Abstract
BackgroundNeutron capture therapy for glioblastoma has focused mainly on the use of 10B as neutron capture isotope. However, 157Gd offers several advantages over boron, such as higher cross section for thermal neutrons and the possibility to perform magnetic resonance imaging during neutron irradiation, thereby combining therapy and diagnostics. We have developed different liposomal formulations of gadolinium-DTPA (Magnevist®) for application in neutron capture therapy of glioblastoma. The formulations were characterized physicochemically and tested in vitro in a glioma cell model for their effectiveness.MethodsLiposomes entrapping gadolinium-DTPA as neutron capture agent were manufactured via lipid/film-extrusion method and characterized with regard to size, entrapment efficiency and in vitro release. For neutron irradiation, F98 and LN229 glioma cells were incubated with the newly developed liposomes and subsequently irradiated at the thermal column of the TRIGA reactor in Mainz. The dose rate derived from neutron irradiation with 157Gd as neutron capturing agent was calculated via Monte Carlo simulations and set in relation to the respective cell survival.ResultsThe liposomal Gd-DTPA reduced cell survival of F98 and LN229 cells significantly. Differences in liposomal composition of the formulations led to distinctly different outcome in cell survival. The amount of cellular Gd was not at all times proportional to cell survival, indicating that intracellular deposition of formulated Gd has a major influence on cell survival. The majority of the dose contribution arises from photon cross irradiation compared to a very small Gd-related dose.ConclusionsLiposomal gadolinium formulations represent a promising approach for neutron capture therapy of glioblastoma cells. The liposome composition determines the uptake and the survival of cells following radiation, presumably due to different uptake pathways of liposomes and intracellular deposition of gadolinium-DTPA. Due to the small range of the Auger and conversion electrons produced in 157Gd capture, the proximity of Gd-atoms to cellular DNA is a crucial factor for infliction of lethal damage. Furthermore, Gd-containing liposomes may be used as MRI contrast agents for diagnostic purposes and surveillance of tumor targeting, thus enabling a theranostic approach for tumor therapy.
Highlights
Neutron capture therapy for glioblastoma has focused mainly on the use of 10B as neutron capture isotope
Gadolinium provides several advantages over boron, namely the highest cross section for thermal neutrons known for stable elements (157Gd: 255,000 barn) and following administration, the possibility to trace the agent through the body via magnetic resonance imaging (MRI), thereby allowing a theranostic approach to cancer treatment [2]
Entrapment efficiencies of the Gd-chelate complex were comparable for all tested liposome compositions (9.4 to 10.2%) except for the slightly lower entrapment in Cardiolipin-containing formulation (6.6%)
Summary
Neutron capture therapy for glioblastoma has focused mainly on the use of 10B as neutron capture isotope. Gadolinium provides several advantages over boron, namely the highest cross section for thermal neutrons known for stable elements (157Gd: 255,000 barn) and following administration, the possibility to trace the agent through the body via magnetic resonance imaging (MRI), thereby allowing a theranostic approach to cancer treatment [2]. Auger- and inner conversion electrons are thought to be the main contributors to the cell killing effect of Gd-NCT. It was shown by Martin and co-authors 1989 [3] that the Auger electrons from Gd-neutron capture reaction led to DNA double-strand breaks and subsequent cell death. In addition to the shortranged Auger and inner conversion electrons, the 157Gd neutron capture reaction produces long-range gamma rays of different energies up to 8 MeV whose flight ranges are not limited to a single cell. An additional dose may be produced by self-absorption of the gamma rays by the gadolinium load at the tumor site, generating further Auger electrons via photoelectric effect
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