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Investigation of complexes with bone affinity using the In vivo generator system {sup 166} Dy/{sup 166} Ho; Investigacion de complejos con afinidad osea utilizando el Sistema de Generador in vivo {sup 166} Dy/{sup 166} Ho

Abstract

The importance of this original research lies in the fact that it has proven that the [{sup 166}Dy]Dy/{sup 166}Ho-EDTMP in vivo generator system is a stable complex that can be used as a therapeutic radiopharmaceutical. Multiple myeloma and other hematological malignancies have been treated by myeloablative radiotherapy/chemotherapy and subsequent stem cell transplantation. Bone-seeking radiopharmaceuticals such as {sup 166}Ho-DOTMP or {sup 153}Sm-DTMP, have been proposed for delivering ablative radiation doses to marrow in multiple myeloma and other hematological malignancies or have shown excellent results in palliative bone metastasis pain therapy, respectively. As lanthanides have similar chemical characteristics the phosphonate with bone affinity (EDTMP) labeled with Dy/Ho can be used for marrow ablation while causing minimal irradiation to normal organs. This in vivo generator system has not been previously reported. The aim of this research was to label EDTMP (ethylene diamine tetramethylene phosphonate) with {sup 166}Dy/{sup 166}Ho; to evaluate the in vitro and in vivo stability of both {sup 166}Dy-EDTMP and {sup 166}Ho-EDTMP complexes when the daughter {sup 166}Ho is formed as a dysprosium decay product; to determine the bone marrow cytotoxic and genotoxic effect in mice and to evaluate, by histopathology, the myeloablative potential of the [{sup 166}Dy]Dy/{sup 166}Ho-EDTMP in vivo  More>>
Authors:
Publication Date:
Jul 01, 2006
Product Type:
Thesis/Dissertation
Report Number:
INIS-MX-2247
Resource Relation:
Other Information: TH: Thesis (Ph.D.)
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; BONE MARROW; COMPLEXES; DIAGRAMS; DOSIMETRY; DYSPROSIUM 166; DYSPROSIUM COMPLEXES; EXPERIMENTAL DATA; HOLMIUM 166; HOLMIUM COMPLEXES; IN VIVO; KEV RANGE; MICE; NUCLEAR REACTIONS; RADIOCHEMICAL ANALYSIS; RADIOISOTOPE GENERATORS; SKELETON; TOXICITY
OSTI ID:
20899205
Research Organizations:
UAEM, Facultad de Medicina, 50000 Toluca, Estado de Mexico (Mexico)
Country of Origin:
Mexico
Language:
Spanish
Other Identifying Numbers:
TRN: MX0700279061402
Availability:
Available from INIS in electronic form
Submitting Site:
MXN
Size:
186 pages
Announcement Date:
Aug 28, 2007

Citation Formats

Pedraza L, M. Investigation of complexes with bone affinity using the In vivo generator system {sup 166} Dy/{sup 166} Ho; Investigacion de complejos con afinidad osea utilizando el Sistema de Generador in vivo {sup 166} Dy/{sup 166} Ho. Mexico: N. p., 2006. Web.
Pedraza L, M. Investigation of complexes with bone affinity using the In vivo generator system {sup 166} Dy/{sup 166} Ho; Investigacion de complejos con afinidad osea utilizando el Sistema de Generador in vivo {sup 166} Dy/{sup 166} Ho. Mexico.
Pedraza L, M. 2006. "Investigation of complexes with bone affinity using the In vivo generator system {sup 166} Dy/{sup 166} Ho; Investigacion de complejos con afinidad osea utilizando el Sistema de Generador in vivo {sup 166} Dy/{sup 166} Ho." Mexico.
@misc{etde_20899205,
title = {Investigation of complexes with bone affinity using the In vivo generator system {sup 166} Dy/{sup 166} Ho; Investigacion de complejos con afinidad osea utilizando el Sistema de Generador in vivo {sup 166} Dy/{sup 166} Ho}
author = {Pedraza L, M}
abstractNote = {The importance of this original research lies in the fact that it has proven that the [{sup 166}Dy]Dy/{sup 166}Ho-EDTMP in vivo generator system is a stable complex that can be used as a therapeutic radiopharmaceutical. Multiple myeloma and other hematological malignancies have been treated by myeloablative radiotherapy/chemotherapy and subsequent stem cell transplantation. Bone-seeking radiopharmaceuticals such as {sup 166}Ho-DOTMP or {sup 153}Sm-DTMP, have been proposed for delivering ablative radiation doses to marrow in multiple myeloma and other hematological malignancies or have shown excellent results in palliative bone metastasis pain therapy, respectively. As lanthanides have similar chemical characteristics the phosphonate with bone affinity (EDTMP) labeled with Dy/Ho can be used for marrow ablation while causing minimal irradiation to normal organs. This in vivo generator system has not been previously reported. The aim of this research was to label EDTMP (ethylene diamine tetramethylene phosphonate) with {sup 166}Dy/{sup 166}Ho; to evaluate the in vitro and in vivo stability of both {sup 166}Dy-EDTMP and {sup 166}Ho-EDTMP complexes when the daughter {sup 166}Ho is formed as a dysprosium decay product; to determine the bone marrow cytotoxic and genotoxic effect in mice and to evaluate, by histopathology, the myeloablative potential of the [{sup 166}Dy]Dy/{sup 166}Ho-EDTMP in vivo generator system. {sup 166}Dy was obtained by neutron irradiation of enriched {sup 164}Dy{sub 2}O{sub 3} in a TRIGA Mark III reactor. Labeling was carried out in an aqueous phosphate medium at pH 8.0 by addition of {sup 166}DyCl{sub 3} to EDTMP at a molar ratio 1:1.75, with >99 % radiochemical purity, as determined by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). In vitro studies demonstrated that {sup 166}Dy/{sup 166}Ho-EDTMP is unstable after dilution in saline but stable in human serum with no translocation of the daughter nucleus subsequent to {beta} decay of {sup 166}Dy, which could release free {sup 166}Ho{sup 3+}. Biodistribution in mice, after I.V. administration, showed a fast blood clearance of {sup 166}Dy/{sup 166}Ho-EDTMP, a rapid renal clearance and no accumulation in other organs. Bone uptake was 22 % and 20 % IA/g at 2 h and 10 d respectively. Biodistribution in mice, after I.P. administration, showed 12.45 {+-} 0.71 IA/g in bone and no activity in any other organ. The mice injected (I.P) for genotoxic, cytotoxic, dosimetric and biopsy studies had a mean bone uptake of 10.76 {+-} 0.96 after 12 d. To evaluate genotoxic and cytotoxic damage to the bone marrow quantification of the number of bone marrow micro nucleated reticulocytes (MN-RETs) and reticulocytes (RETs) in peripheral blood was carried out by flow cytometry. A group of BALB/c mice were intraperitoneally injected with the radiopharmaceutical and two groups of control animals were injected with the cold complex and with 0.9% sodium chloride, respectively. A base line blood sample and samples every 48 h for 1 days postinjection were taken. [{sup 166}Dy]Dy/{sup 166}Ho-EDTMP produced reduction of RETs and elevation of MN-RETs. Statistical results indicate a significant difference between treatments. The histology studies show that there was complete, or almost complete, acellularity, which signifies suppression of bone marrow activity. Theoretical bone marrow absorbed dose calculations indicate that the [{sup 166}Dy]Dy/{sup 166}Ho-EDTMP in vivo generator system would produce 7.80 times more radiation dose to marrow than that produced by {sup 153}Sm-EDTMP and 3.47 times more than {sup 166}Ho-DOTMP per unit of initial activity retained in the skeleton of the mice. Bone marrow absorbed dose was 18-23 Gy calculated with the MCNP4B Monte Carlo computer code. We conclude that [{sup 166}Dy]Dy/{sup 166}Ho-EDTMP forms a stable in vivo generator system which induces genotoxicity, cytotoxicity and severe myelosuppression in bone marrow mice. This research is a first step towards the use of therapeutic radiopharmaceuticals for bone marrow ablation, and since the therapeutic effect of the complex [{sup 166}Dy] Dy/{sup 166}Ho-EDTMP has been confirmed, a new line of research can be justified in clinical studies. (Author)}
place = {Mexico}
year = {2006}
month = {Jul}
}