Abstract
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 γ-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy. 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. The radioprotection efficacy of GT3-Nano was assessed after acute 137Cs whole-body irradiation at a sublethal (4 Gy), a lethal (9 Gy), or a single high-dose administration of 153Sm-ethylenediamine-N,N,N',N'-tetrakis(methylene phosphonic acid) (EDTMP). Flow cytometry and fluorescence microscopy were used to analyze hematopoietic cell population dynamics and the cellular site of GT3-Nano localization in the spleen and bone marrow, respectively. Results: Bone marrow uptake and retention (percentage injected dose per gram of tissue) at 24 h was 6.98 ± 2.34 for 64Cu-GT3-Nano and 7.44 ± 2.52 for 3H-GT3-Nano. GT3-Nano administered 24 h before or after 4 Gy of total-body irradiation (TBI) promoted rapid and complete hematopoietic recovery, whereas 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 the bone marrow indicated that progenitor bone marrow cells MPP2 and CMP 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 the marrow-suppressive effects of sublethal and lethal TBI in mice. GT3-Nano can facilitate rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent 153Sm-EDTMP.
Highlights
Radioiodine-131 therapy for well-differentiated thyroid cancer has played a seminal role in the creation of nuclear medicine as a medical sub-specialty and, for decades, was the only high-dose targeted radionuclide therapy (TRT) regimen considered standard of care in oncology
Characterization of GT3-Nano formulation and GT3 release kinetics of 3H-labeled GT3-Nano GT3 can be incorporated into bone marrow-targeting liposomes by adding up to 20 mole% GT3 in lipid mixture. 64Cu labeling and stability of the colloidal suspension of GT3-Nano was measured and found to be nearly identical to bone marrow-targeting liposome (Fig. 1)
We reasoned that if we loaded liposomal particles with a known radiation mitigator/protector such as GT3, we could protect these sinusoidal endothelial cells as well as other essential stem cell types in the spleen and bone marrow that are responsible for restoration of hematopoietic function after radiation damage by TRT radiopharmaceuticals, as well as other types of acute radiation injury
Summary
Radioiodine-131 therapy for well-differentiated thyroid cancer has played a seminal role in the creation of nuclear medicine as a medical sub-specialty and, for decades, was the only high-dose targeted radionuclide therapy (TRT) regimen considered standard of care in oncology. E.g., reports on [177Lu]-DOTATATE indicate that mild to moderate hematopoietic complications may be expected in the majority of patients, while severe grade 3/4 cytopenia occurs in a small but significant (11%) patient population and appears to be correlated with bone marrow dose [4,5]. Myeloproliferative events, such as myelodysplastic syndrome (MDS) and acute leukemia, have been reported in 2.35% and 1.1% of patients in a 30 [1-180]-month median follow-up [6]. Similar considerations are postulated for other types of radionuclide therapies [7]
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