Rhenium-186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma

Abstract

Although external beam radiation is an essential component to the current standard treatment of primary brain tumors, its application is limited by toxicity at doses more than 80 Gy. Recent studies have suggested that brachytherapy with liposomally encapsulated radionuclides may be of benefit, and we have reported methods to markedly increase the specific activity of rhenium-186 ((186)Re)-liposomes. To better characterize the potential delivery, toxicity, and efficacy of the highly specific activity of (186)Re-liposomes, we evaluated their intracranial application by convection-enhanced delivery in an orthotopic U87 glioma rat model. After establishing an optimal volume of 25 µL, we observed focal activity confined to the site of injection over a 96-hour period. Doses of up to 1850 Gy were administered without overt clinical or microscopic evidence of toxicity. Animals treated with (186)Re-liposomes had a median survival of 126 days (95% confidence interval [CI], 78.4-173 days), compared with 49 days (95% CI, 44-53 days) for controls. Log-rank analysis between these 2 groups was highly significant (P = .0013) and was even higher when 100 Gy was used as a cutoff (P < .0001). Noninvasive luciferase imaging as a surrogate for tumor volume showed a statistically significant separation in bioluminescence by 11 days after 100 Gy or less treatment between the experimental group and the control animals (χ(2)[1, N= 19] = 4.8; P = .029). MRI also supported this difference in tumor size. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model, with clear separation in bioluminescence at 6 days after treatment (χ(2)[1, N= 9] = 4.7; P = .029); median survival in treated animals was not reached at 120 days because lack of mortality, and log-rank analysis of survival was highly significant (P = .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis. These results support the potential efficacy of the highly specific activity of brachytherapy by (186)Re-liposomes convection-enhanced delivery in glioma.

Getting into the brain: liposome-based strategies for effective drug delivery across the blood&ndash;brain barrier

“…294 In this way, recent studies suggest that brachytherapy with liposomally encapsulated 186 Re or 188 Re isotopes holds significant promise for glioma therapy. 229,242,245 These studies demonstrated that animals treated with 186 Re or 188 Re liposomes had significantly prolonged survival, independent of the route of administration. 229,242 Also, 188 Re liposomes have been explored for diagnostic evaluation, revealing the potential of these liposomes as a future theranostic agent for brain gliomas.…”

“…229,242,245 These studies demonstrated that animals treated with 186 Re or 188 Re liposomes had significantly prolonged survival, independent of the route of administration. 229,242 Also, 188 Re liposomes have been explored for diagnostic evaluation, revealing the potential of these liposomes as a future theranostic agent for brain gliomas. 245 A wide variety of liposome-encapsulated anticancer drugs have also been developed for both experimental and clinical oncology.…”

Radiolabeled Nanoparticles in Nuclear Oncology

“…Due to the short path length of 186 Re, the behavior of this nanoconstruct was monitored with SPECT/CT imaging and gamma camera after radiolabeling with 99m Tc. Results showed no overt toxicity of surrounding tissues even at high doses [110]. Aptes-functionalized SPIO nanoparticles were modified with the N-hydroxysuccinimide (NHS) ester of polyethylene glycol maleimide (NHS-PEG-Mal).…”

Glioblastomas: are individual therapies required for individual tumors?

“…In recent in vitro or in vivo studies, they were used for the delivery of cytostatic drugs [57][58][59][60], cytotoxic peptides [61], antibodies [62,63], siRNA [64] or even oncolytic viruses [65], to deliver irradiation [66] or to improve imaging techniques [67]. The frame of this paper does not allow to discuss these new therapeutic opportunities in detail.…”