charge of nanoparticles, hydrophobic mismatch, bending of the ligands, and the packing state of the lipids. Insight in these factors can be used to improve the efficiency of designing nanoparticles for specific applications.

Mechanical-optical-electro modulation by stretching a polymer-metal nanocomposite

We report the simultaneous investigation of both the plasmonic resonance and electrical conductance evolution in stretchable metal–polymer nanocomposite films. The films are produced by the implantation of neutral gold nanoparticles in a polydimethylsiloxane substrate by aerodynamic acceleration in a supersonic expansion. A redshift of the gold nanoparticle plasmon peak is found upon stretching as well as a strong correlation between the plasmonic peak wavelength and the nanocomposite electrical resistance. Optical simulations attribute the optical response to the compression of the polymer perpendicular to the stretching direction, which brings the gold particles closer to each other, increasing the plasmonic coupling. Mechanical stretching can induce a simultaneous modulation of the optical and electrical properties of the nanocomposite.

Electroactive Ionic Soft Actuators with Monolithically Integrated Gold Nanocomposite Electrodes

Electroactive ionic gel/metal nanocomposites are produced by implanting supersonically accelerated neutral gold nanoparticles into a novel chemically crosslinked ion conductive soft polymer. The ionic gel consists of chemically crosslinked poly(acrylic acid) and polyacrylonitrile networks, blended with halloysite nanoclays and imidazolium-based ionic liquid. The material exhibits mechanical properties similar to that of elastomers (Young's modulus ≈ 0.35 MPa) together with high ionic conductivity. The fabrication of thin (≈100 nm thick) nanostructured compliant electrodes by means of supersonic cluster beam implantation (SCBI) does not significantly alter the mechanical properties of the soft polymer and provides controlled electrical properties and large surface area for ions storage. SCBI is cost effective and suitable for the scaleup manufacturing of electroactive soft actuators. This study reports the high-strain electromechanical actuation performance of the novel ionic gel/metal nanocomposites in a low-voltage regime (from 0.1 to 5 V), with long-term stability up to 76 000 cycles with no electrode delamination or deterioration. The observed behavior is due to both the intrinsic features of the ionic gel (elasticity and ionic transport capability) and the electrical and morphological features of the electrodes, providing low specific resistance (<100 Ω cm-2 ), high electrochemical capacitance (≈mF g-1 ), and minimal mechanical stress at the polymer/metal composite interface upon deformation.

Density functional description of size-dependent effects at nucleation on neutral and charged nanoparticles

A numerical study of size-dependent effects in the thermodynamics of a small droplet formed around a solid nanoparticle has been performed within the square-gradient density functional theory. The Lennard-Jones fluid with the Carnahan-Starling model for the hard-sphere contribution to intermolecular interaction in liquid and vapor phases and interfaces has been used for description of the condensate. The intermolecular forces between the solid core and condensate molecules have been taken into account with the help of the Lennard-Jones part of the total molecular potential of the core. The influence of the electric charge of the particle has been considered under assumption of the central Coulomb potential in the medium with dielectric permittivity depending on local condensate density. The condensate density profiles and equimolecular radii for equilibrium droplets at different values of the condensate chemical potential have been computed in the cases of an uncharged solid core with the molecular potential, a charged core without molecular potential, and a core with joint action of the Coulomb and molecular potentials. The appearance of stable equilibrium droplets even in the absence of the electric charge has been commented. As a next step, the capillary, disjoining pressure, and electrostatic contributions to the condensate chemical potential have been considered and compared with the predictions of classical thermodynamics in a wide range of values of the droplet and the particle equimolecular radii. With the help of the found dependence of the condensate chemical potential in droplet on the droplet size, the activation barrier for nucleation on uncharged and charged particles has been computed as a function of the vapor supersaturation. Finally, the work of droplet formation and the work of wetting the particle have been found as functions of the droplet size.

The influence of cell and nanoparticle properties on heating and cell death in a radiofrequency field.

The ability of nanoparticles to either direct heating or increase susceptibility of cancer cells to radiofrequency (RF) energy remains controversial, as is the impact of cell attributes on susceptibility of cells to RF-induced cell death. This manuscript examines the impact of nanoparticle charge, size, and cellular localization on RF-induced cell death and the influence of nanoparticles on the heating rates of water and biologically-relevant media. Susceptibility of immortalized or primary cells to RF energy and the impact of cell size are also examined. The ability to selectively modulate RF heating rates in specific biological locations or in specific cell populations would enhance the therapeutic potential of RF therapy.

Polyphosphoester nanoparticles as biodegradable platform for delivery of multiple drugs and siRNA.

Delivery of multiple therapeutics and/or diagnostic agents to diseased tissues is challenging and necessitates the development of multifunctional platforms. Among the various strategies for design of multifunctional nanocarriers, biodegradable polyphosphoester (PPE) polymers have been recently synthesized via a rapid and simple synthetic strategy. In addition, the chemical structure of the polymer could be tuned to form nanoparticles with varying surface chemistries and charges, which have shown exceptional safety and biocompatibility as compared to several commercial agents. The purpose of this study was to exploit a mixture of PPE nanoparticles of cationic and neutral surface charges for multiple delivery of anticancer drugs (ie, sorafenib and paclitaxel) and nucleic acids (ie, siRNA). Cationic PPE polymers could efficiently complex siRNA, and the stability of the nanoparticles could be maintained in physiological solutions and upon freeze-drying and were able to deliver siRNA in vivo when injected intravenously in mice. Commercially available cationic polyethylenimine polymer had LD50 of ca. 61.7 mg/kg in mice, whereas no animal died after injection of the cationic PPE polymer at a dose of >130 mg/kg. Neutral PPE nanoparticles were able to encapsulate two hydrophobic drugs, namely, sorafenib and paclitaxel, which are commonly used for the treatment of hepatocellular carcinoma. Mixing the neutral and cationic PPE nanoparticles did not result in any precipitation, and the size characteristics of both types of nanoparticles were maintained. Hence, PPE polymers might have potential for the delivery of multiple drugs and diagnostic agents to diseased tissues via simple synthesis of the individual polymers and assembly into nanoparticles that can host several drugs while being mixed in the same administration set, which is of importance for industrial and clinical development.

Counterintuitive cooperative endocytosis of like-charged nanoparticles in cellular internalization: computer simulation and experiment

The nanoparticles (NPs) functionalized with charged ligands are of particular significance due to their potential drug/gene delivery and biomedical applications. However, the molecular mechanism of endocytosis of the charged NPs by cells, especially the effect of the NP–NP and NP–biomembrane interactions on the internalization pathways is still poorly understood. In this work, we systematically investigate the internalization behaviors of the positively charged NPs by combining experiment technology and dissipative particle dynamics (DPD) simulation. We experimentally find an interesting but highly counterintuitive phenomenon, i.e. the multiple positively charged NPs prefer to enter cells cooperatively although the like-charged NPs have obvious electrostatic repulsion. Furthermore, we adopt the DPD simulation to confirm the experimental findings, and reveal that the mechanism of the cooperative endocytosis between like-charged NPs is definitely caused by the interplay of particle size, the charged ligand density on particle surface and local concentration of NPs. Importantly, we not only observe the normal cooperative endocytosis of like-charged NPs in cell biomembrane like neutral NP case, but also predict the ‘bud’ cooperative endocytosis of like-charged NPs which is absence in the neutral NP case. The results indicate that electrostatic repulsion between the positively charged nanoparticles plays an important role in the ‘bud’ cooperative endocytosis of like-charged NPs.

Shedding light on zwitterionic magnetic nanoparticles: limitations for in vivo applications.

Over the last few years several studies have dealt with the importance of the surface charge of nanoparticles in prolonging their blood circulation and minimizing their interaction with plasma proteins. These investigations claimed that zwitterionic nanoparticles exhibited a minimal macrophage response and long blood circulation times compared to nanoparticles with other surface charges. These differences in their in vivo behavior are mainly attributed to the interaction of nanoparticles with plasma proteins. Interestingly, most of these studies considered the total surface charge, instead of the outermost layer of the nanomaterial, as being mainly responsible for these undesirable interactions. However, the first contact with plasma proteins is most likely due to the outermost layer on the nanomaterials. Therefore, here we report a detailed study on the effect of the outermost surface charge of magnetic nanoparticles with regard to biodistribution, pharmacokinetics and bioavailability. Magnetic nanoparticles, coated with PEG chains functionalized with neutral, positive or zwitterionic groups, were intravenously injected into mice, followed in vivo by MRI and then quantified by ICP-MS in blood and the main organs. We found that neutral nanoparticles exhibited long blood circulation times, very good stealth properties and the highest bioavailability, whereas zwitterionic nanoparticles were readily recognized by the mononuclear phagocyte system and avidly taken up by the liver. Also, zwitterionic nanoparticles showed high non-specific cell internalization, whereas neutral nanoparticles showed the lowest cellular uptake, indicating that they require active transport to cross the plasma membrane, which is the desirable situation for therapeutic vehicles with low side effects. Thus, neutral nanoparticles exhibit very favorable characteristics for in vivo applications, whereas zwitterionic nanoparticles show important limitations.

Long-pulse laser launch and ionization of tailored large neutral silver nanoparticles with atomic mass assignment.

We explore the synthesis, characterization, neutral launch and vacuum ultraviolet ionization of massive perfluorinated-alkyl-capped nanoparticles. The presence of the ligand coating in solution is corroborated by Fourier transform infrared spectroscopy (FT-IR) and the particle size distribution is analyzed by transmission electron microscopy (TEM). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry identifies perfluoralkyl coated silver nanoparticles as the most stable species among the materials studied here. They can be launched in high vacuum using long-pulse low-power laser heating - orders of magnitude below typical thresholds for laser desorption. Energy-dispersive X-ray spectroscopy (EDX) of the recaptured silver clusters confirms the expected elemental distribution. Volatilization with subsequent ionization of the neutral nanoparticle beam in high vacuum by 157 nm light allows analyzing their mass with atomic resolution.

Diffusion and Directionality of Charged Nanoparticles on Lipid Bilayer Membrane.

Diffusion dynamics of charged nanoparticles on the lipid membrane is of essential importance to cellular functioning. Yet a fundamental insight into electrostatics-mediated diffusion dynamics of charged nanoparticles on the membrane is lacking and remains to be an urgent issue. Here we present the computational investigation to uncover the pivotal role of electrostatics in the diffusion dynamics of charged nanoparticles on the lipid membrane. Our results demonstrate diffusive behaviors and directional transport of a charged nanoparticle, significantly depending on the sign and spatial distribution of charges on its surface. In contrast to the Fickian diffusion of neutral nanoparticles, randomly charged nanoparticles undergo superdiffusive transport with directionality. However, the dynamics of uniformly charged nanoparticles favors Fickian diffusion that is significantly enhanced. Such observations can be explained in term of electrostatics-induced surface reconstruction and fluctuation of lipid membrane. We finally present an analytical model connecting surface reconstruction and local deformation of the membrane. Our findings bear wide implications for the understanding and control of the transport of charged nanoparticles on the cell membrane.

A Neutralized Noncharged Polyethylenimine-Based System for Efficient Delivery of siRNA into Heart without Toxicity.

Cationic polymers constitute an important class of materials in development of delivery vehicles for nucleic acid-based therapeutics. Among them, polyethylenimine (PEI) has been a classical cationic carrier intensively studied for therapeutic delivery of DNA, RNA, and short RNA molecules to treat diseases. However, the development of PEI for in vivo applications has been hampered by the inherent problems associated with the material, particularly its cytotoxicity and the instability of the nucleic acid complexation systems formed via electrostatic interactions. Here, we demonstrate a strategy to modify PEI polymers via hydrazidation to create neutralized, stable, and multifunctional system for delivering siRNA molecules. Through substitution of the primary amino groups of PEI with neutral hydrazide groups, cross-linked nanoparticles with surface decorated with a model targeting ligands were generated. The neutral cross-linked siRNA nanoparticles not only showed favorable biocompatibility and cell internalization efficiency in vitro but also allowed for significant tissue uptake and gene silencing efficiency in zebrafish heart in vivo. Our study suggests transformation of conventional branched PEI into a neutral polymer that can lead to a new category of nonviral carriers, and the resulting functional delivery systems may be further explored for development of siRNA therapeutics for treating cardiovascular disease/injury.

Antiplatelet effect of differentially charged PEGylated lipid-polymer nanoparticles

PEGylated nanoparticles have been extensively investigated in different platforms for drug delivery. However, the physiological effects related to platelet activation, and the potential procoagulant activity which could lead to thrombosis and further cardiovascular diseases have not been widely examined. In this work, we studied the effect of differentially charged PEGylated lipid-polymer nanoparticles in the human platelet aggregation and activation by light transmission aggregometry and flow cytometry. PEGylated nanoparticles inhibited the platelet aggregation with a dose dependency (350, 700, and 1400μg/mL) in both ADP- and collagen-induced platelet aggregation, and P-selectin expression. Charged nanoparticles (anionic and cationic) presented higher inhibitions of the platelet aggregation compared to neutral nanoparticles, and particularly the cationic particles generated a slightly higher effect. The obtained results demonstrated the safety of the differentially charged PEGylated lipid-polymer nanoparticles, and their ability to inhibit the aggregation and activation of human platelets stimulated by two classic platelet activators.

Gold on carbon and titanium oxides composites: Highly efficient and stable acetylene hydrogenation in large excess of ethylene

Photocatalytically generated gold on carbon and TiO2 composites were used for acetylene hydrogenation in excess ethylene, in a way close to current industrial practices. The crystalline effect of TiO2 and the addition of Pd to supported Au catalysts on acetylene hydrogenation were investigated. Carbon and amorphous TiO2 supported Au were highly active, selective, and stable and possessed the highest ethylene yield of 83% at 210°C with a H2/C2H2 ratio of 2/1 for selective hydrogenation of acetylene to ethylene. With further addition of Pd to the supported Au catalyst, ethylene yield reached a maximum value of 57% at 30°C with a H2/C2H2 ratio of 2/1. The enhanced performance originated from small neutral Au nanoparticles and the formation of bimetallic Au–Pd catalyst. This report opens up promising possibilities for the design of highly efficient heterogeneous supported gold catalysts.

Controlled Fluxes of Silicon Nanoparticles to a Substrate in Pulsed Radio-Frequency Argon–Silane Plasmas

It has been hypothesized that high-energy impact of very small silicon nanoparticles on a substrate may lead to epitaxial growth of silicon films at low substrate temperature. A possible means for producing such energetic nanoparticle fluxes involves pulsing an RF silane-containing plasma, and applying a positive DC bias to the substrate during the afterglow phase of each pulse so as to collect the negatively charged particles generated during the RF power on phase. We here report numerical modeling to provide a preliminary assessment of the feasibility of this scheme. The system modeled is a parallel-plate capacitively-coupled RF argon–silane plasma at pressures around 100 mTorr. Simulation results indicate that it is possible to achieve a periodic steady state in which each pulse delivers a controlled flux of nanoparticles to the biased substrate, that average particle sizes can be kept below 2–3 nm, that impact energies of the negatively-charged nanoparticles that are attracted by the applied bias can be maintained in the ~1 eV/atom range thought to be conducive to epitaxial growth without causing film damage, and that the volume fraction of neutral nanoparticles that deposit by low-velocity diffusion can be kept well below 1 %. The effects of several operating parameters are explored, including RF voltage, pressure, the value of the applied DC bias, and RF power on and off time during each pulse.

Temporal evolution of charged and neutral nanoparticle concentrations during atmospheric new particle formation events and its implications for ion-induced nucleation

Time series of nanoparticle number concentration during new particle formation (NPF) events in the urban environment of Brisbane, Australia, showed that the formation of charged particles often occurred before that of neutral particles. We monitored 241 days during the calendar year 2012 over which NPF events were observed on 108 days. We studied the times at which the charged and neutral particle concentrations in the size range 1.8–3.2 nm reached their peak values and found that they were clearly different in 50 events with the peak neutral particle concentration lagging behind the charged particle concentration during 42 of these events with a mean time lag of 24±12 min. While the charged particles were more likely to form before the neutral particles, once formed, the growth rate of the particles did not depend on their charge. While ion-induced nucleation is not the dominant mechanism of NPF in the atmosphere, our observations suggest that the presence of ions in the atmosphere plays a role that cannot be ignored.

Synthesis of Silicon Nanoparticles in Nonthermal Capacitively-Coupled Flowing Plasmas: Processes and Transport

Control of the size and material properties of silicon nanoparticles plays a critical role in optimizing applications using those nanoparticles, such as photovoltaics and biomedical devices. While synthesis of silicon nanoparticles in low temperature plasmas has many attractive features, the basic mechanisms leading to formation of nanoparticles in these plasmas are poorly understood. A two-dimensional numerical model for synthesis of silicon nanoparticles (<5 nm in diameter) in radio frequency (RF) discharges was developed and used to investigate mechanisms for particle growth for Ar/He/SiH4 gas mixtures. Algorithms for the kinetics of nanoparticle formation were self-consistently embedded into a plasma hydrodynamics simulation to account for nucleation, growth, charging, and transport of nanoparticles. We found that with RF excitation in narrow tubes at pressures of a few Torr, the electric field does not fully confine charged nanoparticles in the axial direction, which then results in a finite residence time of particles in the plasma. We found that because of the high neutral nanoparticle density, coagulation plays a significant role in growth. The model predicts the possibility of synthesizing crystalline silicon nanoparticles under these conditions. Trends in the growth of nanoparticles as a function of power are discussed.

Polypeptide-Nanoparticle Interactions and Corona Formation Investigated by Monte Carlo Simulations.

Biomacromolecule activity is usually related to its ability to keep a specific structure. However, in solution, many parameters (pH, ionic strength) and external compounds (polyelectrolytes, nanoparticles) can modify biomacromolecule structure as well as acid/base properties, thus resulting in a loss of activity and denaturation. In this paper, the impact of neutral and charged nanoparticles (NPs) is investigated by Monte Carlo simulations on polypeptide (PP) chains with primary structure based on bovine serum albumin. The influence of pH, salt valency, and NP surface charge density is systematically studied. It is found that the PP is extended at extreme pH, when no complex formation is observed, and folded at physiological pH. PP adsorption around oppositely-charged NPs strongly limits chain structural changes and modifies its acid/base properties. At physiological pH, the complex formation occurs only with positively-charged NPs. The presence of salts, in particular those with trivalent cations, introduces additional electrostatic interactions, resulting in a mitigation of the impact of negative NPs. Thus, the corona structure is less dense with locally-desorbed segments. On the contrary, very limited impact of salt cation valency is observed when NPs are positive, due to the absence of competitive effects between multivalent cations and NP.

Surface Charge Controls the Suborgan Biodistributions of Gold Nanoparticles

Surface chemistry plays a deciding role in nanoparticle biodistribution, yet very little is known about how surface chemistry influences the suborgan distributions of nanomaterials. Here, using quantitative imaging based on laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), we demonstrate that surface charge dictates the suborgan distributions of nanoparticles in the kidney, liver, and spleen of mice intravenously injected with functionalized gold nanoparticles. Images of the kidney show that positively charged nanoparticles accumulate extensively in the glomeruli, the initial stage in filtering for the nephron, suggesting that these nanoparticles may be filtered by the kidney at a different rate than the neutral or negatively charged nanoparticles. We find that positively and negatively charged nanoparticles accumulate extensively in the red pulp of the spleen. In contrast, uncharged nanoparticles accumulate in the white pulp and marginal zone of the spleen to a greater extent than the positively or negatively charged nanoparticles. Moreover, these uncharged nanoparticles are also more likely to be found associated with Kupffer cells in the liver. Positively charged nanoparticles accumulate extensively in liver hepatocytes, whereas negatively charged nanoparticles show a broader distribution in the liver. Together these observations suggest that neutral nanoparticles having 2 nm cores may interact with the immune system to a greater extent than charged nanoparticles, highlighting the value of determining the suborgan distributions of nanomaterials for delivery and imaging applications.

Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer

Advanced-stage prostate cancer usually metastasizes to bone and is untreatable due to poor biodistribution of intravenously administered anticancer drugs to bone. In this study, we modulated the surface charge/composition of biodegradable nanoparticles (NPs) to sustain their blood circulation time and made them small enough to extravasate through the openings of the bone's sinusoidal capillaries and thus localize into marrow. NPs with a neutral surface charge, achieved by modulating the NP surface-associated emulsifier composition, were more effective at localizing to bone marrow than NPs with a cationic or anionic surface charge. These small neutral NPs (~150nm vs. the more usual ~320nm) were also ~7-fold more effective in localizing in bone marrow than large NPs. We hypothesized that NPs that effectively localize to marrow could improve NP-mediated anticancer drug delivery to sites of bone metastasis, thereby inhibiting cancer progression and preventing bone loss. In a PC-3M-luc cell-induced osteolytic intraosseous model of prostate cancer, these small neutral NPs demonstrated greater accumulation in bone within metastatic sites than in normal contralateral bone as well as co-localization with the tumor mass in marrow. Significantly, a single-dose intravenous administration of these small neutral NPs loaded with paclitaxel (PTX-NPs), but not anionic PTX-NPs, slowed the progression of bone metastasis. In addition, neutral PTX-NPs prevented bone loss, whereas animals treated with the rapid-release drug formulation Cremophor EL (PTX-CrEL) or saline (control) showed >50% bone loss. Neutral PTX-NPs did not cause acute toxicity, whereas animals treated with PTX-CrEL experienced weight loss. These results indicate that NPs with appropriate physical and sustained drug-release characteristics could be explored to treat bone metastasis, a significant clinical issue in prostate and other cancers.

Hot Nanoparticles in Polar or Paramagnetic Liquids Interact as Monopoles.

When neutral nanoparticles are heated or cooled in a polar liquid, they will interact with each other as if they carry an electrostatic charge that is proportional to the temperature difference between the particle and the surrounding fluid. The same should hold for suspensions of asymmetric ferromagnetic particles, in which case the heated nanoparticles should behave as magnetic monopoles. However, the analogy with electrostatics/magnetostatics is not complete: heated/cooled nanoparticles do not move under the influence of an applied homogeneous field. They should, however, interact as monopoles with each other and should move in inhomogeneous fields.