A novel therapeutic strategy of multimodal nanoconjugates for state-of-the-art brain tumor phototherapy

Background The outcome of phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT) for glioblastoma multiforme (GBM), is disappointing due to insufficient photoconversion efficiency and low targeting rate. The development of phototherapeutic agents that target GBM and generate high heat and potent ROS is important to overcome the weak anti-tumor effect. Results In this study, nanoconjugates composed of gold nanoparticles (AuNPs) and photosensitizers (PSs) were prepared by disulfide conjugation between Chlorin e6 (Ce6) and glutathione coated-AuNP. The maximum heat dissipation of the nanoconjugate was 64.5 ± 4.5 °C. Moreover, the proximate conjugation of Ce6 on the AuNP surface resulted in plasmonic crossover between Ce6 and AuNP. This improves the intrinsic ROS generating capability of Ce6 by 1.6-fold compared to that of unmodified-Ce6. This process is called generation of metal-enhanced reactive oxygen species (MERos). PEGylated-lactoferrin (Lf-PEG) was incorporated onto the AuNP surface for both oral absorption and GBM targeting of the nanoconjugate (denoted as Ce6-AuNP-Lf). In this study, we explored the mechanism by which Ce6-AuNP-Lf interacts with LfR at the intestinal and blood brain barrier (BBB) and penetrates these barriers with high efficiency. In the orthotopic GBM mice model, the oral bioavailability and GBM targeting amount of Ce6-AuNP-Lf significantly improved to 7.3 ± 1.2% and 11.8 ± 2.1 μg/kg, respectively. The order of laser irradiation, such as applying PDT first and then PTT, was significant for the treatment outcome due to the plasmonic advantages provided by AuNPs to enhance ROS generation capability. As a result, GBM-phototherapy after oral administration of Ce6-AuNP-Lf exhibited an outstanding anti-tumor effect due to GBM targeting and enhanced photoconversion efficiency. Conclusions The designed nanoconjugates greatly improved ROS generation by plasmonic crossover between AuNPs and Ce6, enabling sufficient PDT for GBM as well as PTT. In addition, efficient GBM targeting through oral administration was possible by conjugating Lf to the nanoconjugate. These results suggest that Ce6-AuNP-Lf is a potent GBM phototherapeutic nanoconjugate that can be orally administered. Graphical Abstract

Understanding the Adsorption of Peptides and Proteins onto PEGylated Gold Nanoparticles

Polyethylene glycol (PEG) surface conjugations are widely employed to render passivating properties to nanoparticles in biological applications. The benefits of surface passivation by PEG are reduced protein adsorption, diminished non-specific interactions, and improvement in pharmacokinetics. However, the limitations of PEG passivation remain an active area of research, and recent examples from the literature demonstrate how PEG passivation can fail. Here, we study the adsorption amount of biomolecules to PEGylated gold nanoparticles (AuNPs), focusing on how different protein properties influence binding. The AuNPs are PEGylated with three different sizes of conjugated PEG chains, and we examine interactions with proteins of different sizes, charges, and surface cysteine content. The experiments are carried out in vitro at physiologically relevant timescales to obtain the adsorption amounts and rates of each biomolecule on AuNP-PEGs of varying compositions. Our findings are relevant in understanding how protein size and the surface cysteine content affect binding, and our work reveals that cysteine residues can dramatically increase adsorption rates on PEGylated AuNPs. Moreover, shorter chain PEG molecules passivate the AuNP surface more effectively against all protein types.

Optimization of the Electrodeposition of Gold Nanoparticles for the Application of Highly Sensitive, Label-Free Biosensor

A highly sensitive electrochemical biosensor with a signal amplification platform of electrodeposited gold nanoparticle (AuNP) has been developed and characterized. The sizes of the synthesized AuNP were found to be critical for the performance of biosensor in which the sizes were dependent on HAuCl4 and acid concentrations; as well as on scan cycles and scan rates in the gold electro-reduction step. Systematic investigations of the adsorption of proteins with different sizes from aqueous electrolyte solution onto the electrodeposited AuNP surface were performed with a potentiometric method and calibrated by design of experiment (DOE). The resulting amperometric glucose biosensors was demonstrated to have a low detection limit (> 50 μM) and a wide linear range after optimization with AuNP electrodeposition.

Tripodal tris-disulfides as capping agents for a controlled mixed functionalization of gold nanoparticles

New tris(SS)-tripodal capping ligands afford AuNP surface composition fine control and SPR sensing for TNT-like explosives.

Highly stable SERS pH nanoprobes produced by co-solvent controlled AuNP aggregation

Production of gold nanoparticle (AuNP) surface-enhanced Raman spectroscopy (SERS) nanoprobes requires replicable aggregation to produce multimers with high signal intensity.

Development of novel bioelectrocatalytic platform based on in situ generated gold nanoparticles for biomedical applications

ABSTRACTGold nanoparticles (AuNp) formed using alkoxysilane precursors are utilized in the development of thin organically modified silicates (ormosil) films. The resulting films are optically transparent thereby retaining the optical properties of AuNp. Surface morphology shows that the in situ generated AuNp retained their nanogeometry in the ormosil films. An application of the AuNp encapsulated ormosils is shown in electrocatalytic determination of hydrogen peroxide. For this purpose, potassium ferricyanide is chosen as electron transfer mediator and is encapsulated in the films. Results show that the presence of AuNp in the ormosil matrix dramatically improves the electrochemical behavior of potassium ferricyanide. The ormosil films are utilized for electrocatalytic determination of hydrogen peroxide. In order to investigate the biocompatibility of the ormosil film, horseradish peroxidase (HRP) is incorporated resulting in improvement in oxidation and reduction of peroxide.