The size distribution and magnetic properties of ultra-small gadolinium oxide crystals (US-Gd 2 O 3 ) were studied, and the impact of polyethylene glycol capping on the relaxivity constants (r 1 , r 2 ) and signal intensity with this contrast agent was investigated. Size distribution and magnetic properties of US-Gd 2 O 3 nanocrystals were measured with a TEM and PPMS magnetometer. For relaxation studies, diethylene glycol (DEG)-capped US-Gd 2 O 3 nanocrystals were reacted with PEG-silane (MW 5000). Suspensions were adequately dialyzed in water to eliminate traces of Gd 3+ and surfactants. The particle hydrodynamic radius was measured with dynamic light scattering (DLS) and the proton relaxation times were measured with a 1.5 T MRI scanner. Parallel studies were performed with DEG-Gd 2 O 3 and PEG-silane-SPGO (Gd 2 O 3 , < 40 nm diameter). The small and narrow size distribution of US-Gd 2 O 3 was confirmed with TEM (∼3nm)andDLS.PEG-silane-US-Gd 2 O 3 relaxation parameters were twice as high as for Gd-DTPA and the r 2 /r 1 ratio was 1.4. PEG-silane-SPGO gave low r 1 relaxivities and high r 2 /r 1 ratios, less compatible with positive contrast agent requirements. Higher r 1 were obtained with PEG-silane in comparison to DEG-Gd 2 O 3 . Treatment of DEG-US-Gd 2 O 3 with PEG-silane provides enhanced relaxivity while preventing aggregation of the oxide cores. This study confirms that PEG-covered Gd 2 O 3 nanoparticles can be used for positively contrasted MR applications requiring stability, biocompatible coatings and nanocrystal functionalization.
Ultrasmall paramagnetic Gd(2)O(3) nanoparticles have been developed as contrast agents for molecular and cellular preclinical MRI procedures. These small particles (mean diameter <5 nm) have the highest Gd density of all paramagnetic contrast agents. They generate strong positive contrast enhancement in T(1)-weighted MRI. Signal enhancement is modulated by the interactions of water molecules with Gd, and very small particles provide the optimal surface-to-volume ratios necessary to reach high relaxivities. Conventional Gd(2)O(3) nanocrystal synthesis techniques, and subsequent polyethylene glycol (PEG) grafting procedures are usually time-consuming and recovery losses are also limitative. The present study reports on a new, fast, and efficient one-pot Gd(2)O(3) synthesis technique that provides PEGylated nanoparticles of very small size (mean diameter = 1.3 nm). Readily coated with PEG, the particles are colloidally stable in aqueous media and provide high longitudial relaxivities and small r(2)/r(1) ratios (r(1) = 14.2 mM(-1) s(-1) at 60 MHz; r(2)/r(1) = 1.20), ideal for T(1)-weighted MRI. In this study, F98 brain cancer cells (glioblastoma multiforme) were labeled with the contrast agent and implanted in vivo (mice brains). The labeled cells appeared positively contrasted at least 48 h after implantation. Each one of the implanted animals developed a brain tumor. The performance of PEG-Gd(2)O(3) was also compared with that of commercially available iron oxide nanoparticles. This study demonstrated that ultrasmall PEG-Gd(2)O(3) nanoparticles provide strong positive contrast enhancement in T(1)-weighted imaging, and allow the visualization of labeled cells implanted in vivo.
Mesoporous silica nanoparticles (MSNs) are considered as one of the most promising nanovectors for controlled drug delivery. For the design of ideal drug nanocarriers, several factors have to be taken into account, such as size and surface chemistry. Here, we report how MSNs surface functionalization and particle size critically affect the drug release performances and therapeutic capabilities. We illustrate the size effect of these functionalized MSNs on in vitro, intracellular, and in vivo drug release efficiency, as well as on nanoparticle and drug diffusion into the targeted tissues (tumor). For this, dispersible MSNs with different particle sizes (from 500 down to 45 nm), similar physicochemical properties (e.g., structural and textural properties), and high colloidal stability (even in saline conditions), were synthesized. Their surface was specifically functionalized with a phosphonate-silane according to a novel postgrafting strategy, for better control over loading and release of positively charged drugs. An efficient particle-size-dependent and pH-dependent release of the loaded drug (i.e., doxorubicin) was achieved in physiological conditions with phosphonated-MSNs compared to pure-MSNs. The cellular uptake efficiency is much higher with the smallest phosphonated-nanoparticles (45 nm). Furthermore, doxorubicin is efficiently released from the nanoparticles into the intracellular compartments, and the drug reaches the nucleus in a time- and particle size-dependent manner. Intratumoral diffusion of the developed nanoparticles, as well as the drug release and its diffusion into the tumor matrix, is clearly enhanced with the smallest phosphonated-nanoparticles (45 nm), leading ultimately to a superior cell and tumor growth inhibition.
Over the last few decades, gold nanoparticles (GNPs) have emerged as "radiosensitizers" in oncology. Radiosensitizers are additives that can enhance the effects of radiation on biological tissues treated with radiotherapy. The interaction of photons with GNPs leads to the emission of low-energy and short-range secondary electrons, which in turn increase the dose deposited in tissues. In this context, GNPs are the subject of intensive theoretical and experimental studies aiming at optimizing the parameters leading to greater dose enhancement and highest therapeutic effect. This review describes the main mechanisms occurring between photons and GNPs that lead to dose enhancement. The outcome of theoretical simulations of the interactions between GNPs and photons is presented. Finally, the findings of the most recent in vivo studies about interactions between GNPs and photon sources (e.g., external beams, brachytherapy sources, and molecules labeled with radioisotopes) are described. The advantages and challenges inherent to each of these approaches are discussed. Future directions, providing new guidelines for the successful translation of GNPs into clinical applications, are also highlighted.
Ultrasmall gadolinium oxide nanoparticles doped with terbium ions were synthesized by the polyol route and characterized as a potentially bifunctional material with both fluorescent and magnetic contrast agent properties. The structural, optical, and magnetic properties of the organic-acid-capped and PEGylated Gd 2 O 3 :Tb 3+ nanocrystals were studied by HR-TEM, XPS, EDX, IR, PL, and SQUID. The luminescent/fluorescent property of the particles is attributable to the Tb 3+ ion located on the crystal lattice of the Gd 2 O 3 host. The paramagnetic behavior of the particles is discussed. Pilot studies investigating the capability of the nanoparticles for fluorescent labeling of living cells and as a MRI contrast agent were also performed. Cells of two cell lines (THP-1 cells and fibroblasts) were incubated with the particles, and intracellular particle distribution was visualized by confocal microscopy. The MRI relaxivity of the PEGylated nanoparticles in water at low Gd concentration was assessed showing a higher T 1 relaxation rate compared to conventional Gd-DTPA chelates and comparable to that of undoped Gd 2 O 3 nanoparticles.
The majority of contrast agents used in magnetic resonance imaging (MRI) is based on the rare-earth element gadolinium. Gadolinium-based nanoparticles could find promising applications in pre-clinical diagnostic procedures of certain types of cancer, such as glioblastoma multiforme. This is one of the most malignant, lethal and poorly accessible forms of cancer. Recent advances in colloidal nanocrystal synthesis have led to the development of ultra-small crystals of gadolinium oxide (US-Gd(2)O(3), 2-3 nm diameter). As of today, this is the smallest and the densest of all Gd-containing nanoparticles. Cancer cells labeled with a sufficient quantity of this compound appear bright in T(1)-weighted MRI images. Here we demonstrate that US-Gd(2)O(3) can be used to label GL-261 glioblastoma multiforme cells, followed by localization and visualization in vivo using MRI. Very high amounts of Gd are efficiently internalized and retained in cells, as confirmed with TEM and ICP-MS. Labeled cells were visualized in vivo at 1.5 T using the chicken embryo model. This is one more step toward the development of "positively contrasted" cell tracking procedures with MRI.
Mesoporous silica nanoparticles (MSNs) have emerged as promising biomaterials for drug delivery and cell tracking applications, for which MRI is the medical imaging modality of choice. In this contribution, MRI contrast agents (DTPA‐Gd) and polyethylene glycol (PEG) are grafted selectively at the surface of MSNs, in order to achieve optimal relaxometric and drug loading performances. In fact, DTPA and PEG grafting procedures reported until now, have resulted in significant pore obstruction, which is detrimental to the drug delivery function of MSNs. This usually induces a dramatic decrease in surface area and pore volume, thus limiting drug loading capacity. Therefore, these molecules must be selectively grafted at the outer surface of MSNs. In this study, 3D pore network MSNs (MCM‐48‐type) are synthesized and functionalized with a straightforward and efficient grafting procedure in which DTPA and PEG are selectively grafted at the outer surface of MSNs. No pore blocking is observed, and more than 90% of surface area, pore volume and pore diameter are retained. The thus‐treated particles are colloidally stable in SBF and cell culture media, they are not cytotoxic and they have high drug loading capacity. Upon labeling with Gd, the nanoparticle suspensions have strong relaxometric properties (r2/r1 = 1.47, r1 = 23.97 mM−1 s−1), which confers a remarkable positive contrast enhancement potential to the compound. The particles could serve as efficient drug carriers, as demonstrated with a model of daunorubicin submitted to physiological conditions. The selective nanoparticle surface grafting procedures described in the present article represent a significant advance in the design of high colloidal stability silica‐based vectors with high drug loading capacity, which could provide novel theranostic nanocompounds.
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