Jaime Simon

Organis amine phosphonic acid complexes for the treatment of calcific tumors

Particle-emitting radionuclides, e.g. Samarium-153, have been complexed with organic aminoalkylenephosphonic acids wherein the nitrogen and phosphorus are interconnected by an alkylene group or substituted alkylene group. These complexes have been found useful in compositions for the therapeutic treatment of calcific tumors in animals.

153Sm radiotherapeutic bone agents

Samarium-153 is a radionuclide which can be produced in high yield by neutron irradiation and which has nuclear properties that make it attractive for use as a radiotherapeutic agent. Several phosphonate complexes of 153Sm were synthesized and characterized by electrophoresis and HPLC. A procedure based on cation exchange chromatography was developed for measuring complex yields. The complexes could be produced in yields greater than 99%, were anionic, and most exhibited a single HPLC peak.

Radioactive compositions for the treatment of calcific tumors

Certain particle-emitting radionuclides, e.g. Samarium-153, have been complexed with certain alkylenepolyaminocarboxylic acid chelants. Compositions containing these complexes have been found useful in the treatment of calcific tumors in animals. The stability constant, log K, of the useful complexes is from about 14 to about 17 and the molar ratio of chelant to radionuclide in the compositions is such that the chelant is present in an amount sufficient to inhibit uptake of the radionuclide by soft tissue.

Methods of producing high specific activity Sn-117m with commercial cyclotrons

Sn-117m is a theragnostic isotope of increasing interest. It has ideal imaging and therapeutic properties for many applications. Production of high specific activity Sn-117m can only be achieved with accelerators and the Sb(p,x) and Cd-116(α,3n) reactions provide the highest yields for this isotope. This paper describes the production and a new purification method for obtaining commercial quantities of Sn-117m via the Cd-116(α,3n) reaction. The purified Sn-117m has subsequently been chelated with an aminobenzyl derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and then conjugated with annexin V-128 to produce an agent for the diagnosis and treatment of vulnerable plaque.

A preclinical investigation of the saturation and dosimetry of 153Sm-DOTMP as a bone-seeking radiopharmaceutical.

INTRODUCTION The therapeutic potential of the bone-seeking radiopharmaceutical 153Sm-labeled 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid (153Sm-DOTMP) was assessed by measuring its dosage-dependent skeletal uptake at two chelant-to-metal ratios and its source organ residence times at a chelant-to-metal ratio of 1.5:1. A similar agent, 153Sm-labeled ethylenediaminetetramethylenephosphonic acid (153Sm-EDTMP), has been reported to exhibit dosage-limiting skeletal saturation. METHODS Sm-DOTMP was prepared with tracer activity of 153Sm and sufficient stable, unenriched Sm to simulate different activities. Cohorts of seven 280-g Sprague-Dawley rats were administered the equivalent of 296, 592, 888, 1184 and 1480 MBq (8, 16, 24, 32 and 40 mCi) at a fixed chelant-to-metal ratio of 1.5:1 and euthanized 3 h after administration. Cohorts of three 128-g Sprague-Dawley rats were administered equivalent dosages of 10.4, 592 and 888 (0.28, 16 and 32 mCi) at a fixed chelant-to-metal ratio of 270:1 and euthanized 2 h after administration. A simulated activity of 1480 MBq (40 mCi) at a chelant-to-metal ratio of 1.5:1 was administered to cohorts of seven rats that were euthanized at 2, 4, 24 or 48 h postadministration. The heart, lungs, liver, spleen, kidneys, small intestine, large intestine, urinary bladder, muscle and a femur were excised, weighed and counted. The data were analyzed to determine skeletal uptake and source organ residence times. RESULTS No statistically significant skeletal saturation was observed up to human-equivalent dosages of 370 GBq (10 Ci) at a chelant-to-metal ratio of 1.5:1, but the skeletal uptake dropped by 40% over the range of dosages at a chelant-to-metal ratio of 270:1. At a chelant-to-metal ratio of 1.5:1, the preferred ratio, the skeletal uptake fraction in rats was 0.408 (95% confidence interval 0.396-0.419) with an effective half-life of 47.3 h (95% confidence interval 42.3-53.7; the physical half-life of 153Sm is 46.3 h). Extrapolating to an adult human model, 52.9 GBq (1.43 Ci) of 153Sm-DOTMP would deliver 40 Gy to the red marrow. CONCLUSION 153Sm-DOTMP has dosimetry equivalent to that of 153Sm-EDTMP at low dosages, yet with no skeletal saturation at higher administered activities.

In vivo skeletal localization properties of 99mTc complexes of large phosphonate ligands

Tetramethylenephosphonate derivatives of norborane (TPNB) and dicyclopentadiene (TPDCPD) were shown to readily form stable chelates with 99mTc that had high and selective bone uptake. The skeletal uptake and blood clearance properties of 99mTc-TPNB were similar to 99mTc-MDP in both rats and rabbits. This suggests additional studies to further evaluate 99mTc-TPNB or perhaps other large-organic based multidentate phosphonate ligands as potential bone imaging agents is warranted.

Dosimetry of a 90Y-hydroxide liquid brachytherapy treatment approach to canine osteosarcoma using PET/CT

A new treatment strategy based on direct injections of (90)Y-hydroxide into the tumor bed in dogs with osteosarcoma was studied. Direct injections of the radiopharmaceutical into the tumor bed were made according to a pretreatment plan established using (18)F-FDG images. Using a special drill, cannulas were inserted going through tissue, tumor and bone. Using these cannulas, direct injections of the radiopharmaceutical were made. The in vivo biodistribution of (90)Y-hydroxide and the anatomical tumor bed were imaged using a time-of-flight (TOF) PET/CT scanner. The material properties of the tissues were estimated from corresponding CT numbers using an electron-density calibration. Radiation absorbed dose estimates were calculated using Monte Carlo methods where the biodistribution of the pharmaceutical from PET images was sampled using a collapsing 3-D rejection technique. Dose distributions in the tumor bed and surrounding tissues were calculated, showing significant heterogeneity with multiple hot spots at injection sites. Dose volume histograms showed that approximately 33.9% of bone and tumor and 70.2% of bone marrow and trabecular bone received an absorbed dose over 200Gy; approximately 3.2% of bone and tumor and 31.0% of bone marrow and trabecular bone received a total dose of over 1000Gy.