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. 2008 Oct;35(10):1838-46.
doi: 10.1007/s00259-008-0735-z. Epub 2008 May 9.

188Re-loaded lipid nanocapsules as a promising radiopharmaceutical carrier for internal radiotherapy of malignant gliomas

E Allard  1 , F Hindre, C Passirani, L Lemaire, N Lepareur, N Noiret, P Menei, J-P Benoit
Affiliations

188Re-loaded lipid nanocapsules as a promising radiopharmaceutical carrier for internal radiotherapy of malignant gliomas

E Allard et al. Eur J Nucl Med Mol Imaging. 2008 Oct.

Abstract

Purpose: Lipid nanocapsules (LNC) entrapping lipophilic complexes of (188)Re ((188)Re(S(3)CPh)(2)(S(2)CPh) [(188)Re-SSS]) were investigated as a novel radiopharmaceutical carrier for internal radiation therapy of malignant gliomas. The present study was designed to evaluate the efficacy of intra-cerebral administration of (188)Re-SSS LNC by means of convection-enhanced delivery (CED) on a 9L rat brain tumour model.

Methods: Female Fischer rats with 9L glioma were treated with a single injection of (188)Re-SSS LNC by CED 6 days after cell implantation. Rats were put into random groups according to the dose infused: 12, 10, 8 and 3 Gy in comparison with blank LNC, perrhenate solution (4 Gy) and non-treated animals. The radionuclide brain retention level was evaluated by measuring (188)Re elimination in faeces and urine over 72 h after the CED injection. The therapeutic effect of (188)Re-SSS LNC was assessed based on animal survival.

Results: CED of (188)Re perrhenate solution resulted in rapid drug clearance with a brain T (1/2) of 7h. In contrast, when administered in LNC, (188)Re tissue retention was greatly prolonged, with only 10% of the injected dose being eliminated at 72 h. Rat median survival was significantly improved for the group treated with 8 Gy (188)Re-SSS LNC compared to the control group and blank LNC-treated animals. The increase in the median survival time was about 80% compared to the control group; 33% of the animals were long-term survivors. The dose of 8 Gy proved to be a very effective dose, between toxic (10-12 Gy) and ineffective (3-4 Gy) doses.

Conclusions: These findings show that CED of (188)Re-loaded LNC is a safe and potent anti-tumour system for treating malignant gliomas. Our data are the first to show the in vivo efficacy of (188)Re internal radiotherapy for the treatment of brain malignancy.

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Figures

Figure 1
Figure 1
Graph of Kaplan-Meier survival curve associated with treatment of rat bearing 9L glioma with single CED infusion of blank LNC, 188Re-SSS LNC or 188Re perrhenate. On day 6, rats were treated with 12 Gy 188Re-SSS LNC (n=4;-⊕-), 10 Gy 188Re-SSS LNC (n=4;-×- ), 8 Gy 188Re-SSS LNC (n=6; -▾-), 3 Gy 188Re-SSS LNC (n=5; -⋄-), 4 Gy 188Re perrhenate (n=4; -◂-), blank LNC (n=7; -○-), or no treatment (n=8; -▪-). Four rats (*) were long-term survivors (>100 days).
Figure 2
Figure 2
188Re elimination measured in urine and faeces by a gamma counter during 72h after CED infusion of 188Re perrhenate, and 188Re-SSS LNC in 9L glioma bearing rats 6 days post 9L cell implantation (A). Repartition between urines and faeces for 188Re perrhenate solution (B) and 188Re-SSS LNC (C).
Figure 3
Figure 3
Evolution of weight measurements during 30 days after 9L inoculation in rats which received 188Re-SSS LNC or 188Re perrhenate solution for internal radiotherapy.
Figure 4
Figure 4
T2-weighted axial magnetic resonance images of a non treated rat (A) at Day 16 after 9L inoculation compared with a long-term survivor rat which received 10 Gy 188Re-SSS LNC at Day 16 (B).
Figure 5
Figure 5
T2-weighted axial magnetic resonance images of one long-term survivor rat which received 10 Gy 188Re-SSS LNC at Days 83, 100, and 140, respectively for A, B and C. D represents the 1H-MR spectra realised at Day 100. Signal intensities of creatine (Cr), N-acetyl aspartate (NAA) and Lactate (Lac) were compared between affected striatum (i) and safe striatum (ii). iii represents the difference between the two spectra.
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