2. Academic Validation
  3. γ-Tocotrienol-Loaded Liposomes for Radioprotection from Hematopoietic Side Effects Caused by Radiotherapeutic Drugs

γ-Tocotrienol-Loaded Liposomes for Radioprotection from Hematopoietic Side Effects Caused by Radiotherapeutic Drugs

  • J Nucl Med. 2021 Apr;62(4):584-590. doi: 10.2967/jnumed.120.244681.
Sang-Gyu Lee 1,  Teja Muralidhar Kalidindi 1,  Hanzhi Lou 2,  Kishore Gangangari 1 3,  Blesida Punzalan 1,  Ariana Bitton 4,  Casey J Lee 4,  Hebert A Vargas 1,  Soobin Park 5,  Lisa Bodei 1,  Michael G Kharas 2,  Vijay K Singh 6 7,  Naga Vara Kishore Pillarsetty 1 8,  Steven M Larson 9 2 8
Affiliations

Affiliations

  • 1 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 2 Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 3 Department of Chemistry, Hunter College, City University of New York, New York, New York.
  • 4 New York University, New York, New York.
  • 5 Hunter College, New York, New York.
  • 6 Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
  • 7 Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and.
  • 8 Department of Radiology, Weill Cornell Medical College, New York, New York.
  • 9 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York [email protected].
PMID: 32826318 DOI: 10.2967/jnumed.120.244681
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.

Keywords

bone marrow; liposome; radiation protection; γ-tocotrienol.

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