Biodegradable Gold Nanoclusters with Improved Excretion Due to pH-Triggered Hydrophobic-to-Hydrophilic Transition.
ABSTRACT: Gold is a highly useful nanomaterial for many clinical applications, but its poor biodegradability can impair long-term physiological clearance. Large gold nanoparticles (∼10-200 nm), such as those required for long blood circulation times and appreciable tumor localization, often exhibit little to no dissolution and excretion. This can be improved by incorporating small gold particles within a larger entity, but elimination may still be protracted due to incomplete dispersion of gold. The present study describes a novel gold nanoparticle formulation capable of environmentally triggered decomposition. Ultrasmall gold nanoparticles are coated with thiolated dextran, and hydrophobic acetal groups are installed through direct covalent modification of the dextran. This hydrophobic exterior allows gold to be densely packed within ∼150 nm polymeric micelles. Upon exposure to an acidic environment, the acetal groups are cleaved and the gold nanoparticles become highly water-soluble, leading to destabilization of the micelle. Within 24 h, the ultrasmall water-soluble gold particles are released from the micelle and readily dispersed. Micelle degradation and gold nanoparticle dispersion was imaged in cultured macrophages, and micelle-treated mice displayed progressive physiological clearance of gold, with >85% elimination from the liver over three months. These particles present a novel nanomaterial formulation and address a critical unresolved barrier for clinical translation of gold nanoparticles.
Project description:Recent in vivo studies have established ultrasmall (<3 nm) gold nanoparticles coated with glutathione (AuGSH) as a promising platform for applications in nanomedicine. However, systematic in vitro investigations to gain a more fundamental understanding of the particles' biointeractions are still lacking. Herein we examined the behavior of ultrasmall AuGSH in vitro, focusing on their ability to resist aggregation and adsorption from serum proteins. Despite having net negative charge, AuGSH particles were colloidally stable in biological media and able to resist binding from serum proteins, in agreement with the favorable bioresponses reported for AuGSH in vivo. However, our results revealed disparate behaviors depending on nanoparticle size: particles between 2 and 3 nm in core diameter were found to readily aggregate in biological media, whereas those strictly under 2 nm were exceptionally stable. Molecular dynamics simulations provided microscopic insight into interparticle interactions leading to aggregation and their sensitivity to the solution composition and particle size. These results have important implications, in that seemingly small variations in size can impact the biointeractions of ultrasmall AuGSH, and potentially of other ultrasmall nanoparticles as well.
Project description:Emerging nanotechnologies demand the manipulation of nanoscale components with the same predictability and programmability as is taken for granted in molecular synthetic methodologies. Yet installing appropriately reactive chemical functionality on nanomaterial surfaces has previously entailed compromises in terms of reactivity scope, functionalization density, or both. Here, we introduce an idealized dynamic covalent nanoparticle building block for divergent and adaptive post-synthesis modification of colloidal nanomaterials. Acetal-protected monolayer-stabilized gold nanoparticles are prepared via operationally simple protocols and are stable to long-term storage. Tunable surface densities of reactive aldehyde functionalities are revealed on-demand, leading to a wide range of adaptive surface engineering options from one nanoscale synthon. Analytically tractable with molecular precision, interfacial reaction kinetics and dynamic surface constitutions can be probed in situ at the ensemble level. High functionalization densities combined with rapid equilibration kinetics enable environmentally adaptive surface constitutions and rapid nanoparticle property switching in response to simple chemical effectors.
Project description:Accurate evaluation of engineered nanomaterial toxicity requires not only comprehensive physical-chemical characterization of nanomaterials as produced, but also thorough understanding of nanomaterial properties and behavior under conditions similar to those used for in vitro and in vivo toxicity studies. In this investigation, TiO(2) nanoparticles were selected as a model nanoparticle and bovine serum albumin (BSA) was selected as a model protein for studying the effect of protein-nanoparticle interaction on TiO(2) nanoparticle dispersion in six different mammalian, bacteria, and yeast cell culture media. Great improvement in TiO(2) dispersion was observed upon the addition of BSA, even though the degree of dispersion varied from medium to medium and phosphate concentration in the cell culture media was one of the key factors governing nanoparticle dispersion. Fetal bovine serum (FBS) was an effective dispersing agent for TiO(2) nanoparticles in all six media due to synergistic effects of its multiple protein components, successfully reproduced using a simple "FBS mimic" protein cocktail containing similar concentrations of BSA, ?-globulin, and apo-transferrin.
Project description:The aim of this study was to determine the size-dependent penetration ability of gold nanoparticles and the potential application of ultrasmall gold nanoparticles for intranucleus delivery and therapy. We synthesized gold nanoparticles with diameters of 2, 6, 10, and 16 nm and compared their intracellular distribution in MCF-7 breast cancer cells. Nanoparticles smaller than 10 nm (2 and 6 nm) could enter the nucleus, whereas larger ones (10 and 16 nm) were found only in the cytoplasm. We then investigated the possibility of using ultrasmall 2 nm nanoparticles as carriers for nuclear delivery of a triplex-forming oligonucleotide (TFO) that binds to the c-myc promoter. Compared to free TFO, the nanoparticle-conjugated TFO was more effective at reducing c-myc RNA and c-myc protein, which resulted in reduced cell viability. Our result demonstrated that the entry of gold nanoparticles into the cell nucleus is critically dependent on the size of the nanoparticles. We developed a strategy for regulating gene expression, by directly delivering TFOs into the nucleus using ultrasmall gold nanoparticles. More importantly, guidelines were provided to choose appropriate nanocarriers for different biomedical purposes.
Project description:Ultrasmall gold atom clusters (<2 nm in diameter) or gold nanoclusters exhibit emergent photonic properties (near-infrared absorption and emission) compared to larger plasmonic gold particles because of the significant quantization of their conduction band. Although single gold nanocluster properties and applications are being increasingly investigated, little is still known about their behavior and properties when assembled into suprastructures, and even fewer studies are investigating their use for biomedical applications. Here, a simple synthetic pathway combines gold nanoclusters with thermosensitive diblock copolymers of poly(ethylene glycol) (PEG) and poly( N-isopropylacrylamide) (PNIPAm) to form a new class of gold-polymer, micelle-forming, hybrid nanoparticle. The nanohybrids' design is uniquely centered on enabling the temperature-dependent self-assembly of gold nanoclusters into the hydrophobic cores of micelles. This nonbulk assembly not only preserves but also enhances the attractive near-infrared photonics of the gold nanoclusters by significantly increasing their native fluorescent signal. In parallel to the fundamental insights into gold nanocluster ordering and assembly, the gold-polymer nanohybrids also demonstrated great potential as fluorescent live-imaging probes in vitro. This innovative material design based on the temperature-dependent, self-assembly of gold nanoclusters within a polymeric micelle's core shows great promise toward bioassays, nanosensors, and nanomedicine.
Project description:Ultrasmall gold nanoparticles (diameter about 2?nm) were surface-functionalized with cysteine-carrying precision macromolecules. These consisted of sequence-defined oligo(amidoamine)s (OAAs) with either two or six cysteine molecules for binding to the gold surface and either with or without a PEG chain (3400?Da). They were characterized by <sup>1</sup> H?NMR spectroscopy, <sup>1</sup> H?NMR diffusion-ordered spectroscopy (DOSY), small-angle X-ray scattering (SAXS), and high-resolution transmission electron microscopy. The number of precision macromolecules per nanoparticle was determined after fluorescent labeling by UV spectroscopy and also by quantitative <sup>1</sup> H?NMR spectroscopy. Each nanoparticle carried between 40 and 100 OAA ligands, depending on the number of cysteine units per OAA. The footprint of each ligand was about 0.074?nm<sup>2</sup> per cysteine molecule. OAAs are well suited to stabilize ultrasmall gold nanoparticles by selective surface conjugation and can be used to selectively cover their surface. The presence of the PEG chain considerably increased the hydrodynamic diameter of both dissolved macromolecules and macromolecule-conjugated gold nanoparticles.
Project description:Nanomaterials hold much promise for biological applications, but they require appropriate functionalization to provide biocompatibility in biological environments. For noncovalent functionalization with biocompatible polymers, the polymer must also remain attached to the nanomaterial after removal of its excess to mimic the high-dilution conditions of administration in vivo. Reported here are the synthesis and utilization of singly substituted conjugates of dextran and a phospholipid (dextran-DSPE) as stable coatings for nanomaterials. Suspensions of single-walled carbon nanotubes were found not only to be stable to phosphate buffered saline (PBS), serum, and a variety of pH's after excess polymer removal, but also to provide brighter photoluminescence than carbon nanotubes suspended by poly(ethylene glycol)-DSPE. In addition, both gold nanoparticles (AuNPs) and gold nanorods (AuNRs) were found to maintain their dispersion and characteristic optical absorbance after transfer into dextran-DSPE and were obtained in much better yield than similar suspensions with PEG-phospholipid and commonly used thiol-PEG. These suspensions were also stable to PBS, serum, and a variety of pH's after removal of excess polymer. dextran-DSPE thus shows great promise as a general surfactant material for the functionalization of a variety of nanomaterials, which could facilitate future biological applications.
Project description:In this work, we reported for the first time, a facile and one step synthesis of gold nanoparticles from HAuCl(4), employing tetraphenylborate as the reducing agent. The synthesis is not only facile but also yields "dumb-bell-shaped"particles. This shape appears to arise from a possible emulsion of the products of oxidation/decomposition of tetraphenylborate by HAuCl(4), surrounding the particle. The size and shape of the AuNPs were characterized by Transmission electron microscopy (TEM) and UV-visible Spectroscopy. Interestingly, the addition of polyvinylpyrrolidone (PVP) during the synthesis was found to enhance the stability of the nanoparticle dispersion. The particles synthesized under these conditions assume "spherical" shape with the appearance of only transverse surface plasmon resonance band. The highlight of the observations is that the gold nanoparticles synthesized using tetraphenylborate as reducing agent and PVP as stabilizer are highly stable in alkaline medium, in contrast to the synthesis wherein borohydride is used as reducing agent. The AuNPs synthesized using tetraphenylborate and PVP show their mercury sensing behavior only in the alkaline medium. The color of the nanoparticle dispersion undergoes distinct color change from pink to blue with the addition of mercury ions. They also show dramatic selectivity to mercury ions in presence of other interfering ions, Pb(2+), Zn(2+) and Ca(2+).
Project description:In photodynamic therapy (PDT), photosensitizers and light are used to cause photochemically induced cell death. The selectivity and the effectiveness of the phototoxicity in cancer can be increased by a specific uptake of the photosensitizer into tumor cells. A promising target for this goal is the folic acid receptor ? (FR?), which is overexpressed on the surface of many tumor cells and mediates an endocytotic uptake. Here, we describe a polysaccharide-based nanoparticle system suitable for targeted uptake and its photochemical and photobiological characterization. The photosensitizer 5, 10, 15, 20-tetraphenyl-21H, 23H-porphyrine (TPP) was encapsulated in spermine- and acetal-modified dextran (SpAcDex) nanoparticles and conjugated with folic acid (FA) on the surface [SpAcDex(TPP)-FA]. The particles are successfully taken up by human HeLa-KB cells, and a light-induced cytotoxicity is observable. An excess of free folate as the competitor for the FR?-mediated uptake inhibits the phototoxicity. In conclusion, folate-modified SpAcDex particles are a promising drug delivery system for a tumor cell targeted photodynamic therapy.
Project description:The size, shape and chemical composition of europium (Eu3+) cobalt ferrite (CFEu) nanoparticles were optimized for use as a "multimodal imaging nanoprobe" for combined fluorescence and magnetic resonance bioimaging. Doping Eu3+ ions into a CF structure imparts unique bioimaging and magnetic properties to the nanostructure that can be used for real-time screening of targeted nanoformulations for tissue biodistribution assessment. The CFEu nanoparticles (size ?7.2nm) were prepared by solvothermal techniques and encapsulated into poloxamer 407-coated mesoporous silica (Si-P407) to form superparamagnetic monodisperse Si-CFEu nanoparticles with a size of ?140nm. Folic acid (FA) nanoparticle decoration (FA-Si-CFEu, size ?140nm) facilitated monocyte-derived macrophage (MDM) targeting. FA-Si-CFEu MDM uptake and retention was higher than seen with Si-CFEu nanoparticles. The transverse relaxivity of both Si-CFEu and FA-Si-CFEu particles were r2=433.42mM-1s-1 and r2=419.52mM-1s-1 (in saline) and r2=736.57mM-1s-1 and r2=814.41mM-1s-1 (in MDM), respectively. The results were greater than a log order-of-magnitude than what was observed at replicate iron concentrations for ultrasmall superparamagnetic iron oxide (USPIO) particles (r2=31.15mM-1s-1 in saline) and paralleled data sets obtained for T2 magnetic resonance imaging. We now provide a developmental opportunity to employ these novel particles for theranostic drug distribution and efficacy evaluations.A novel europium (Eu3+) doped cobalt ferrite (Si-CFEu) nanoparticle was produced for use as a bioimaging probe. Its notable multifunctional, fluorescence and imaging properties, allows rapid screening of future drug biodistribution. Decoration of the Si-CFEu particles with folic acid increased its sensitivity and specificity for magnetic resonance imaging over a more conventional ultrasmall superparamagnetic iron oxide particles. The future use of these particles in theranostic tests will serve as a platform for designing improved drug delivery strategies to combat inflammatory and infectious diseases.