Abstract
Rationale: With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow—both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of gamma-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy (TRT). Methods: GT3 was loaded into liposomes using passive loading. [64Cu]-GT3-Nano and 3H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. Radioprotection efficacy of GT3-Nano was assessed after acute 137Cs whole-body irradiation at sublethal (4 Gy), lethal (9 Gy), or single high-dose [153Sm]-EDTMP administration. Flow cytometry was used to analyze hematopoietic cell population dynamics and fluorescence microscopy was used to assess the cellular site of GT3-Nano localization in the spleen and bone marrow. Results: Bone marrow uptake and retention of [64Cu]-GT3-Nano was 6.98 ± 2.34 %ID/g, while [3H]-GT3-Nano uptake and retention was 7.44 ± 2.52 %ID/g at 24 h, respectively. GT3-Nano administered 24 hours before or after 4 Gy TBI promoted rapid and complete hematopoietic recovery while recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9 Gy TBI. Flow cytometry of bone marrow indicated progenitor bone marrow cells MPP2 and CMP cells were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. Conclusion: GT3-Nano is highly effective in mitigating marrow suppressive effects of sub-lethal and lethal TBI in mice. GT3-Nano can aid in rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent [153Sm]-EDTMP.
- Hematology
- Radiation Safety
- Radiobiology/Dosimetry
- Bone marrow
- gamma-tocotrienol
- liposome
- radiation protection
Footnotes
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