Yi-Cheun Yeh
University of Massachusetts Amherst
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Featured researches published by Yi-Cheun Yeh.
Current Opinion in Chemical Biology | 2010
Subinoy Rana; Yi-Cheun Yeh; Vincent M. Rotello
Covalent and non-covalent conjugation of proteins to nanoparticles provides access to functional hybrid systems with applications in biotechnology, medicine, and catalysis. The creation of effective conjugates requires the retention of protein structure and function, a challenging task. In this review we discuss successes, challenges and opportunities in the area of protein-nanoparticle bioconjugation.
Nature Chemistry | 2011
Zheng-Jiang Zhu; Yi-Cheun Yeh; Rui Tang; Bo Yan; Joshua Tamayo; Richard W. Vachet; Vincent M. Rotello
Quantum dots (QDs) are highly fluorescent and photostable, making them excellent tools for imaging. When using these QDs in cells and animals, however, intracellular biothiols (e.g., glutathione and cysteine) can degrade the QD monolayer compromising function. Here, we describe a label-free method to quantify the intracellular stability of monolayers on QD surfaces that couples laser desorption/ionization mass spectrometry (LDI-MS) with inductively coupled plasma mass spectrometry (ICP-MS). Using this new approach we have demonstrated that QD monolayer stability is correlated with both QD particle size and monolayer structure, with proper choice of both particle size and ligand structure required for intracellular stability.
Small | 2012
Sung Tae Kim; Apiwat Chompoosor; Yi-Cheun Yeh; Sarit S. Agasti; David J. Solfiell; Vincent M. Rotello
Small interfering RNA (siRNA) is a versatile tool for regulation of gene expression.[1] The ability of siRNA to silence translation and protein expression of cognate cellular mRNA provides the potential to regulate a wide array of therapeutically-relevant processes.[2] Despite the therapeutic promise of siRNA, there are challenges to its effective clinical and laboratory use.[3] Naked siRNA has low stability against nuclease activity and exhibits poor transfection efficacy due to its relatively large molecular weight and anionic character.[4] These challenges have been addressed using viral and synthetic delivery vehicles.[5] Viral delivery systems feature high transfection efficiencies,[6] however, these vectors can face challenges arising from immunogenicity[7] and mutagenicity.[8] Non-viral siRNA delivery systems have the potential to provide improved safety and predictability relative to viral vectors,[9] and can be broken down into two major groups: covalently conjugated particles[10] and assemblies formed through electrostatic assembly with cationic materials.[11] Both strategies are effective, with the supramolecular strategy allowing the release of genetic material from the surface of the delivery vehicle into the cytosol following uptake, an important requirement for some applications.[12] A variety of cationic materials have been used to condense siRNA for delivery, including cationic lipids[13] and polymers.[14, 15] Functionalized inorganic nanomaterials including carbon nanotubes,[16] iron oxide nanoparticles,[17] quantum dots,[18] and gold nanoparticles[19] provide alternative platforms for siRNA delivery, featuring diverse structures, sizes, core properties and ease of functionalization.[20] Additionally, these materials produce the structural properties of high molecular weight polymers using low molecular weight ligands, with the inorganic core functioning as a space-filling structural element for the presentation of the surface monolayer.[21] We hypothesized that reducing the bulk of the collapsible structure of a polymer to an inorganic nanoparticle would reduce the toxicity of the vehicle (by eliminating unnecessary exposable functionalities that are hidden during complexation), while retaining the favorable properties of polymer delivery vectors through proper functionalization of the surface monolayer. This is an important feature for siRNA delivery. Due to the small size of siRNA, the molecule experiences less efficient interactions with cationic delivery materials than plasmid-sized DNA. SiRNA therefore requires a greater number of vehicles per molecule, or a vehicle with a greater amount of cationic character. Both cases potentially lead to greater toxicity issues. We report here the use of gold nanoparticles featuring dendritic polyethylenimine-like ligands[22] to generate a supramolecular siRNA delivery vehicle featuring high knockdown efficiency and low toxicity. Three different particles featuring gold cores (2 nm diameter) and triethylenetetramine (TETA) terminated dendron ligands were generated for this study via Murray place-exchange reaction (Scheme 1a).[23] The dendronized ligands feature biodegradable glutamic acid scaffolds and cationic TETA moieties that interact electrostatically with negatively charged siRNA (Scheme 1b). All three particles are cationic and resist aggregation as indicated by their zeta potentials. (Figure 1 and Figure S1). Figure 1 Hydrodynamic diameter and zeta potential of G0-AuNP, G1-AuNP, and G2-AuNP. Gel retardation assay of AuNP/β-gal-siRNA complexation at different molar ratios showed a decrease in band intensity due to the fluorescence quenching by complexation with ... Scheme 1 a) Chemical structures of G0-AuNP, G1-AuNP, and G2-AuNP. b) Schematic illustration of AuNP/ β-gal-siRNA complexation and transfection into cells. The molar ratio of dendronized AuNPs to anionic siRNA required for efficient formation of condensed complexes was determined through an agarose gel retardation assay (Figure 1). All of the particles appeared to interact with siRNA, as band intensities associated with free siRNA fell with increasing concentrations of each. The G2 particle, however, appeared to be most efficient at retarding the electrophoretic mobility of siRNA, showing complete retardation at a NP/siRNA molar ratio of 2. Both the G0-AuNP and G1-AuNP still showed free siRNA bands at a NP/β-gal-siRNA ratio of 4 (Figure 1). In further experiments, we found that, when allowed to fully complex with siRNA, G0-AuNP/β-gal-siRNA and G1-AuNP/β-gal-siRNA complexes precipitated at these higher NP/β-gal-siRNA ratios, thus limiting their utility. These results indicate that tuning the degree of multivalency is important for generating AuNP/siRNA complexes that are useful for delivery applications. For this reason, G2-AuNP, capable of generating the most stable self-assembled nanoplexes with siRNA, was used for all subsequent studies. To confirm the condensation ratio between G2-AuNP and siRNA, an ethidium bromide (EtBr) fluorescence exclusion assay, in which the quenching of EtBr upon displacement by G2-AuNP, was performed (Figure S2). The corrected fluorescence curve likewise demonstrated the minimum binding ratio for G2-AuNP/β-gal-siRNA complexation was 2:1. The G2-AuNP/β-gal-siRNA complexes were characterized by dynamic light scattering (DLS). Nanoplexes in ddH2O (double distilled water, MilliQ) were ~110 nm diameter (Figure S3). The assembly size increased to ~700 nm in a serum-containing media (OptiMEM®). The size (~825 nm) did not respond to significant changes even in the presence of media composed of 40% serum (Figure S4). Such changes are typical of supramolecular systems, which are easily affected by changes in pH, ionic strength (which can shield charges and alter the protonation state of surface ligands) and proteins (which can adsorb to the surfaces of nanoparticles and form supramolecular “coronas”).[24] SiRNA mediated knockdown of β-galactosidase (β-gal) expression was studied using an enzyme activity assay in SVR-bag4 endothelial cells. To determine the optimal concentration of siRNA, SVR-bag4 cells were treated with G2-AuNP/β-gal siRNA at different concentrations (NP/siRNA = 2). β-gal silencing appeared to be saturated at G2-AuNP/β-gal-siRNA complex concentrations above 0.042 μM (Figure 2a). To investigate the correlation between gene silencing efficiency and NP/siRNA ratios, SVR-bag4 cells were also treated with a series of G2-AuNP/β-gal-siRNA complexes with molar ratios of 0.5, 1, and 2 (Figure 2b). Gene silencing was found to increase with NP/siRNA ratio, with maximum gene silencing (48%) observed in the case of completely complexed siRNA (NP/siRNA = 2). The knockdown efficiency observed for G2-AuNP/β-gal-siRNA at NP/siRNA 2 was similar to Lipofectamine™ (Invitrogen), a commercially available vehicle with a validated protocol. (Figure 2b). In the absence of either AuNP, siRNA, or a correct siRNA sequence, no significant suppression of β-gal was observed (Figure 2b). Figure 2 β-gal gene silencing in SVR-bag4 cell. a) Gene silencing effect of G2-AuNP/β-gal-siRNA with different concentration from 0.021 to 0.084 μM (NP/siRNA=2). b) Gene silencing effect of naked β-gal siRNA, naked nonsense siRNA, ... Cytotoxicity of both G2-AuNP and G2-AuNP/β-gal-siRNA complexes was evaluated by Alamar blue® assay. Again, SVR bag4 cells were used. Exposure of cells to the G2-AuNP alone for 2 days led to a slight decrease in cell viability (Figure 3a). Exposure of cells to G2-AuNP/β-gal-siRNA complexes for an identical period of time resulted in no significant toxicity (Figure 3b), likely through the charge-quenching effects of siRNA in the nanoparticle complex. Figure 3 Cell viability determined by Alamar blue® assay. Cell viability was determined after the treatment of a) G2-AuNP and b) G2-AuNP/β-gal-siRNA complex at various molar ratios (β-gal siRNA=75 pmol). In summary, we have demonstrated the utility of dendronized AuNPs as a vector for siRNA delivery. In these studies, G2-AuNP suppressed β-gal expression by ~ 50% with minimal toxicity. These nanoparticle vectors possess the benefits of polymeric delivery vehicles such as PEI, while minimizing toxicity through the use of non-toxic core functionality. The application of these systems in biotechnology and biomedicine are currently being explored and will be reported in due course.
Analytical Chemistry | 2012
Zheng-Jiang Zhu; Rui Tang; Yi-Cheun Yeh; Oscar R. Miranda; Vincent M. Rotello; Richard W. Vachet
Monolayer stability of core-shell nanoparticles is a key determinant of their utility in biological studies such as imaging and drug delivery. Intracellular thiols (e.g., cysteine, cysteamine, and glutathione) can trigger the release of thiolate-bound monolayers from nanoparticles, a favorable outcome for controllable drug release applications but an unfavorable outcome for imaging agents. Here, we describe a method to quantify the monolayer release of gold nanoparticles (AuNPs) in living cells using parallel measurements by laser desorption/ionization (LDI) and inductively coupled plasma (ICP) mass spectrometry. This combination of methods is tested using AuNPs with structural features known to influence monolayer stability and on cells types with varying concentrations of glutathione. On the basis of our results, we predict that this approach should help efforts to engineer nanoparticle surface monolayers with tunable stability, providing stable platforms for imaging agents and controlled release of therapeutic monolayer payloads.
Bioconjugate Chemistry | 2015
Chang Soo Kim; Rubul Mout; Yunlong Zhao; Yi-Cheun Yeh; Rui Tang; Youngdo Jeong; Bradley Duncan; Jeanne A. Hardy; Vincent M. Rotello
Combination therapy employing proteins and small molecules provides access to synergistic treatment strategies. Co-delivery of these two payloads is challenging due to the divergent physicochemical properties of small molecule and protein cargos. Nanoparticle-stabilized nanocapsules (NPSCs) are promising for combination treatment strategies since they have the potential to deliver small molecule drugs and proteins simultaneously into the cytosol. In this study, we loaded paclitaxel into the hydrophobic core of the NPSC and self-assembled caspase-3 and nanoparticles on the capsule surface. The resulting combination NPSCs showed higher cytotoxicity than either of the single agent NPSCs, with synergistic action established using combination index values.
Nanoscale | 2013
Yi-Cheun Yeh; Krishnendu Saha; Bo Yan; Oscar R. Miranda; Xi Yu; Vincent M. Rotello
The effect of ligand structure on the cytotoxicity of cationic CdSe/ZnS quantum dots (QDs) was systematically investigated using mono- and bidentate ligands. Monothiol-functionalized QDs are more cytotoxic than dithiol-functionalized QDs.
Angewandte Chemie | 2014
Yi-Cheun Yeh; Rui Tang; Rubul Mout; Youngdo Jeong; Vincent M. Rotello
Multifunctional self-assembled systems present platforms for fundamental research and practical applications as they provide tunability of structure, functionality, and stimuli responsiveness. Pragmatic structures for biological applications have multiple design requirements, including control of size, stability, and environmental response. Here we present the fabrication of multifunctional nanoparticle-stabilized capsules (NPSCs) by using a set of orthogonal supramolecular interactions. In these capsules, fluorescent proteins are attached to quantum dots through polyhistidine coordination. These anionic assemblies interact laterally with cationic gold nanoparticles that are anchored to the fatty acid core through guanidinium-carboxylate interactions. The lipophilic core then provides a reservoir for hydrophobic endosome-disrupting agents, thereby generating a system featuring stimuli-responsive release of a payload into the cytosol with fluorescence monitoring.
Advanced Materials | 2014
Rui Tang; Daniel F. Moyano; Chandramouleeswaran Subramani; Bo Yan; Eunhee Jeoung; Gulen Yesilbag Tonga; Bradley Duncan; Yi-Cheun Yeh; Ziwen Jiang; Chaekyu Kim; Vincent M. Rotello
A robust monolayer of nanoparticles is formed via dip-coating of cell culture plates. These surfaces provide cell type-specific modulation of growth behavior without the uptake of nanoparticles.
Journal of Materials Chemistry | 2011
Vikas Nandwana; Chandramouleeswaran Subramani; Yi-Cheun Yeh; Boqian Yang; Stefan Dickert; Michael D. Barnes; Mark T. Tuominen; Vincent M. Rotello
Patterned quantum dot (QD) nanostructures were prepared by direct electron beam lithography on QD films. Time resolved photoluminescence measurements show that the optical properties of these QDs were retained after cross-linking.
Advanced Materials | 2012
Xi Yu; Jonathan T. Pham; Chandramouleeswaran Subramani; Brian Creran; Yi-Cheun Yeh; Kan Du; Debabrata Patra; Oscar R. Miranda; Alfred J. Crosby; Vincent M. Rotello
Gold nanoparticles are engineered for direct imprinting of stable structures. This imprinting strategy provides access to new device architectures, as demonstrated through the fabrication of a prototype photoswitchable device.