Browsing by Author "Zhang, Rui"
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- Ammonium Bisphosphonate Polymeric Magnetic Nanocomplexes for Platinum Anticancer Drug Delivery and Imaging with Potential Hyperthermia and Temperature-Dependent Drug ReleaseZhang, Rui; Fellows, Benjamin; Pothayee, Nikorn; Hu, Nan; Pothayee, Nipon; Jo, Ami; Bohórquez, Ana C.; Rinaldi, Carlos; Mefford, Olin Thompson; Davis, Richey M.; Riffle, Judy S. (Hindawi, 2018-08-05)Novel magnetite-ammonium bisphosphonate graft ionic copolymer nanocomplexes (MGICs) have been developed for potential drug delivery, magnetic resonance imaging, and hyperthermia applications. The complexes displayed relatively uniform sizes with narrow size distributions upon self-assembly in aqueous media, and their sizes were stable under simulated physiological conditions for at least 7 days. The anticancer drugs, cisplatin and carboplatin, were loaded into the complexes, and sustained release of both drugs was observed. The transverse NMR relaxivities (s) of the complexes were 244 s−1 (mM Fe)−1 which is fast compared to either the commercial T2-weighted MRI agent Feridex IV® or our previously reported magnetite-block ionomer complexes. Phantom MRI images of the complexes demonstrated excellent negative contrast effects of such complexes. Thus, the bisphosphonate-bearing MGICs could be promising candidates for dual drug delivery and magnetic resonance imaging. Moreover, the bisphosphonate MGICs generate heat under an alternating magnetic field of 30 kA·m−1 at 206 kHz. The temperature of the MGIC dispersion in deionized water increased from 37 to 41°C after exposure to the magnetic field for 10 minutes, corresponding to a specific absorption rate of 77.0 W·g−1. This suggests their potential as hyperthermia treatment agents as well as the possibility of temperature-dependent drug release, making MGICs more versatile in potential drug delivery applications.
- Encapsulation of PI3K Inhibitor LY294002 within Polymer Nanoparticles Using Ion Pairing Flash NanoprecipitationFergusson, Austin D.; Zhang, Rui; Riffle, Judy S.; Davis, Richey M. (MDPI, 2023-04-06)Flash nanoprecipitation (FNP) is a turbulent mixing process capable of reproducibly producing polymer nanoparticles loaded with active pharmaceutical ingredients (APIs). The nanoparticles produced with this method consist of a hydrophobic core surrounded by a hydrophilic corona. FNP produces nanoparticles with very high loading levels of nonionic hydrophobic APIs. However, hydrophobic compounds with ionizable groups are not as efficiently incorporated. To overcome this, ion pairing agents (IPs) can be incorporated into the FNP formulation to produce highly hydrophobic drug salts that efficiently precipitate during mixing. We demonstrate the encapsulation of the PI3K inhibitor, LY294002, within poly(ethylene glycol)-b-poly(D,L lactic acid) nanoparticles. We investigated how incorporating two hydrophobic IPs (palmitic acid (PA) and hexadecylphosphonic acid (HDPA)) during the FNP process affected the LY294002 loading and size of the resulting nanoparticles. The effect of organic solvent choice on the synthesis process was also examined. While the presence of either hydrophobic IP effectively increased the encapsulation of LY294002 during FNP, HDPA resulted in well-defined colloidally stable particles, while the PA resulted in ill-defined aggregates. The incorporation of hydrophobic IPs with FNP opens the door for the intravenous administration of APIs that were previously deemed unusable due to their hydrophobic nature.
- Fabrication and characterization of PLGA nanoparticles encapsulating large CRISPR–Cas9 plasmidJo, Ami; Ringel-Scaia, Veronica M.; McDaniel, Dylan K.; Thomas, Cassidy A.; Zhang, Rui; Riffle, Judy S.; Allen, Irving C.; Davis, Richey M. (2020-01-20)Background The clustered regularly interspaced short palindromic repeats (CRISPR) and Cas9 protein system is a revolutionary tool for gene therapy. Despite promising reports of the utility of CRISPR–Cas9 for in vivo gene editing, a principal problem in implementing this new process is delivery of high molecular weight DNA into cells. Results Using poly(lactic-co-glycolic acid) (PLGA), a nanoparticle carrier was designed to deliver a model CRISPR–Cas9 plasmid into primary bone marrow derived macrophages. The engineered PLGA-based carriers were approximately 160 nm and fluorescently labeled by encapsulation of the fluorophore 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS pentacene). An amine-end capped PLGA encapsulated 1.6 wt% DNA, with an encapsulation efficiency of 80%. Release studies revealed that most of the DNA was released within the first 24 h and corresponded to ~ 2–3 plasmid copies released per nanoparticle. In vitro experiments conducted with murine bone marrow derived macrophages demonstrated that after 24 h of treatment with the PLGA-encapsulated CRISPR plasmids, the majority of cells were positive for TIPS pentacene and the protein Cas9 was detectable within the cells. Conclusions In this work, plasmids for the CRISPR–Cas9 system were encapsulated in nanoparticles comprised of PLGA and were shown to induce expression of bacterial Cas9 in murine bone marrow derived macrophages in vitro. These results suggest that this nanoparticle-based plasmid delivery method can be effective for future in vivo applications of the CRISPR–Cas9 system.
- Ionic Copolymer-Magnetite Complexes for Magnetic Resonance Imaging and Drug DeliveryZhang, Rui (Virginia Tech, 2015-06-18)This thesis is focused on the design, synthesis and characterization of magnetite-ionic copolymer complexes as nanocarriers for drug delivery and magnetic resonance imaging. The polymers included phosphonate and carboxylate-containing graft and block copolymers. Oleic-acid coated magnetite nanoparticles (8-nm and 16-nm diameters) were investigated. Cisplatin and carboplatin were used as sample drugs. The potentials of the magnetite-ionomer complexes as dual drug delivery carriers and magnetic resonance imaging agents were evaluated. An acrylate-functional poly(ethylene oxide) macromonomer and hexyl (and propyl) ammonium bisphosphonate methacrylate monomers were synthesized. Conventional free radical copolymerizations were conducted to synthesize the graft copolymers. The acrylate-functional poly(ethylene oxide) macromonomer was also used to form graft copolymers with tert-butyl acrylate. Block ionomers containing poly(tert-butyl acrylate) were synthesized via atom transfer radical polymerization, then the tert-butyl groups were removed to afford anions. All the monomers and polymers were characterized by 1H NMR to confirm their structures and assess their compositions. Phosphonate-containing polymers were also characterized by 31P NMR. Magnetite nanoparticles (8-nm diameter) were synthesized by reducing Fe(acac)3 with benzyl alcohol. The 16-nm diameter magnetite was synthesized by thermal decomposition of an iron oleate precursor in trioctylamine as a high-boiling solvent. The iron-oleate precursor was synthesized with iron (III) chloride hexahydrate and sodium oleate with mixed solvents. TEM images of the magnetite were obtained. Magnetite-ionomer complexes were synthesized by binding a portion of the anions (carboxylate or phosphonate) on the copolymers onto the surfaces the magnetite. The remainder of the anions was used to bind with cisplatin and carboplatin via chelation. Physicochemical properties of the complexes were measured by dynamic light scattering. All the complexes with different polymers and magnetite nanoparticles displayed relatively uniform sizes and good size distributions. The magnetite-ionomer complexes displayed good colloidal stabilities in simulated physiological conditions for at least 24 hours. Those graft and block copolymer-magnetite complexes may be good candidates as drug carriers for delivery applications. After cisplatin and carboplatin loading, the sizes of the complexes increased slightly and the zeta potential decreased slightly, which indicated that the loadings were successful. Minimal loss of iron was found, signaling that the binding strengths between the magnetite and the anions of the graft copolymers were strong. 8.7 wt% of platinum was found in the cisplatin loaded complexes and 6.9% in the carboplatin loaded complexes. The results indicated that the magnetite-graft ionomer complexes were capable of loading drugs. Drug release studies were performed at pH 4.6 and 7.4 to mimick endosomal conditions and the physiological environment. Sustained release of drugs was observed. This further indicated the potential for using the magnetite-ionomer complexes as drug carriers. Transverse relaxivities of the magnetite-ionomer complexes with and without drugs were measured and compared to a commercial T2-weighted iron MRI contrast agent-Feridex®. All the complexes had higher relaxivities compared to Feridex®. Thus, the magnetite-ionomer complexes are promising candidates for dual magnetic resonance imaging and drug delivery.Moreover, the aqueous dispersion of the complexes was found to heat upon exposure to an AC magnetic field, thus potentially allowing heat-induced drug release.
- Nanoscale Liquid Dynamics in Membrane Matrices: Insights into Confinement, Molecular Interactions, and HydrationZhang, Rui (Virginia Tech, 2021-06-10)This dissertation focuses on the fundamental understanding of liquid dynamics confined in polymer membranes. Such knowledge guides the development of better polymer membranes for practical applications and contributes to the general understanding of confined liquid dynamics in various nanoporous materials. First, we investigate the membrane transport by experimental measurements on a PFSA membrane and computer modeling of the confined liquid molecules. We probe the nano-scale environment in the ionomer membrane by determining the activation energy of diffusion. We notice two structural features of the PFSA membrane that dominate membrane transport. At relatively high hydrations, the nano-scale phase-separation creates bulk-like water in the ionomer membrane and prompts fast transport of mobile species. At relatively low hydrations, the nanoconfinement of the polymer matrix leads to the ordering of confined water and prompts a high energy barrier for transport. We then delve deeper into the confinement effect by molecular modeling of various nanoconfining geometries, including carbon nanotubes, parallel graphene sheets, and parallel rigid rods. We notice retarded water dynamics under hydrophobic confinement regardless of the geometry. We further investigate the confined water by determining the residence time of water around water, which evaluates the timescale of associations between water molecules. We learn that a decreasing confinement size prompts longer associations among water molecules. Further, we propose that the prolonged associations are responsible for the retarded water dynamics under hydrophobic confinement. Next, we turn our attention to the effect of interactions between mobile species (mostly water molecules) and a confining surface. In ionomer membranes, interactions between mobile species and the ionic groups dominate the water-surface interactions. We start by looking at water-ion interactions in bulk solutions. Using solutions at varying concentrations, we notice a temperature-concentration superposition behavior from diffusion coefficients of water molecules and ions in the solutions in both experimental and computational results. Observation of this superposition behavior in bulk solutions is unprecedented. The temperature-concentration superposition parallels the well-known time-temperature superposition. We are able to extract the offset of reciprocal temperature, which fits well to a Williams-Landel-Ferry type equation. The temperature-concentration superposition points to the new perspective that the effect of ions on water dynamics can be similar to the effect of lowering temperature. We further investigate the effect of ions by modeling ions/charges onto confining geometries. Remarkably, we reveal that the presence of ions can break the ordered water structure induced by confinement. The hydrophobic confinement prompts the ordering of water molecules, which leads to slower diffusion and higher activation energy. The presence of ions/charges on the confining surface has multiple effects on the dynamics of confined water. First, the ions associate strongly with neighboring water molecules while breaking the hydrogen-bonding network between water molecules. Second, the disruption of the hydrogen-bonding network leads to decreased activation energy of diffusion and enhanced water mobility. At relatively high ion density, the water-ion interactions overcome the structure-breaking effect and lead to retarded water diffusion. Overall, the studies presented in this dissertation augment our understanding of water transport in nanostructures by revealing the rich behavior of liquid-water dynamics under both hydrophobic and ionic confinement.
- Polymeric Complexes and Composites for Aerospace and Biomedical ApplicationsZhang, Rui (Virginia Tech, 2018-08-01)Polymers, among metals and ceramics, are major solid materials which are widely used in all kinds of applications. Polymers are of particular interest because they can be tailored with desirable properties. Polymer-based complexes and composites, which contain both the polymers and other components such as metal oxide/salts, are playing a more and more important role in the material fields. Such complexes and composites may display the benefits of both the polymer and other materials, endowing them with excellent functionalities for targeted applications. In this dissertation, a great deal of research was conducted to synthesize novel polymers and build polymeric complexes and composites for biomedical and aerospace applications. In chapter 3, two methods were developed and optimized to fabricate sub-micron high-performance polymer particles which were subsequently used to coat onto functional carbon fibers via electrostatic interactions, for the purpose of fabricating carbon fiber reinforced polymer composites. In chapter 4, a novel Pluronic® P85-bearing penta-block copolymer was synthesized and formed complexes with magnetite. The complexes displayed non-toxicity to cells normally but were able to selectively kill cancer cells without killing normal cells when subjected to a low-frequency alternating current magnetic field. Such results demonstrated the potential of such polymeric complexes in cancer treatment. Chapter 5 described the synthesis of several ionic graft copolymers primarily bisphosphonate-containing polymers, and the fabrication of polymer-magnetite complexes. The in-depth investigation results indicated the capability of the complexes for potential drug delivery, imaging, and other biomedical applications. Chapter 6 described additional polymer synthesis and particle or complex fabrication for potential drug delivery and imaging, as well as radiation shielding.
- Remote Actuation of Magnetic Nanoparticles For Cancer Cell Selective Treatment Through Cytoskeletal DisruptionMaster, Alyssa M.; Williams, Philise N.; Pothayee, Nikorn; Pothayee, Nipon; Zhang, Rui; Vishwasrao, Hemant M.; Golovin, Yuri I.; Riffle, Judy S.; Sokolsky, Marina; Kabanov, Alexander V. (Springer Nature, 2016-09-20)Motion of micron and sub-micron size magnetic particles in alternating magnetic fields can activate mechanosensitive cellular functions or physically destruct cancer cells. However, such effects are usually observed with relatively large magnetic particles (> 250 nm) that would be difficult if at all possible to deliver to remote sites in the body to treat disease. Here we show a completely new mechanism of selective toxicity of superparamagnetic nanoparticles (SMNP) of 7 to 8 nm in diameter to cancer cells. These particles are coated by block copolymers, which facilitates their entry into the cells and clustering in the lysosomes, where they are then magneto-mechanically actuated by remotely applied alternating current (AC) magnetic fields of very low frequency (50 Hz). Such fields and treatments are safe for surrounding tissues but produce cytoskeletal disruption and subsequent death of cancer cells while leaving healthy cells intact.
- Resolving atomic-scale phase transformation and oxygen loss mechanism in ultrahigh-nickel layered cathodes for cobalt-free lithium-ion batteriesWang, Chunyang; Han, Lili; Zhang, Rui; Cheng, Hao; Mu, Linqin; Kisslinger, Kim; Zou, Peichao; Ren, Yang; Cao, Penghui; Lin, Feng; Xin, Huolin L. (2021-06-02)Doped LiNiO2 has recently become one of the most promising cathode materials for its high specific energy, long cycle life, and reduced cobalt content. Despite this, the degradation mechanism of LiNiO2 and its derivatives still remains elusive. Here, by combining in situ electron microscopy and first-principles calculations, we elucidate the atomic-level chemomechanical degradation pathway of LiNiO2-derived cathodes. We uncover that the O1 phase formed at high voltages acts as a preferential site for rock-salt transformation via a two-step pathway involving cation mixing and shear along (003) planes. Moreover, electron tomography reveals that planar cracks nucleated simultaneously from particle interior and surface propagate along the [100] direction on (003) planes, accompanied by concurrent structural degradation in a discrete manner. Our results provide an in-depth understanding of the degradation mechanism of LiNiO2-derived cathodes, pointing out the concept that suppressing the O1 phase and oxygen loss is key to stabilizing LiNiO2 for developing next-generation high-energy cathode materials.