Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours.

OBJECTIVE: Stromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC. DESIGN: Nitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro-in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo. RESULTS: The delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy. CONCLUSION: The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

The effect of ligand-ligand interactions on the formation of photoluminescent gold nanoclusters embedded in Au(i)-thiolate supramolecules.

In this study, we prepared photoluminescent l-cysteine (Cys)-capped gold nanoclusters (Cys-Au NCs) via NaBH4-mediated reduction of aggregated coordination polymers (supramolecules) of -[Cys-Au(i)]n-. The -[Cys-Au(i)]n- supramolecules with interesting chiral properties were formed through simple reactions of chloroauric acid (HAuCl4) with Cys at certain pH values (pH 3-7). The -[Cys-Au(i)]n- polymers could self-assemble into -[Cys-Au(i)]n- supramolecules with irregular morphologies and diameters larger than 500 nm through stacked hydrogen bonding and zwitterionic interactions between Cys ligands and through Au(i)Au(i) aurophilic interactions in solutions with pH values ≤7. The photoluminescent Au NCs (quantum yield = 11.6%) dominated by a Au13 core were embedded in -[Cys-Au(i)]n- supramolecules after NaBH4-mediated reduction. The optical and structural properties of Cys-Au NCs/-[Cys-Au(i)]n- nanocomposites were investigated, revealing that the interaction between Cys ligands plays a critical role in the self-assembly of -[Cys-Au(i)]n- supramolecules and in the formation of photoluminescent Cys-Au NCs embedded in the supramolecules. To further demonstrate that the photoluminescence properties and structures of the nanocomposites are mediated by the intermolecular forces of thiol ligands, other thiol ligands (l-penicillamine, l-homocysteine, 3-mercaptopropionic acid, and l-glutathione) and a ligand-crosslinking agent [bis(sulfosuccinimidyl) suberate; BS3] were used. We concluded that the electrostatic interactions, hydrogen bonding and steric effects dominate the polymer self-assembly into thiol-ligand-Au(i) supramolecules and thus the formation of Au NCs. Our study provides insights into the bottom-up synthesis of photoluminescent Au NCs from thiol-ligand-Au(i) complexes, polymers, and supramolecules. The hybrid Au NCs/-[Cys-Au(i)]n- nanocomposites can potentially be employed as drug carriers and bioimaging agents.

Detection of arsenic(III) through pulsed laser-induced desorption/ionization of gold nanoparticles on cellulose membranes.

We have developed an assay based on gold nanoparticle-modified mixed cellulose ester membrane (Au NPs-MCEM) coupled with laser-induced desorption/ionization mass spectrometry (LDI-MS)-for the detection of arsenic(III) ions (arsenite, AsO2(-)) in aqueous solution. When the Au NPs reacted with lead ions (Pb(2+)) in alkaline solution (5 mM glycine-NaOH, pH 12), Au-Pb complexes, PbO, and Pb(OH) were formed immediately on the Au NP surfaces. The Pb species reacted rapidly with subsequently added AsO2(-) to form PbOAs2O3, (PbO)2As2O3, and/or (PbO)3As2O3 shells (2-5 nm) on the Au NPs' surfaces. As a result, significant observable aggregation of the Au NPs occurred in the solution. This Pb(2+)/Au NP probe allowed the detection of AsO2(-) at concentrations as low as 0.6 µM with high selectivity (at least 100-fold over other anions and metal ions). To further improve the sensitivity, we prepared Au NPs-MCEM for the LDI-MS-based detection of AsO2(-) ions. The intensity of the signal for the [Pb](+) ions in the mass spectra increased when the Au NPs-MCEM reacted with AsO2(-); in contrast, the intensity of the signal for [Au](+) ions decreased. Accordingly, the [Pb](+)/[Au](+) peak ratio increased upon increasing the AsO2(-) concentration over the range from 10 nM to 10 µM. The limit of detection at a signal-to-noise ratio of 3 was 2.5 nM, far below the action level of As (133 nM, ca. 10 ppb) permitted by the US EPA for drinking water. Relative to other nanoparticle-based arsenic sensors, this approach is rapid, specific, and sensitive; in addition, it can be applied to the detection of AsO2(-) in natural water samples (in this case, streamwater, lake water, tap water, groundwater, and mineral water).

NIR-activated quercetin-based nanogels embedded with CuS nanoclusters for the treatment of drug-resistant biofilms and accelerated chronic wound healing.

We have developed multifunctional nanogels with antimicrobial, antioxidant, and anti-inflammatory properties, facilitating rapid wound healing. To prepare the multifunctional nanogels, we utilized quercetin (Qu) and a mild carbonization process to form carbonized nanogels (CNGs). These CNGs possess excellent antioxidative and bacterial targeting properties. Subsequently, we utilized the Qu-CNGs as templates to prepare nanogels incorporating copper sulfide (CuS) nanoclusters, further enhancing their functionality. Notably, the CuS/Qu-CNGs nanocomposites demonstrated an exceptional minimum inhibitory concentration against tested bacteria, approximately 125-fold lower than monomeric Qu or Qu-CNGs. This enhanced antimicrobial effect was achieved by leveraging near-infrared II (NIR-II) light irradiation. Additionally, the CuS/Qu-CNGs exhibited efficient penetration into the extracellular biofilm matrix, eradicating methicillin-resistant Staphylococcus aureus-associated biofilms in diabetic mice wounds. Furthermore, the nanocomposites were found to suppress proinflammatory cytokines, such as IL-1ß, at the wound sites while regulating the expression of anti-inflammatory factors, including IL-10 and TGF-ß1, throughout the recovery process. The presence of CuS/Qu-CNGs promoted angiogenesis, epithelialization, and collagen synthesis, thereby accelerating wound healing. Our developed CuS/Qu-CNGs nanocomposites have great potential in addressing the challenges associated with delayed wound healing caused by microbial pathogenesis.

Capping 1,3-propanedithiol to boost the antibacterial activity of protein-templated copper nanoclusters.

We have prepared copper nanoclusters (Cu NCs) in the presence of bovine serum albumin (BSA) and 1,3-propanedithiol (PDT). The PDT/BSA-Cu NCs possess great activities against different types of bacteria, including non-multidrug-resistant bacteria (Escherichia coli, Salmonella Enteritidis, Pseudomonas aeruginosa, and Staphylococcus aureus) and multidrug-resistant bacteria (methicillin-resistant S. aureus). Their minimal inhibitory concentration (MIC) values are at least 242-fold and 10-fold lower than that of the free PDT and BSA-Cu NCs, respectively. The PDT/BSA-Cu NCs are strongly bound to the bacterial membrane, in which they induce the generation of ascorbyl (Asc) and perhydroxyl (HOO) radicals that result in disruption of their membrane integrity. At a concentration of 100-fold higher than their MIC for Escherichia coli, the PDT/BSA-Cu NCs exhibit negligible cytotoxicity towards the tested mammalian cells and show insignificant hemolysis. We have further demonstrated that low-cost PDT/BSA-Cu NCs-coated carbon fiber fabrics (CFFs) are effective against antibacterial growth, showing their great potential for antifouling applications.

Antibacterial cellulose paper made with silver-coated gold nanoparticles.

In this study, we investigated the antibacterial activity of silver-coated gold nanoparticles (Au-Ag NPs) immobilized on cellulose paper. Ag NPs are known to have strong antibacterial properties, while Au NPs are biocompatible and relatively simple to prepare. We made the Au-Ag NPs using a facile process called Ag enhancement, in which Au NPs serve as the nuclei for precipitation of a Ag coating, the thickness of which can be easily controlled by varying the ratio of the reactants. After synthesis, electron microscopy showed that the Au-Ag NPs displayed a core-shell structure, and that they could be successfully immobilized onto a cellulose membrane by heat treatment. We then investigated the antibacterial properties of this NP-coated cellulose paper against E. coli JM109. The inhibition rate, growth curve, and AATCC 100 activity test showed that cellulose paper coated with 15 nm Au-Ag NPs possessed excellent antibacterial activity against E. coli JM109. These results suggest that Au-Ag NPs immobilized on cellulose paper could be a valuable antibacterial technology for applications such as food packaging, clothing, wound dressings, and other personal care products.

Carbon nanodots prepared from o-phenylenediamine for sensing of Cu(2+) ions in cells.

A simple hydrothermal method was applied to prepare carbon nanodots (C dots) from o-phenylenediamine (OPD). The C dots exhibit photoluminescence at 567 nm when excited at 420 nm. In the presence of Cu(2+) ions, the colour of C dots changes from yellow to orange, with an increased PL intensity as a result of the formation of Cu(OPD)2 complexes on the surfaces of C dots. The D-band to G-band ratios of C dots in the absence and presence of 80 nM Cu(2+) ions are 1.31 and 4.75, respectively. The C dots allow the detection of Cu(2+) ions with linearity over a concentration range of 2-80 nM, with a limit of detection of 1.8 nM at a signal-to-noise ratio of 3. The cell viability values of A549, MCF-10A, and MDA-MB-231 cells treated with 3 µg mL(-1) of C dots are all greater than 99%, showing their great biocompatibility. Having great water dispersibility, photostability, chemical stability (against NaCl up to 0.5 M), great selectivity, and biocompatibility, the C dots have been employed for the localization of Cu(2+) ions in the cancer cells (A549 cells) treated with 10 µM Cu(2+) ions.

Gold-nanoparticles-modified cellulose membrane coupled with laser desorption/ionization mass spectrometry for detection of iodide in urine.

We report an efficient method for the determination of iodide (I(-)) ions by using gold-iodide hybrid cluster ions on gold nanoparticles (Au NPs) modified mixed cellulose ester membrane (Au NPs-MCEM) by pulsed laser desorption/ionization mass spectrometry (LDI-MS). When I(-) ions were deposited and concentrated on the surfaces of Au NPs (32 nm) via strong Au(+)-I(-) interaction on the MECM, the Au NPs-MCEM was observed to function as an efficient surface-assisted LDI substrate with very low background noise. When pulsed laser radiation (355 nm) was applied, I(-) binding to Au NPs ions induced the enhancement of the desorption and ionization efficiency of gold-iodide hybrid cluster ions from the Au NPs surfaces. The reproducibility of the probe for both shot-to-shot and sample-to-sample (both less than 10%) ion production was also improved by the homogeneous nature of the substrate surface. Thus, it allows the accurate and precise quantification of I(-) ions in high-salinity real samples (i.e., edible salt samples and urine) at the nanomolar range. This novel LDI-MS approach provides a simple route for the high-speed analysis of I(-) ions with high sensitivity and selectivity in real biological samples.