Bone marrow transplantation in dogs after radio-ablation with a new Ho- 166 amino phosphonic acid bone-seeking agent (DOTMP)

Abstract

beta-emitting 166Ho (t1/2 = 26.78 hours, E(beta)max = 1.8 MeV) complexed with the phosphonic acid chelator, 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid) (DOTMP) at a ligand-to-metal ratio of 1.5:1 binds to bone. This radioactive complex is a marrow-ablating radiopharmaceutical that appears useful for preparation of bone marrow (BM) transplant recipients without the morbidity usually associated with total body irradiation preparatory regimens. We have found with seven splenectomized young adult beagle dogs that a 166Ho radiopharmaceutical dosage of 370 MBq/kg body weight provides an initial skeletal radioactivity burden of at least 1.5 GBq/kg skeleton and results in complete ablation of hematopoietic marrow cell populations within 7 days. The beta particle flux distribution in BM-forming skeletal tissue is not uniform. Red marrow radiation doses varied from 30 to 115 Gy as estimated by direct radioassay and autoradiographic analyses of both bone biopsies and postmortem samples; the median value of 61 Gy agreed with our theoretical expectations. In vivo radioactivity distribution was evaluated with nuclear imaging methods. Apparently, normal hematopoiesis was restored in three dogs with autologous BM transplants performed 5 to 6 days after administration of the marrow ablative radiopharmaceutical, 166Ho-DOTMP. BM biopsies at 7 to 10 months posttransplantation indicate continued normal hematopoietic activity.

Therapeutic Radiopharmaceuticals

“…Since these highly penetrating β particles destroy bone marrow cells remote from the surface of the bone where 166 Ho-DOTMP deposits, it can be used for eradication of multiple myeloma cells and the normal stem cells located in the marrow space. 154,155,215,216 In contrast, the β-particles emitted by 153 Sm-EDTMP located on bone surfaces following administration of extremely high doses of 153 Sm-EDTMP (i.e., .1.0 mCi/kg or 37 MBq/ kg) were found to be too low for complete ablation of the normal bone marrow in dogs. 177,218 The choice of DOTMP as the chelating agent (and not EDTMP) to deliver 166 Ho to the skeleton was made based on the mass of material to be administered.…”

“…The use of sufficient quantities of 166 Ho (i.e., g2 Ci or 74 GBq) that are required for marrow ablation would require several milligrams of holmium target. 197,215 Since the 153 Sm-EDTMP preparation for human application uses nearly a 300-fold ligand excess, the amount of EDTMP required relative to the mass of holmium would be excessive. 153,189 In contrast, DOTMP has been shown to form a kinetically inert complex with 166 Ho.…”

The various therapeutic applications of the medical isotope holmium-166: a narrative review

“…When combined with radioactive isotopes, the complexes can deliver high levels of radiation to bone and bone marrow, leaving normal tissues unaffected. The isotope 166 Ho has been conjugated to several bone-seeking agents for bone marrow ablation such as EDTMP (ethylene-diamine-tetramethylene phosphonic acid) (Sohaib et al 2011; Bahrami-Samani et al 2010; Appelbaum et al 1992; Louw et al 1996), DOTMP (Bayouth et al 1995a; Bayouth et al 1995b; Parks et al 1993; Giralt et al 2003; Breitz et al 2006; Rajendran et al 2002; Ueno et al 2009; Breitz et al 2003a), TTHMP (triethylene tetramine hexa (methylene phos- phonic acid)) (Yousefnia et al 2014), PAM (pamidronate) (Vaez-Tehrani et al 2016), APDDMP (N,N-dimethylenephosphonate-1-hydroxy-4-aminopropylidene-diphosphonate) (Marques et al 2006; Zeevaart et al 2001), among others. The preparation of the 166 Ho-radiolabelled complexes is performed very similarly with the different bone-seeking agents.…”

“…In an animal study on splenectomized young adult beagle dogs, a complete ablation of hematopoietic marrow was seen within 7 days after receiving a radiopharmaceutical dosage of 370 MBq/kg body weight of [ 166 Ho]Ho DOTMP (Parks et al 1993). The pharmacokinetics, biodistribution and absorbed dose estimation of the [ 166 Ho]Ho DOTMP complex has also been studied in six patients suffering from multiple myeloma.…”

Радиофармпрепараты На Основе Полиаминофосфоновых Кислот, Меченных Альфа-, Бета- И Гамма-Излучающими Радионуклидами (Обзор)

“…ÄÎÒÌÔ îáðàçóåò êèíåòè÷åñêè èíåðòíûé êîìïëåêñ ñ 166 Íî. Äëÿ åãî ïîëó÷åíèÿ ìîëÿðíîå ñîîòíîøåíèå ëèãàíä -ìåòàëë íå ïðåâûøàåò 1,5:1 [59], òîãäà êàê äëÿ ñèíòåçà 166 Íî-ÝÄÒÌÔ ìîëÿðíîå ñîîòíîøåíèå ëèãàíä -ìåòàëë áóäåò ñîñòàâëÿòü 267:1 [60].…”