Gd-nanoparticles functionalization with specific peptides for ß-amyloid plaques targeting.

BACKGROUND: Amyloidoses are characterized by the extracellular deposition of insoluble fibrillar proteinaceous aggregates highly organized into cross-ß structure and referred to as amyloid fibrils. Nowadays, the diagnosis of these diseases remains tedious and involves multiple examinations while an early and accurate protein typing is crucial for the patients' treatment. Routinely used neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) using Pittsburgh compound B, [(11)C]PIB, provide structural information and allow to assess the amyloid burden, respectively, but cannot discriminate between different amyloid deposits. Therefore, the availability of efficient multimodal imaging nanoparticles targeting specific amyloid fibrils would provide a minimally-invasive imaging tool useful for amyloidoses typing and early diagnosis. In the present study, we have functionalized gadolinium-based MRI nanoparticles (AGuIX) with peptides highly specific for Aß amyloid fibrils, LPFFD and KLVFF. The capacity of such nanoparticles grafted with peptide to discriminate among different amyloid proteins, was tested with Aß(1-42) fibrils and with mutated-(V30M) transthyretin (TTR) fibrils. RESULTS: The results of surface plasmon resonance studies showed that both functionalized nanoparticles interact with Aß(1-42) fibrils with equilibrium dissociation constant (Kd) values of 403 and 350 µM respectively, whilst they did not interact with V30M-TTR fibrils. Similar experiments, performed with PIB, displayed an interaction both with Aß(1-42) fibrils and V30M-TTR fibrils, with Kd values of 6 and 10 µM respectively, confirming this agent as a general amyloid fibril marker. Thereafter, the ability of functionalized nanoparticle to target and bind selectively Aß aggregates was further investigated by immunohistochemistry on AD like-neuropathology brain tissue. Pictures clearly indicated that KLVFF-grafted or LPFFD-grafted to AGuIX nanoparticle recognized and bound the Aß amyloid plaque localized in the mouse hippocampus. CONCLUSION: These results constitute a first step for considering these functionalized nanoparticles as a valuable multimodal imaging tool to selectively discriminate and diagnose amyloidoses.

Orotracheal administration of contrast agents: a new protocol for brain tumor targeting.

The development of new non-invasive diagnostic and therapeutic approaches is of paramount importance in order to improve the outcome of patients with glioblastoma (GBM). In this work we investigated a completely non-invasive pre-clinical protocol to effectively target and detect brain tumors through the orotracheal route, using ultra-small nanoparticles (USRPs) and MRI. A mouse model of GBM was developed. In vivo MRI acquisitions were performed before and after intravenous or orotracheal administration of the nanoparticles to identify and segment the tumor. The accumulation of the nanoparticles in neoplastic lesions was assessed ex vivo through fluorescence microscopy. Before the administration of contrast agents, MR images allowed the identification of the presence of abnormal brain tissue in 73% of animals. After orotracheal or intravenous administration of USRPs, in all the mice an excellent co-localization of the position of the tumor with MRI and histology was observed. The elimination time of the USRPs from the tumor after the orotracheal administration was approximately 70% longer compared with intravenous injection. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify and longitudinally monitor the development of GBMs. The absence of ionizing radiation and high resolution of MRI, along with the complete non-invasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge, this is the first time that the advantages of a needle-free orotracheal administration route have been demonstrated for the investigation of the pathomorphological changes due to GBMs.

Silver Nanoshells with Optimized Infrared Optical Response: Synthesis for Thin-Shell Formation, and Optical/Thermal Properties after Embedding in Polymeric Films.

We describe a new approach to making ultrathin Ag nanoshells with a higher level of extinction in the infrared than in the visible. The combination of near-infrared active ultrathin nanoshells with their isotropic optical properties is of interest for energy-saving applications. For such applications, the morphology must be precisely controlled, since the optical response is sensitive to nanometer-scale variations. To achieve this precision, we use a multi-step, reproducible, colloidal chemical synthesis. It includes the reduction of Tollens' reactant onto Sn2+-sensitized silica particles, followed by silver-nitrate reduction by formaldehyde and ammonia. The smooth shells are about 10 nm thick, on average, and have different morphologies: continuous, percolated, and patchy, depending on the quantity of the silver nitrate used. The shell-formation mechanism, studied by optical spectroscopy and high-resolution microscopy, seems to consist of two steps: the formation of very thin and flat patches, followed by their guided regrowth around the silica particle, which is favored by a high reaction rate. The optical and thermal properties of the core-shell particles, embedded in a transparent poly(vinylpyrrolidone) film on a glass substrate, were also investigated. We found that the Ag-nanoshell films can convert 30% of the power of incident near-infrared light into heat, making them very suitable in window glazing for radiative screening from solar light.

Seeded growth of ultrathin gold nanoshells using polymer additives and microwave radiation.

Nanoshells made of a silica core and a gold shell possess an optical response that is sensitive to nanometer-scale variations in shell thickness. The exponential red shift of the plasmon resonance with decreasing shell thickness makes ultrathin nanoshells (less than 10 nm) particularly interesting for broad and tuneable ranges of optical properties. Nanoshells are generally synthesised by coating gold onto seed-covered silica particles, producing continuous shells with a lower limit of 15 nm, due to an inhomogeneous droplet formation on the silica surface during the seed regrowth. In this paper, we investigate the effects of three variations of the synthesis protocol to favour ultrathin nanoshells: seed density, polymer additives and microwave treatment. We first maximised gold seed density around the silica core, but surprisingly its effect is limited. However, we found that the addition of polyvinylpyrrolidone during the shell synthesis leads to higher homogeneity and a thinner shell and that a post-synthetic thermal treatment using microwaves can further smooth the particle surface. This study brings new insights into the synthesis of metallic nanoshells, pushing the limits of ultrathin shell synthesis.

Increasing Silver Nanowire Network Stability through Small Molecule Passivation.

Silver nanowire (AgNW) transparent electrodes show promise as an alternative to indium tin oxide (ITO). However, these nanowire electrodes degrade in air, leading to significant resistance increases. We show that passivating the nanowire surfaces with small organic molecules of 11-mercaptoundecanoic acid (MUA) does not affect electrode transparency contrary to typical passivation films, and is inexpensive and simple to deposit. The sheet resistance of a 32 nm diameter silver nanowire network coated with MUA increases by only 12% over 120 days when exposed to atmospheric conditions but kept in the dark. The increase is larger when exposed to daylight (588%), but is still nearly two orders of magnitude lower than the resistance increase of unpassivated networks. The difference between the experiments performed under daylight versus the dark exemplifies the importance of testing passivation materials under light exposure.

Plasmon-induced hot electron transfer in AgNW@TiO2@AuNPs nanostructures.

Compared to the limited absorption cross-section of conventional photoactive TiO2 nanoparticles (NPs), plasmonic metallic nanoparticles can efficiently convert photons from an extended spectrum range into energetic carriers because of the localized surface plasmon resonance (LSPR). Using these metal oxide semiconductors as shells for plasmonic nanoparticles (PNPs) that absorb visible light could extend their applications. The photophysics of such systems is performed using transient absorption measurements and steady extinction simulations and shows that the plasmonic energy transfer from the AgNWs core to the TiO2 shell results from a hot carrier injection process. Lifetimes obtained from photobleaching decay dynamics suggest that (i) the presence of gold nanoparticles (AuNPs) in AgNWs@TiO2@AuNPs systems can further promote the hot carrier transfer process via plasmonic coupling effects and (ii) the carrier dynamics is greatly affected by the shell thickness of TiO2. This result points out a definite direction to design appropriate nanostructures with tunable charge transfer processes toward photo-induced energy conversion applications.

Multimodal imaging Gd-nanoparticles functionalized with Pittsburgh compound B or a nanobody for amyloid plaques targeting.

AIM: Gadolinium-based nanoparticles were functionalized with either the Pittsburgh compound B or a nanobody (B10AP) in order to create multimodal tools for an early diagnosis of amyloidoses. MATERIALS & METHODS: The ability of the functionalized nanoparticles to target amyloid fibrils made of ß-amyloid peptide, amylin or Val30Met-mutated transthyretin formed in vitro or from pathological tissues was investigated by a range of spectroscopic and biophysics techniques including fluorescence microscopy. RESULTS: Nanoparticles functionalized by both probes efficiently interacted with the three types of amyloid fibrils, with KD values in 10 micromolar and 10 nanomolar range for, respectively, Pittsburgh compound B and B10AP nanoparticles. Moreover, they allowed the detection of amyloid deposits on pathological tissues. CONCLUSION: Such functionalized nanoparticles could represent promising flexible and multimodal imaging tools for the early diagnostic of amyloid diseases, in other words, Alzheimer's disease, Type 2 diabetes mellitus and the familial amyloidotic polyneuropathy.

Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases: Proof of Concept before Phase I Trial.

Nanoparticles containing high-Z elements are known to boost the efficacy of radiation therapy. Gadolinium (Gd) is particularly attractive because this element is also a positive contrast agent for MRI, which allows for the simultaneous use of imaging to guide the irradiation and to delineate the tumor. In this study, we used the Gd-based nanoparticles, AGuIX®. After intravenous injection into animals bearing B16F10 tumors, some nanoparticles remained inside the tumor cells for more than 24 hours, indicating that a single administration of nanoparticles might be sufficient for several irradiations. Combining AGuIX® with radiation therapy increases tumor cell death, and improves the life spans of animals bearing multiple brain melanoma metastases. These results provide preclinical proof-of-concept for a phase I clinical trial.