title: Holmium-loaded PLLA nanoparticles for intratumoral radiotherapy via the TMT technique: preparation, characterization, and stability evaluation after neutron irradiation.
abstract: 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.
authors.affiliation: Pharmaceutical Technology Group, Laboratoire d'Automatique et de Genie de Procedes, UMR CNRS, Universite Claude Bernard Lyon1, ISPBL-Faculte de Pharmacie de Lyon, Villeurbanne Cedex, France.
authors.forename: Misara
authors.initials: M
authors.lastname: Hamoudeh
authors.forename: Hatem
authors.initials: H
authors.lastname: Fessi
authors.forename: Hani
authors.initials: H
authors.lastname: Salim
authors.forename: Dumitru
authors.initials: D
authors.lastname: Barbos
mesh_terms: D001672:Biocompatible Materials; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006695:Holmium / Q000737:chemistry*; D006885:Hydroxybutyrates / Q000737:chemistry*; D053758:Nanoparticles; D036103:Nanotechnology / Q000379:methods*; D010316:Particle Size; D010422:Pentanones / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D001672:Biocompatible Materials; D006885:Hydroxybutyrates; D010422:Pentanones; D011091:Polyesters; D019275:Radiopharmaceuticals; C049529:acetyl acetonate; C033616:poly(lactide); D006695:Holmium