Characterization and biodistribution of Au nanoparticles loaded in PLGA nanocarriers using an original encapsulation process.

Due to their imaging and radiosensitizing properties, ultrasmall gadolinium chelate-coated gold nanoparticles (AuNP) represent a promising approach in the diagnosis and the treatment of tumors. However, their poor pharmacokinetic profile, especially their rapid renal clearance prevents from an efficient exploitation of their potential for medical applications. The present study focuses on a strategy which resides in the encapsulation of AuNP in large polymeric NP to avoid the glomerular filtration and then to prolong the vascular residence time. An original encapsulation procedure using the polyethyleneimine (PEI) was set up to electrostatically entrap AuNP in biodegradable poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol -PLGA (PLGA-PEG) NP. Hydrodynamic diameters of NP were dependent of the PEI/Au ratio and comprised between 115 and 196 nm for ratios equal or superior to 4. Encapsulation yield was close to 90 % whereas no loading was observed without PEI. No toxicity was observed after 24 h exposure in hepatocyte cell-lines. Entrapement of AuNP in polymeric nanocarriers facilitated the passive uptake in cancer cells after only 2 h incubation. In healthy rat, the encapsulation allowed increasing the gold concentration in the blood within the first hour after intravenous administration. Polymeric nanoparticles were sequestered in the liver and the spleen rather than the kidneys. T1-weighted magnetic resonance demonstrated that encapsulation process did not alter the contrast agent properties of gadolinium. The encapsulation of the gold nanoparticles in PLGA particles paves the way to innovative imaging-guided anticancer therapies in personalized medicine.

Functionalization of theranostic AGuIX® nanoparticles for PET/MRI/optical imaging.

A novel trifunctional imaging probe containing a chelator of radiometal for PET, a NIR heptamethine cyanine dye, and a bioconjugatable handle, has been grafted onto AGuIX® nanoparticles via a Michael addition reaction. The resulting functionalized nanoparticles have been fully characterized, radiolabelled with 64Cu, and evaluated in a mice TSA tumor model using multimodal (PET/MRI/optical) imaging.

Functionalization of Gadolinium Chelates Silica Nanoparticle through Silane Chemistry for Simultaneous MRI/64Cu PET Imaging.

Multimodal nanoprobes are highly demanded for biomedical imaging applications to enhance the reliability of the diagnostic results. Among different types of nano-objects, ultrasmall silica gadolinium nanoparticle (SiGdNP) appears as a safe, effective, and versatile platform for this purpose. In this study, a new method to functionalize SiGdNP based on silane chemistry has been reported. Two types of chelating silanes (APTES-DOTAGA and APTES-NODAGA) have been synthesized and grafted on SiGdNP by a simple one-step protocol. This functionalization strategy requires no other reactants or catalyzers and does not compromise the ultrasmall size of the particles. NODAGA-functionalized particle has been labeled with 64Cu isotope and injected intravenously to mice bearing TS/A carcinoma tumor for biodistribution study to demonstrate its potential as a bimodal MRI/PET imaging agent. A fully integrated MRI/PET system was used to simultaneously monitor the distribution of the particle. The results showed that the functionalized particle maintained properties of a renal clearable NP which could rapidly escape through kidneys and had low retention in other organs, especially liver, even though its accumulation in the tumor was modest.

One-pot direct synthesis for multifunctional ultrasmall hybrid silica nanoparticles.

Ultrasmall silica nanoparticles (NPs), having hydrodynamic diameters under 10 nm are promising inorganic platforms for imaging and therapeutic applications in medicine. Herein is described a new way for synthesizing such kind of NPs in a one-pot scalable protocol. These NPs bear DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) ligands on their surface that can chelate different metals suitable for a wide variety of biomedical applications. By varying the ratio of the precursors, the hydrodynamic diameters of the particles can be controlled over the range of 3 to 15 nm. The resulting NPs have been characterized extensively by complementary techniques like dynamic light scattering (DLS), high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), mass spectrometry (MS), phosphorescence titration, photophysical measurements, relaxometry and elemental analysis to elucidate their structures. Chelation of gadolinium (Gd) allowed its use as an effective intravenous contrast agent in MRI and was illustrated in mice bearing colorectal CT26 tumors. The new particle appears to sufficiently accumulate in the tumors and efficiently clear out of animal bodies through kidneys. This new synthesis is an original, time/material-saving and very flexible process that can be applied for creating versatile ultrasmall multifunctional nanomedicines.

Functionalization density dependent toxicity of oxidized multiwalled carbon nanotubes in a murine macrophage cell line.

The present study investigates the effect of functionalization density on the toxicity and cellular uptake of oxidized multiwalled carbon nanotubes (f-MWCNTs) in vitro. The toxicity of f-MWCNTs at varying degrees of carboxylation was assessed in a murine macrophage RAW 264.7 cell line, a model for liver Kupffer cells. In vitro cytotoxicity of oxidized MWCNTs was directly proportional to their functionalization density. The increased cytotoxicity was associated with a concurrent increase in the number of apoptotic cells and production of reactive nitrogen species (RNS). In contrast, reactive oxygen species (ROS) generation was the highest in the case of pristine MWCNTs and decreased with increased functionalization density. Quantitative cellular uptake studies indicated that endogenous ROS production was independent of the concentration of CNTs internalized by a specific cell population and was directly proportional to their surface hydrophobicity. Mechanistic studies suggested that cellular uptake of CNTs was critically charge-dependent and mediated through scavenger receptors, albeit the involvement of nonscavenger receptor mechanisms at low CNT concentrations and their saturation at the experimental concentration cannot be ruled out. A mathematical model was established to correlate between the cellular uptake of CNTs with their length and zeta potential. In an attempt to correlate the results of in vitro toxicity experiments with those of the in vivo toxicity in the mouse model, we found that the toxicity trends in vitro and in vivo are rather opposing. The apparent anomaly was explained on the basis of different experimental conditions and doses associated with cells under in vivo and in vitro culture conditions.

Carbon nanotubes in cancer theragnosis.

Carbon nanotubes as a unique and novel class of nanomaterials have shown considerable promise in cancer therapy and diagnosis amidst the myriad of nanocarriers. The presence of a large surface area enables the engineering of the surface of nanotubes, thus making them biocompatible, and large benefits can be harnessed from them. Together with their ability to encapsulate small molecules, stacking interactions and conjugation, nanotubes have improved the profile of anticancer agents. The propensity to absorb the body transparent NIR radiation also envisages photothermal and photoacoustic therapy using nanotubes. This article sheds light on the role of carbon nanotubes in cancer therapy and diagnosis based on recent findings.