Yoonjee Park

Stability of superparamagnetic iron oxide nanoparticles at different pH values: Experimental and theoretical analysis

The detection of superparamagnetic nanoparticles using NMR logging has the potential to provide enhanced contrast in oil reservoir rock formations. The stability of the nanoparticles is critical because the NMR relaxivity (R(2) ≡ 1/T(2)) is dependent on the particle size. Here we use a molecular theory to predict and validate experimentally the stability of citric acid-coated/PEGylated iron oxide nanoparticles under different pH conditions (pH 5, 7, 9, 11). The predicted value for the critical surface coverage required to produce a steric barrier of 5k(B)T for PEGylated nanoparticles (MW 2000) was 0.078 nm(-2), which is less than the experimental value of 0.143 nm(-2), implying that the nanoparticles should be stable at all pH values. Dynamic light scattering (DLS) measurements showed that the effective diameter did not increase at pH 7 or 9 after 30 days but increased at pH 11. The shifts in NMR relaxivity (from R(2) data) at 2 MHz agreed well with the changes in hydrodynamic diameter obtained from DLS data, indicating that the aggregation behavior of the nanoparticles can be easily and quantitatively detected by NMR. The unexpected aggregation at pH 11 is due to the desorption of the surface coating (citric acid or PEG) from the nanoparticle surface not accounted for in the theory. This study shows that the stability of the nanoparticles can be predicted by the theory and detected by NMR quantitatively, which suggests the nanoparticles to be a possible oil-field nanosensor.

Effect of PEG molecular weight on stability, T2 contrast, cytotoxicity, and cellular uptake of superparamagnetic iron oxide nanoparticles (SPIONs)

Superparamagnetic iron oxide nanoparticles (SPIONs) are currently unavailable as MRI contrast agents for detecting atherosclerosis in the clinical setting because of either low signal enhancement or safety concerns. Therefore, a new generation of SPIONs with increased circulation time, enhanced image contrast, and less cytotoxicity is essential. In this study, monodisperse SPIONs were synthesized and coated with polyethylene glycol (PEG) of varying molecular weights. The resulting PEGylated SPIONs were characterized, and their interactions with vascular smooth muscle cells (VSMCs) were examined. SPIONs were tested at different concentrations (100 and 500 ppm Fe) for stability, T2 contrast, cytotoxicity, and cellular uptake to determine an optimal formulation for in vivo use. We found that at 100 ppm Fe, the PEG 2K SPIONs showed adequate stability and magnetic contrast, and exhibited the least cytotoxicity and nonspecific cellular uptake. An increase in cell viability was observed when the SPION-treated cells were washed with PBS after 1h incubation compared to 5 and 24h incubation without washing. Our investigation provides insight into the potential safe application of SPIONs in the clinic.

Adsorption of superparamagnetic iron oxide nanoparticles on silica and calcium carbonate sand.

Superparamagnetic iron oxide (SPIO) nanoparticles have the potential to be used in the characterization of porous rock formations in oil fields as a contrast agent for NMR logging because they are small enough to traverse through nanopores and enhance contrast by shortening NMR T2 relaxation time. However, successful development and application require detailed knowledge of particle stability and mobility in reservoir rocks. Because nanoparticle adsorption to sand (SiO2) and rock (often CaCO3) affects their mobility, we investigated the thermodynamic equilibrium adsorption behavior of citric acid-coated SPIO nanoparticles (CA SPIO NPs) and poly(ethylene glycol)-grafted SPIO nanoparticles (PEG SPIO NPs) on SiO2 (silica) and CaCO3 (calcium carbonate). Adsorption behavior was determined at various pH and salt conditions via chemical analysis and NMR, and the results were compared with molecular theory predictions. Most of the NPs were recovered from silica, whereas far fewer NPs were recovered from calcium carbonate because of differences in the mineral surface properties. NP adsorption increased with increasing salt concentration: this trend was qualitatively explained by molecular theory, as was the role of the PEG grafting in preventing NPs adsorption. Quantitative disagreement between the theoretical predictions and the data was due to NP aggregation, especially at high salt concentration and in the presence of calcium carbonate. Upon aggregation, NP concentrations as determined by NMR T2 were initially overestimated and subsequently corrected using the relaxation rate 1/T2, which is a function of aggregate size and fractal dimension of the aggregate. Our experimental validation of the theoretical predictions of NP adsorption to minerals in the absence of aggregation at various pH and salt conditions demonstrates that molecular theory can be used to determine interactions between NPs and relevant reservoir surfaces. Importantly, this integrated experimental and theoretical approach can be used to gain insight into NP mobility in the reservoir.

Tunable Diacetylene Polymerized Shell Microbubbles as Ultrasound Contrast Agents

Monodisperse gas microbubbles, encapsulated with a shell of photopolymerizable diacetylene lipids and phospholipids, were produced by microfluidic flow focusing, for use as ultrasound contrast agents. The stability of the polymerized shell microbubbles against both aggregation and gas dissolution under physiological conditions was studied. Polyethylene glycol (PEG) 5000, which was attached to the diacetylene lipids, was predicted by molecular theory to provide more steric hindrance against aggregation than PEG 2000, and this was confirmed experimentally. The polymerized shell microbubbles were found to have higher shell-resistance than nonpolymerizable shell microbubbles and commercially available microbubbles (Vevo MicroMarker). The acoustic stability under 7.5 MHz ultrasound insonation was significantly greater than that for the two comparison microbubbles. The acoustic stability was tunable by varying the amount of diacetylene lipid. Thus, our polymerized shell microbubbles are a promising platform for ultrasound contrast agents.

Monodisperse Micro-Oil Droplets Stabilized by Polymerizable Phospholipid Coatings as Potential Drug Carriers.

There is a critical need to formulate stable micron-sized oil droplets as hydrophobic drug carriers for efficient drug encapsulation, long-term storage, and sustained drug release. Microfluidic methods were developed to maximize the stability of micron-sized, oil-in-water (o/w) emulsions for potential use in drug delivery, using doxorubicin-loaded triacetin oil as a model hydrophobic drug formulation. Initial experiments examined multiple flow conditions for the dispersed (oil) and continuous (liposome aqueous) phases in a microfluidic device to establish the parameters that influenced droplet size. These data were fit to a mathematical model from the literature and indicate that the droplet sizes formed are controlled by the ratio of flow rates and the height of the device channel, rather than the orifice size. Next, we investigated effects of o/w emulsion production methods on the stability of the droplets. The stability of o/w emulsion produced by microfluidic flow-focusing techniques was found to be much greater (5 h vs 1 h) than for emulsions produced by mechanical agitation (vortexing). The increased droplet stability was attributed to the uniform size and lipid distribution of droplets generated by flow-focusing. In contrast, vortexed populations consisted of a wide size distribution that resulted in a higher prevalence of Ostwald ripening. Finally, the effects of shell polymerization on stability were investigated by comparing oil droplets encapsulated by a photopolymerizable diacetylene lipid shell to those with a nonpolymerizable lipid shell. Shell polymerization was found to significantly enhance stability against dissolution for flow-focused oil droplets but did not significantly affect the stability of vortexed droplets. Overall, results of these experiments show that flow-focusing is a promising technique for generating tunable, stable, monodisperse oil droplet emulsions, with potential applications for controlled delivery of hydrophobic drug formulations.

Ultrasound-assisted drug delivery with targeted-microbubbles in blood vessels on a chip

Ultrasound contrast imaging using micron-sized bubbles (less than 8 μm in diameter) has demonstrated detectable echogenic signals in vivo. However, challenges remain in terms of producing monodisperse microbubbles stable against destruction from aggregation and gas dissolution for improving blood circulation times and reducing clogging of small blood vessels. In the case of drug delivery, it is crucial to control destruction to release encapsulated contents only to the targeted area with minimal prior passive leakage of drug. Polymerizable lipid mixtures were used as microbubble shell materials. The monodisperse Polymerized Shell Microbubbles (PSM) containing 25 mol% of polymerizable diacetylene lipids were more stable than commercially acquired microbubbles or non-polymerizable shell microbubbles in terms of dissolution. The PSM showed a significantly slower decrease in intensity of gray-scale ultrasound image brightness than the two. In addition, the bubbles that were polymerized to different extents showed variable destruction rates at different ultrasound power levels, suggesting that polymerization can not only provide passive bubble longevity but tunable rupture capability. Lastly, drug-loaded targeted microbubbles have been observed in the in vitro blood vessels on a chip under ultrasound application to test drug delivery to the vessels. Compared to control targeted microbubbles with no drug, the drug-loaded targeted microbubbles kill the cells on the vessel wall selectively with ultrasound assistance.

Light-Activatable Theranostic Agents for Image-Monitored Controlled Drug Delivery

A novel drug delivery vehicle using nanodroplets activated by light irradiation for drug release in a controlled manner has been developed. The drug encapsulated in the nanodroplets was released upon phase transition from a liquid droplet to microbubbles (vaporization) by plasmonic photothermal heat from gold nanorods adsorbed on the surface of the nanodroplets. The nanodroplets were stable against aggregation and dissolution at 4 °C over 3 months to date. The phase transition was quantitatively analyzed by ultrasound imaging to examine the amount of drug release noninvasively. In vitro studies showed that cell death occurred only when light irradiation was performed on the drug-encapsulated nanodroplets. Ex vivo studies demonstrated a potential application of the nanodroplets for treating posterior eye diseases. Thus, it has been demonstrated that our gold-nanorod-coated light-activatable nanodroplets can be a candidate for a controlled release and a dosage-monitored drug delivery system.

Microbubbles as Theranostics Agents

Clinically, ultrasound (US) has been used as a cheap, quick, and effective form of imaging that provides information useful for diagnostic purposes. With the advent of microbubbles as US contrast agents, this simple imaging technique has evolved into a tool capable of providing molecularly targeted visualization of disease and controlled delivery of therapeutics. The simple, yet robust, structure of the microbubble allows for both internal and external modifications, which lead to a wide variety of clinical uses. This chapter will introduce the reader to microbubble fabrication, stabilization, drug loading, and targeting. The reader will also be briefly exposed to specific examples of current work done using microbubbles in areas of cancer treatment and protein/gene therapies. The work reviewed here is only a small fraction of the literature available on the subject matter and serves as an introduction to microbubbles as contrast agents, drug delivery vehicles, and theranostic particles.

Investigating the effect of fabrication method on the stability and acoustic response of microbubble agents

Microbubbles stabilized by a surfactant or polymer coating are already in clinical use as ultrasound imaging contrast agents. They have also been widely investigated as vehicles for drug delivery and gene therapy that can be tracked and triggered using ultrasound. Extensive studies have been made of the effects of the coating material and gas core on microbubble characteristics, but the influence of the fabrication method has received less attention. The aim of this study was to compare the behavior of microbubbles prepared using different techniques. Phospholipid-coated microbubbles were produced using sonication, electrospraying, or in a specially designed microfluidic device. The microbubbles were observed using optical, electron, and fluorescence lifetime imaging microscopy (FLIM) to interrogate their surface microstructure and stability over time. Their acoustic response was then determined in a flow chamber by detecting the pressure scattered from individual microbubbles as they passed through the f...