Tb-Doped core-shell-shell nanophosphors for enhanced X-ray induced luminescence and sensitization of radiodynamic therapy.

The development of radiation responsive materials, such as nanoscintillators, enables a variety of exciting new theranostic applications. In particular, the ability of nanophosphors to serve as molecular imaging agents in novel modalities, such as X-ray luminescence computed tomography (XLCT), has gained significant interest recently. Here, we present a radioluminescent nanoplatform consisting of Tb-doped nanophosphors with an unique core/shell/shell (CSS) architecture for improved optical emission under X-ray excitation. Owing to the spatial confinement and separation of luminescent activators, these CSS nanophosphors exhibited bright optical luminescence upon irradiation. In addition to standard physiochemical characterization, these CSS nanophosphors were evaluated for their ability to serve as energy mediators in X-ray stimulated photodynamic therapy, also known as radiodynamic therapy (RDT), through attachment of a photosensitizer, rose bengal (RB). Furthermore, cRGD peptide was used as a model targeting agent against U87 MG glioblastoma cells. In vitro RDT efficacy studies suggested the RGD-CSS-RB in combination with X-ray irradiation could induce enhanced DNA damage and increased cell killing, while the nanoparticles alone are well tolerated. These studies support the utility of CSS nanophosphors and warrants their further development for theranostic applications.

Synthesis of Radioluminescent CaF2:Ln Core, Mesoporous Silica Shell Nanoparticles for Use in X-ray Based Theranostics.

X-ray radiotherapy is a common method of treating cancerous tumors or other malignant lesions. The side effects of this treatment, however, can be deleterious to patient quality of life if critical tissues are affected. To potentially lower the effective doses of radiation and negative side-effects, new classes of nanoparticles are being developed to enhance reactive oxygen species production during irradiation. This report presents the synthesis and radiotherapeutic efficacy evaluation of a new nanoparticle formulation designed for this purpose, composed of a CaF2 core, mesoporous silica shell, and polyethylene glycol coating. The construct was additionally doped with Tb and Eu during the CaF2 core synthesis to prepare nanoparticles (NPs) with X-ray luminescent properties for potential application in fluorescence imaging. The mesoporous silica shell was added to provide the opportunity for small molecule loading, and the polyethylene glycol coating was added to impart aqueous solubility and biocompatibility. The potential of these nanomaterials to act as radiosensitizers for enhancing X-ray radiotherapy was supported by reactive oxygen species generation assays. Further, in vitro experiments indicate biocompatibility and enhanced cellular damage during X-ray radiotherapy.

Lanthanide Metal-Organic Frameworks for Multispectral Radioluminescent Imaging.

In this report, we describe the X-ray luminescent properties of two lanthanide-based nanoscale metal-frameworks (nMOFs) and their potential as novel platforms for optical molecular imaging techniques such as X-ray excited radioluminescence (RL) imaging. Upon X-ray irradiation, the nMOFs display sharp tunable emission peaks that span the visible to near-infrared spectral region (∼400-700 nm) based on the identity of the metal (Eu, Tb, or Eu/Tb). Surface modification of the nMOFs with polyethylene glycol (PEG) resulted in nanoparticles with enhanced aqueous stability that demonstrated both cyto- and hemo-compatibility important prerequisites for biological applications. Importantly, this is the first report to document and investigate the radioluminescent properties of lanthanide nMOFs. Taken together, the observed radioluminescent properties and low in vitro toxicity demonstrated by the nMOFs render them promising candidates for in vivo translation.

Inverse-micelle synthesis of doxorubicin-loaded alginate/chitosan nanoparticles and in vitro assessment of breast cancer cytotoxicity.

Naturally-derived polysaccharides, such as alginate and chitosan, can be assembled to form nanocarriers for the delivery of therapeutic agents. Here we exploit the electrostatic complexation of alginate/chitosan in a water-in-oil (w/o) emulsion process to produce doxorubicin (DOX)-loaded nanoparticles (~80 nm) with exceptional spherical morphology and uniformity. This robust synthetic route utilizes an aqueous phase dispersed in a cyclohexane/dodecylamine organic phase and is capable of encapsulating DOX in the nanoparticle solution. The uptake and efficacy of this novel formulation was evaluated in a murine breast cancer cell line, 4T1, with comparable 72 h IC50 values of the nanoparticle solution (0.15 µg/mL) and free DOX (0.13 µg/mL). Overall, the favorable performance, physiochemical properties, and their facile production support these nanocarriers as promising platform for the delivery of aqueous soluble drugs.

Facile Synthesis of Ligand-Free Iridium Nanoparticles and Their In Vitro Biocompatibility.

High-density inorganic nanoparticles have shown promise in medical applications that utilize radiation including X-ray imaging and as radiation dose enhancers for radiotherapy. We have developed an aqueous synthetic method to produce small (~ 2 nm) iridium nanoparticles (IrNPs) by reduction of iridium(III) chloride using a borohydride reducing agent. Unlike other solution-based synthesis methods, uniform and monodispersed IrNPs are produced without the use of surfactants or other solubilizing ligands. These nanoparticles are highly crystalline as observed by X-ray diffraction and high-resolution transmission electron microscopy (TEM). In vitro metabolic toxicity assays using hepatocyte and macrophage cells demonstrate that both IrNPs and iridium(III) chloride are well tolerated at concentrations of up to 10 µM iridium. Furthermore, the IrNPs were assessed in a hemolytic assay and found to have no significant impact on red blood cells when exposed to concentrations up to 100 µM. Overall, these results support the potential for the in vivo application of this nanomaterial.