RESUMO
Contrast agents are currently used in a variety of diagnostic imaging techniques, including computer tomography for early cancer detection. Radiopaque nanoparticles have recently been proposed as an alternative method to traditional contrast agents that may allow for long-term image tracking. The aim of this study was the preparation and characterization of aqueous suspensions of radiopaque nanoparticles made of poly(allyl amine) derivatives. Poly(allylamine) (PA) was modified by grafting either 4-iodobenzoyl chloride or 2,3,5-triiodobenzoyl chloride to make the polymer x-ray visible. Nanoparticles of the modified PA were prepared by the nanoprecipitation method and purified with respect to residual organic solvents. Stable suspensions of spherical particles of sub-micronic diameter were characterized by dynamic light scattering and transmission electron microscopy. In addition, the 4.5 wt% suspensions of nanoparticles displayed an x-ray visibility ranging between 185 and 235 HU. The non-clustering ability of the novel PA radiopaque nanoparticles suggests they could be injected via a catheter without clogging or sedimentation.
Assuntos
Meios de Contraste , Nanopartículas/química , Poliaminas/química , Cloretos/química , Meios de Contraste/síntese química , Meios de Contraste/química , Iodobenzoatos/química , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ácidos Tri-Iodobenzoicos/química , Espectroscopia por Absorção de Raios XRESUMO
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.
Assuntos
Ácido Láctico/química , Nanopartículas/química , Nêutrons , Polímeros/química , Compostos Radiofarmacêuticos/administração & dosagem , Rênio/química , Animais , Varredura Diferencial de Calorimetria , Feminino , Óxido Ferroso-Férrico/química , Membro Posterior/patologia , Membro Posterior/efeitos da radiação , Injeções Intramusculares , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos , Microscopia Eletrônica de Varredura , Peso Molecular , Nanopartículas/efeitos da radiação , Tamanho da Partícula , Transição de Fase/efeitos da radiação , Poliésteres , Porosidade/efeitos da radiação , Compostos Radiofarmacêuticos/química , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Esterilização , Propriedades de Superfície/efeitos da radiação , Temperatura de Transição/efeitos da radiação , Difração de Raios XRESUMO
Drug delivery systems can benefit from intrinsic radiopacity as this property will allow following up the diffusion path of the nanoparticles containing the therapeutic drug after their local administration. Herein, we report the synthesis of iodinated derivatives of cellulose acetate (CA) and their formulation into aqueous radiopaque nanoparticle suspensions. Modification and purification of CA with mono- or tri-iodobenzoyl chloride were characterized by NMR spectroscopy and elemental analysis of iodine. In particular, measurements of diffusion coefficients by the DOSY 2D NMR method allowed controlling the complete elimination of non-grafted iodinated materials. Pure radiopaque CA was successfully achieved with an iodine content varying between 14 and 32%. Aqueous suspensions of nanoparticles were successfully formed, characterized by being spherical, <100 nm in size and stable as a suspension over 3 months. The degree of substitution, in particular the triiodo moieties, imparted a good level of radiopacity whether in dry powder form (2627 HU) or as a nanoparticle suspension (298 HU). These values are comparable to radiopacity of systems reported in literature to be in vivo visible. Loading of paclitaxel was successfully attempted, suggesting that the developed radiopaque nanoparticles can ultimately function as a drug delivery system.