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

Abstract

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 (1 × 10 11 n/cm 2/s for 0.5 h) which was used for rhenium content determination (neutron activation analysis, NAA). However, when loaded nanoparticles were irradiated at the higher neutron flux (1.45 × 10 13 n/cm 2/s, 1 h), 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 24 h 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 450 kGy, 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.