Guandong Zhang

Enhanced penetration into 3D cell culture using two and three layered gold nanoparticles

Nano-scale particles sized 10–400 nm administered systemically preferentially extravasate from tumor vasculature due to the enhanced permeability and retention effect. Therapeutic success remains elusive, however, because of inhomogeneous particle distribution within tumor tissue. Insufficient tumor vascularization limits particle transport and also results in avascular hypoxic regions with non-proliferating cells, which can regenerate tissue after nanoparticle-delivered cytotoxicity or thermal ablation. Nanoparticle surface modifications provide for increasing tumor targeting and uptake while decreasing immunogenicity and toxicity. Herein, we created novel two layer gold-nanoshell particles coated with alkanethiol and phosphatidylcholine, and three layer nanoshells additionally coated with high-density-lipoprotein. We hypothesize that these particles have enhanced penetration into 3-dimensional cell cultures modeling avascular tissue when compared to standard poly(ethylene glycol) (PEG)-coated nanoshells. Particle uptake and distribution in liver, lung, and pancreatic tumor cell cultures were evaluated using silver-enhancement staining and hyperspectral imaging with dark field microscopy. Two layer nanoshells exhibited significantly higher uptake compared to PEGylated nanoshells. This multilayer formulation may help overcome transport barriers presented by tumor vasculature, and could be further investigated in vivo as a platform for targeted cancer therapies.

Tunability and stability of gold nanoparticles obtained from chloroauric acid and sodium thiosulfate reaction

In the quest for producing an effective, clinically relevant therapeutic agent, scalability, repeatability, and stability are paramount. In this paper, gold nanoparticles (GNPs) with precisely controlled near-infrared (NIR) absorption are synthesized by a single-step reaction of HAuCl4 and Na2S2O3 without assistance of additional templates, capping reagents, or seeds. The anisotropy in the shape of gold nanoparticles offers high NIR absorption, making it therapeutically relevant. The synthesized products consist of GNPs with different shapes and sizes, including small spherical colloid gold particles and non-spherical gold crystals. The NIR absorption wavelengths and particle size increase with increasing molar ratio of HAuCl4/Na2S2O3. Non-spherical gold particles can be further purified and separated by centrifugation to improve the NIR-absorbing fraction of particles. In-depth studies reveal that GNPs with good structural and optical stability only form in a certain range of the HAuCl4/Na2S2O3 molar ratio, whereas higher molar ratios result in unstable GNPs, which lose their NIR absorption peak due to decomposition and reassembly via Ostwald ripening. Tuning the optical absorption of the gold nanoparticles in the NIR regime via a robust and repeatable method will improve many applications requiring large quantities of desired NIR-absorbing nanoparticles.

Gold/Chitosan nanocomposites with specific near infrared absorption for photothermal therapy applications

Gold/chitosan nanocomposites were synthesized and evaluated as a therapeutic agent for the photothermal therapy. Gold nanoparticles (Au NPs) with controllable optical absorption in the near infrared (NIR) region were prepared by the reaction of chloroauric acid and sodium thiosulfate. To apply these particles to cancer therapy, the bare Au NPs were coated with chitosan (CS), O-carboxymethyl chitosan (CMCS), and a blend of CS and CMCS for utilizations in physiologic conditions. The surface properties, optical stability, and photothermal ablation efficiency on hepatocellular carcinoma cells (HepG2) and human dermal fibroblast cells (HDF) demonstrate that these gold nanocomposites have great potential as a therapeutic agent in in vitro tests. The CS-coated nanocomposites show the highest efficiency for the photo-ablation on the HepG2 cells, and the CS and CMCS blended coated particles show the best discrimination between the cancer cell and normal cells. The well-controlled NIR absorption and the biocompatible surface of these nanocomposites allow low-power NIR laser activation and low-dosage particle injection for the cancer cell treatment.

Detection of Phosphatidylcholine-Coated Gold Nanoparticles in Orthotopic Pancreatic Adenocarcinoma using Hyperspectral Imaging

Nanoparticle uptake and distribution to solid tumors are limited by reticuloendothelial system systemic filtering and transport limitations induced by irregular intra-tumoral vascularization. Although vascular enhanced permeability and retention can aid targeting, high interstitial fluid pressure and dense extracellular matrix may hinder local penetration. Extravascular diffusivity depends upon nanoparticle size, surface modifications, and tissue vascularization. Gold nanoparticles functionalized with biologically-compatible layers may achieve improved uptake and distribution while enabling cytotoxicity through synergistic combination of chemotherapy and thermal ablation. Evaluation of nanoparticle uptake in vivo remains difficult, as detection methods are limited. We employ hyperspectral imaging of histology sections to analyze uptake and distribution of phosphatidylcholine-coated citrate gold nanoparticles (CGN) and silica-gold nanoshells (SGN) after tail-vein injection in mice bearing orthotopic pancreatic adenocarcinoma. For CGN, the liver and tumor showed 26.5±8.2 and 23.3±4.1 particles/100μm2 within 10μm from the nearest source and few nanoparticles beyond 50μm, respectively. The spleen had 35.5±9.3 particles/100μm2 within 10μm with penetration also limited to 50μm. For SGN, the liver showed 31.1±4.1 particles/100μm2 within 10μm of the nearest source with penetration hindered beyond 30μm. The spleen and tumor showed uptake of 22.1±6.2 and 15.8±6.1 particles/100μm2 within 10μm, respectively, with penetration similarly hindered. CGH average concentration (nanoparticles/μm2) was 1.09±0.14 in the liver, 0.74±0.12 in the spleen, and 0.43±0.07 in the tumor. SGN average concentration (nanoparticles/μm2) was 0.43±0.07 in the liver, 0.30±0.06 in the spleen, and 0.20±0.04 in the tumor. Hyperspectral imaging of histology sections enables analysis of phosphatidylcholine-coated gold-based nanoparticles in pancreatic tumors with the goal to improve nanotherapeutic efficacy.

Infrared light-absorbing gold/gold sulfide nanoparticles induce cell death in esophageal adenocarcinoma

Gold nanoparticles and near infrared-absorbing light are each innocuous to tissue but when combined can destroy malignant tissue while leaving healthy tissue unharmed. This study investigated the feasibility of photothermal ablation therapy for esophageal adenocarcinoma using chitosan-coated gold/gold sulfide (CS-GGS) nanoparticles. A rat esophagoduodenal anastomosis model was used for the in vivo ablation study, and three human esophageal cell lines were used to study the response of cancer cells and benign cells to near infrared light after treatment with CS-GGS. The results indicate that both cancerous tissue and cancer cells took up more gold nanoparticles and were completely ablated after exposure to near infrared light. The benign tissue and noncancerous cells showed less uptake of these nanoparticles, and remained viable after exposure to near infrared light. CS-GGS nanoparticles could provide an optimal endoluminal therapeutic option for near infrared light ablation of esophageal cancer.

A high yield, one-pot dialysis-based process for self-assembly of near infrared absorbing gold nanoparticles

HYPOTHESIS A facile, dialysis-based synthesis of stable near infrared (nIR) absorbing plasmonic gold nanoparticles (λmax=650-1000 nm) will increase the yield of nIR particles and reduce the amount of gold colloid contaminant in the product mixture. EXPERIMENTS Chloroauric acid and sodium thiosulfate were reacted using a dialysis membrane as a reaction vessel. Product yield and composition was determined and compared to traditional synthesis methods. The product particle distribution, yield, and partitioning of gold between dispersed product and membrane-adsorbed gold were determined. FINDINGS The synthesis results in polydisperse particle suspensions comprised of 70% spheroid-like particles, 27% triangular plates, and 3% rod-like structures with a 3% batch-to-batch variation and a prominent nIR absorption band with λmax=650-1000 nm. The amount of small gold colloid (λmax=530 nm; d<10 nm) in the isolated product was reduced by 96% compared to traditional methods. Additionally, 91.1% of the gold starting material is retained in the solution-based nanoparticle mixture while 8.2% is found on the dialysis membrane. The synthesis results in a quality ratio (QR=Abs(nIR)/Abs(530)) of 1.7-2.4 (twice that of previous techniques) and 14.3 times greater OD∗ml yield of the nIR-absorbing nanoparticle fraction.

A high yield, controllable process for producing tunable near infrared-absorbing gold nanoplates†

The purpose of this study was to optimize a new synthesis technique, “DiaSynth,” to produce near-infrared (nIR) absorbing gold nanoplates with prescribed localized surface plasmon resonance (LSPR) wavelengths in higher yields over conventional synthesis methods without the need for laborious purification steps. The molecular weight cut off (MWCO; 3.5, 8, 12, 15, 25 & 50 kDa) of the regenerated cellulose membranes (RCM), temperature (25, 37, 50 & 100 °C) and surface area to volume (SA/Vol) ratio (220, 340 & 470 mm2 ml−1) of the RCM to the gold nanoplate solution were varied during the synthesis process to determine the effect of each parameter on gold nanoplates yield, LSPR peak placement and stability. Results indicate the ability of the RCM to remove ∼99% of the contaminant small gold colloid (<10 nm) produced during the synthesis process, while producing a 72% higher yield of gold nanoplates compared to a conventional one-step fabrication process. Increasing the MWCO of the RCM from 3.5 kDa to 15 kDa was found to blue shift the LSPR peak down by 40 nm. Increasing the SA/Vol ratio and temperature blue shifted the LSPR peak wavelength by hundreds of nanometers with the nIR absorbing gold nanoplate LSPR peak occurring within the range of 650–1100 nm. It was also discovered that the gold nanoplates fabricated via the DiaSynth process with dialysis (Process 1) displayed an increase in stability over time without the need of a capping agent. With the increased gold nanoplate stability, further purification and isolation of gold nanoplates was possible through sedimentation over time. This study demonstrated that increasing the temperature, SA/Vol, and MWCO of the RCM allows production of gold nanoplates of increased purity compared to other methods and the ability to tailor the tunability of the LSPR peak to a desired wavelength.