Positive contrast with therapeutic iron nanoparticles at 4.7 T.

OBJECT: The purpose of the study was to show the feasibility of a positive contrast technique GRadient echo Acquisition for Superparamagnetic particles with Positive contrast (GRASP), for a specific type of magnetic particles, designed for tumor treatment under MRI monitoring. MATERIALS AND METHODS: A simulation study was performed to estimate field inhomogeneity intensities induced by increasing concentrations of particles at different static fields. The GRASP sequence was setup on a 4.7 T Bruker system during an in vitro study. Six mice, included in the in vivo study received particles in the left calf muscle and contrast enhancement values, were measured over three time points, for both negative and positive contrast images. RESULTS: Comparing values obtained by simulation at 1.5, 3, and 4.7 T, the strongest susceptibility effect was obtained at 4.7 T. Based on simulation and in vitro data, gradient settings were chosen for in vivo imaging. GRASP resulted in bright regions at and around the injection site, and higher enhancement values, compared to standard GRE imaging. Both contrasts were useful for longitudinal follow-up, with a faster decay over time for GRASP. CONCLUSION: The magnetic nanoparticles for drug delivery can be detected using positive contrast. Combining imaging sequences, i.e., negative contrast and susceptibility methods, increased imaging specificity of large magnetic particles and enabled their follow-up for theranostic applications.

Microencapsulation of cytarabine using poly(ethylene glycol)-poly(epsilon-caprolactone) diblock copolymers as surfactant agents.

BACKGROUND: The high water solubility and the low molecular weight of cytarabine (Ara-C) are major obstacles against its particulate formulation as a result of its low affinity to the commonly used hydrophobic polymers. METHODS: Biodegradable cytarabine loaded-microparticles (Ara-C MPs) were elaborated using poly(-caprolactone) (PCL) and monomethoxy polyethylene glycol (mPEG)-PCL diblock copolymer in order to increase the hydrophilicity of the polymeric matrix. For this purpose, a series of mPEG-PCL diblock copolymers with different PCL block lengths were synthesized. Compositions and molecular weights of obtained copolymers were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, size exclusion chromatography, and size exclusion chromatography-multi-angle laser light scattering. Ara-C MPs were prepared by double emulsion-solvent evaporation method. The effects of varying PCL block lengths on microparticle encapsulation efficiency, size, and zeta potential were evaluated. RESULTS: Increasing the PCL block lengths of copolymers substantially increased the Ara-C encapsulation efficiency and the microparticle size but it decreased their zeta potential. Microparticles were spherical in shape, with a smooth surface and composed of homogenously distributed Ara-C-containing aqueous domains in the polymer matrix. The in vitro drug release kinetics of the optimized microparticles showed a hyperbolic profile with an initial burst release. CONCLUSION: These results showed the important role of the amphiphilic diblock copolymers as stabilizing agent in the encapsulation of Ara-C in PCL microparticles, suggesting their potential use for the microparticulate formulations of other small hydrophilic bioactive molecules.

Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer.

The recent developments of nuclear medicine in oncology have involved numerous investigations of novel specific tumor-targeting radiopharmaceuticals as a major area of interest for both cancer imaging and therapy. The current progress in pharmaceutical nanotechnology field has been exploited in the design of tumor-targeting nanoscale and microscale carriers being able to deliver radionuclides in a selective manner to improve the outcome of cancer diagnosis and treatment. These carriers include chiefly, among others, liposomes, microparticles, nanoparticles, micelles, dendrimers and hydrogels. Furthermore, combining the more recent nuclear imaging multimodalities which provide high sensitivity and anatomical resolution such as PET/CT (positron emission tomography/computed tomography) and SPECT/CT (combined single photon emission computed tomography/computed tomography system) with the use of these specific tumor-targeting carriers constitutes a promising rally which will, hopefully in the near future, allow for earlier tumor detection, better treatment planning and more powerful therapy. In this review, we highlight the use, limitations, advantages and possible improvements of different nano- and microcarriers as potential vehicles for radionuclides delivery in cancer nuclear imaging and radiotherapy.

Dirhenium decacarbonyl-loaded PLLA nanoparticles: influence of neutron irradiation and preliminary in vivo administration by the TMT technique.

In a previous study, we have described the elaboration of PLLA-based nanoparticles loaded with non radioactive dirhenium decacarbonyl [Re(2)(CO)(10)], a novel neutron-activatable radiopharmaceutical dosage form for intra-tumoral radiotherapy. These nanoparticles are designed for a neutron irradiation which can be carried out in a nuclear reactor facility. This new paper describes the neutron irradiation influence on these Re(2)(CO)(10)-loaded PLLA nanoparticles. The loaded nanoparticles with 23% (w/w) of metallic rhenium have shown to remain stable and separated and to keep out their sphericity at the lower neutron flux (1x10(11)n/cm(2)/s for 0.5h) which was used for rhenium content determination (neutron activation analysis, NAA). However, when loaded nanoparticles were irradiated at the higher neutron flux (1.45x10(13)n/cm(2)/s, 1h), they have shown to be partially coagglomerated and some pores appeared at their surface. Furthermore, DSC results showed a decrease in the PLLA melting point and melting enthalpy in both blank and loaded nanoparticles indicating a decrease in polymer crystallinity. In addition, the polymer molecular weights (M(n), M(w)) decreased after irradiation but without largely affecting the polymer polydispersity index (P.I.) which indicated that an irradiation-induced PLLA chain scission had occurred in a random way. The XRD patterns of irradiated PLLA provided another proof of polymer loss of crystallinity. FTIR spectra results have shown that irradiated nanoparticles retained the chemical identity of the used Re(2)(CO)(10) and PLLA despite the reduction in polymer crystallinity and molecular weight. Nanoparticles suspending after irradiation became also more difficult, but it was properly achievable by adding PVA (1%) and ethanol (10%) into the dispersing medium. Moreover, after 24h incubation of different irradiated nanoparticles in two different culture mediums, visual examination did not show bacterial growth indicating that applied neutron irradiation, yielding an absorbed dose of 450kGy, can be a terminal method for nanoparticles sterilisation. Thereafter, in a preliminary in vivo experiment, superparamagnetic non radioactive nanoparticles loaded with Re(2)(CO)(10) and oleic-acid coated magnetite have been successfully injected into a mice animal model via targeted multi therapy (TMT) technique which would be our selected administration method for future in vivo studies. In conclusion, although some induced neutron irradiation damage to nanoparticles occurs, dirhenium decacarbonyl-loaded PLLA nanoparticles retain their chemical identity and remain almost as re-dispersible and injectable nanoparticles by the TMT technique. These nanoparticles represent a novel interesting candidate for local intra-tumoral radiotherapy.

Holmium-loaded PLLA nanoparticles for intratumoral radiotherapy via the TMT technique: preparation, characterization, and stability evaluation after neutron irradiation.

This article describes the preparation of biocompatible radioactive holmium-loaded particles with appropriate nanoscale size for radionuclide intratumoral administration by the targeted multitherapy (TMT) technique. For this objective, holmium acetylacetonate has been encapsulated in poly-L-lactide (PLLA)-based nanoparticles (NP) by oil-in-water emulsion-solvent evaporation method. NP sizes ranged between 100 and 1,100 m being suitable for the TMT administration method. Elemental holmium loading was found to be around 18% wt/wt and the holmium acetylacetonate trihydrate (HoAcAc) encapsulation efficacy was about 90%. Different experiments demonstrated an amorphous state of HoAcAc after incorporation in NPs. The NPs were irradiated in a nuclear reactor with a neutron flux of 1.1 x 10(13) n/cm(2)/s for 1 h, which yielded a specific activity of about 27.4 GBq/g of NPs being sufficient for our desired application. Microscopic analysis of irradiated NPs showed some alteration after neutron irradiation as some NPs looked partially coagglomerated and a few pores appeared at their surface because of the locally released heat in the irradiation vials. Furthermore, differential scanning calorimetry (DSC) results indicated a clear decrease in PLLA melting point and melting enthalpy reflecting a decrease in polymer crystallinity. This was accompanied by a clear decrease in polymer molecular weights, which can be ascribed to a radiation-induced chain scission mechanism. However, interestingly, other experiments confirmed the chemical identity retention of both HoAcAc and PLLA in irradiated NPs despite this detected decrease in the polymer crystallinity and molecular weight. Although neutron irradiation has induced some NPs damage, these NPs kept out their overall chemical composition, and their size distribution remained suitable for the TMT administration technique. Coupled with the TMT technique, these NPs may represent a novel potential radiopharmaceutical agent for intratumoral radiotherapy.

Paclitaxel-loaded microparticles for intratumoral administration via the TMT technique: preparation, characterization, and preliminary antitumoral evaluation.

In our pursuit to develop suitable therapeutic particulate systems for intratumoral delivery by the targeted multi-therapy (TMT) technique, we describe the preparation of paclitaxel-loaded poly(D,L-lactic-co-glycolic) acid (PLGA) microparticles (MPs) (drug loading 35-38%, wt/wt; size 0.7-5 microm). Magnetite (15%, wt/wt) was also incorporated in some preparations for a future magnetic resonance imaging (MRI)-guided delivery. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) experiments showed that paclitaxel was not encapsulated in its initial crystalline form. The paclitaxel in vitro release pattern showed a biphasic tendency with a burst effect followed by a sustained release (28% released amount after 1 month), which was accompanied with MP erosion and degradation signs as confirmed by scanning electronic microscopy (SEM) micrographs. The paclitaxel-loaded MPs demonstrated a dose-dependent antitumor effect on human uterine cancer cells, with an IC(50) value relatively close to that of commercial Taxol. This paclitaxel delivery system represents a potent antiprofilerative and radiosensitizer agent for intratumoral administration via the TMT technique.

Nucleoside analogue delivery systems in cancer therapy.

Nucleoside analogues (NAs) are important agents in the treatment of hematological malignancies. They are prodrugs that require activation by phosphorylation. Their rapid catabolism, cell resistance and overdistribution in the body jeopardize nucleoside analogue chemotherapy. Accordingly, therapeutic doses of NAs are particularly high and regularly have to be increased, resulting in severe toxicity and narrow therapeutic index. The major challenge is to concentrate the drug at the tumour site, avoiding its distribution to normal tissues. New drug carriers and biomaterials are being developed to overcome some of these obstacles. This review highlights novel NA delivery systems and discusses new technologies that could improve NA cancer therapy.

Preparation and characterization of radioactive dirhenium decacarbonyl-loaded PLLA nanoparticles for radionuclide intra-tumoral therapy.

This study describes the development of biocompatible radioactive rhenium-loaded nanoparticles for radionuclide anti-cancer therapy. To achieve this goal, dirhenium decacarbonyl [Re2(CO)10] has been encapsulated in poly(L-lactide) based nanoparticles by an oil-in-water emulsion-solvent evaporation method. A 3(3) factorial design method was applied to investigate the influence of both the proceeding and formulation parameters including the stirring speed and the concentration of both the PLLA polymer and the poly(vinyl alcohol) stabiliser on both nanoparticles size and the Re2(CO)10 encapsulation efficacy. The factorial design results attributed a clear negative effect for the stirring speed and the stabiliser concentration on the nanoparticles size while the polymer concentration exhibited a positive one. Regarding the Re2(CO)10 encapsulation efficacy, higher values were obtained when higher polymer concentrations, lower stabiliser concentrations or slower stirring speeds were applied in the preparation. Different tests were thereafter performed to characterize the Re2(CO)10-loaded nanoparticles. The nanoparticles size, being experimentally controlled by the above mentioned parameters, ranged between 330 and 1500 nm and the maximum rhenium loading was 24% by nanoparticles weight as determined by atomic emission assays and neutron activation analysis. Furthermore, the rhenium distribution within nanoparticles has been shown to be homogeneous as confirmed by the energy dispersive X-ray spectrometry. DSC assays demonstrated that Re2(CO)10 was encapsulated in its crystalline initial state. Other experiments including FT-IR and NMR did not show interactions between PLLA and Re2(CO)10. To render them radioactive, these nanoparticles have been bombarded with a neutron flux of 1.45x10(13) n/cm2/s during 1 h. The SEM micrographs of nanoparticles after neutron bombardment showed that the nanoparticles remained spherical and separated but slightly misshaped. These applied neutron activation conditions yielded a specific activity of about 32.5 GBq per gram of nanoparticles. Preliminary estimations allow us to think that a sole injection of 50 mg of these activated nanoparticles into a brain tumor model (4.2 cm diameter) would deliver a tumor absorbed dose of up to 47 Gy. In conclusion, these dirhenium decacarbonyl-loaded nanoparticles represent a novel promising tool for radionuclide anti-cancer therapy.

Elaboration of PLLA-based superparamagnetic nanoparticles: characterization, magnetic behaviour study and in vitro relaxivity evaluation.

Oleic acid-coated magnetite has been encapsulated in biocompatible magnetic nanoparticles (MNP) by a simple emulsion evaporation method. The different parameters influencing the particles size were studied. Between these parameters, the stirring speed and the polymer concentration were found to influence positively or negatively, respectively, the MNP size which varied between 320 and 1500nm. The magnetite encapsulation efficacy was about than 90% yielding a high magnetite loading of up to 30% (w/w). X-ray diffraction showed that magnetite crystalline pattern was not modified after emulsification and solvent evaporation. The X-ray photoelectron spectroscopy (XPS) results indicated the presence of less than 0.1% of iron atoms at the nanoparticles surface. Vibration simple magnetometer (VSM) showed a superparamagnetic behaviour of the MNP and a saturation magnetization increasing with the increased magnetite amount used in formulation. Moreover, T(1) and T(2) relaxivities of MNP (4.7T, 20 degrees C) were 1.7+/-0.1 and 228.3+/-13.1s(-1)mM(-1), respectively, rendering them in the same category of known negative contrast agents which shorten the T(2) relaxation time. Therefore, by using an appropriate anticancer drug in their formulation, these magnetic nanoparticles can present a promising mean for simultaneous tumor imaging, drug delivery and real time monitoring of therapeutic effect.

Preparation, characterization and surface study of poly-epsilon caprolactone magnetic microparticles.

Magnetic microparticles (MMP) have shown to be applied in increasing applications in various fields of biotechnology and medicine. One of their most promising utilization is the magnetic resonance imaging (MRI) in which superparamagnetic substances as magnetite are used in a nanometric size (less than 30 nm) and encapsulated within locally injected biodegradable microparticles. In this paper, magnetite has been encapsulated in polymer-based microparticles. The MMP have been prepared by an emulsion evaporation method. The different parameters influencing the particles size were investigated. The size was found to decrease as the stirring speed or the stabilizer amount (to certain limit) increases. The encapsulation efficacy was more than 90% yielding a magnetite loading of up to 30%, w/w. The X-ray photoelectron spectroscopy (XPS) showed less than 2% of iron atoms at the microparticles surface. The zeta potential response of MMP towards pH variation was very similar to that of magnetite-free microparticles confirming the encapsulation of magnetite within the microparticles. X-ray diffraction assays showed that magnetite crystalline structure was conserved after emulsification and MMP formation. Vibration simple magnetometer (VSM) showed a superparamagnetic profile of the MMP with a magnetic saturation increasing with the increased magnetite amount in the microparticles. These magnetic microparticles can enable clinicians to control microparticles distribution after a local administration in tumors by MRI. They can also be administered to target a defined tumor area by focusing a magnetic field on the surfaces covering the cancerous tissue.