Hamoudeh Misara, Fessi Hatem, Salim Hani, Barbos Dumitru
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.
Drug Dev Ind Pharm. 2008 Aug;34(8):796-806. doi: 10.1080/03639040801918623.
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.
本文描述了通过靶向多疗法（TMT）技术制备具有适当纳米级尺寸的生物相容性载钬放射性粒子，用于瘤内放射性核素给药。为此，通过水包油乳液-溶剂蒸发法将乙酰丙酮钬封装在聚-L-丙交酯（PLLA）基纳米颗粒（NP）中。NP的尺寸在100至1100 m之间，适合TMT给药方法。发现钬元素负载量约为18%（重量/重量），乙酰丙酮钬三水合物（HoAcAc）的包封率约为90%。不同实验表明，HoAcAc掺入NP后呈无定形状态。NP在核反应堆中以1.1×10(13) n/cm(2)/s的中子通量辐照1小时，产生的比活度约为27.4 GBq/g的NP，足以满足我们的预期应用。对辐照后NP的显微镜分析表明，中子辐照后出现了一些变化，一些NP看起来部分凝聚，由于辐照瓶中局部释放的热量，其表面出现了一些孔隙。此外，差示扫描量热法（DSC）结果表明，PLLA的熔点和熔化焓明显降低，反映出聚合物结晶度的降低。这伴随着聚合物分子量的明显降低，这可归因于辐射诱导的链断裂机制。然而，有趣的是，其他实验证实，尽管检测到聚合物结晶度和分子量降低，但辐照后NP中HoAcAc和PLLA的化学特性保持不变。尽管中子辐照引起了一些NP损伤，但这些NP保持了其整体化学成分，其尺寸分布仍然适合TMT给药技术。与TMT技术相结合，这些NP可能代表一种用于瘤内放射治疗的新型潜在放射性药物。
