Estudio biocinético y dosimétrico de un kit de producción local de 177Lu-EDTMP para su uso como agente paliativo del dolor / Biokinetic and dosimetric study of 177Lu-EDTMP in the palliative treatment of skeletal metastasis

Los radiofármacos con afinidad por el tejido óseo como el ácido etilen-diamino-tetrametilen-fosfónico (EDTMP) marcado con radioisótopos emisores beta- han demostrado su eficacia en el tratamiento paliativo de las metástasis óseas. Se realizó un estudio biocinético y dosimétrico del 177Lu-EDTMP en ratones NIH. Los resultados obtenidos fueron extrapolados a humanos. Se estimó la dosis absorbida en órganos para dos modelos: un hombre adulto y una mujer adulta. El 177Lu-EDTMP posee una selectiva captación en hueso, una rápida eliminación en sangre e insignificante captación en tejidos no óseos. La dosis en hueso estimada para el hombre se encuentra entre 14,7-15,3 cGy/mCi y entre 19,6-20,4 cGy/mCi para la mujer. La toxicidad en médula ósea representa el factor limitante de este tipo de terapia, y para evitar superar la dosis máxima que ésta puede tolerar (200 cGy), se encontró que la actividad máxima segura de 177Lu-EDTMP que puede ser inyectada al hombre (73,9Kg), corresponde a un valor de 1,01 mCi/kg y a un valor de 1,25 mCi/Kg para la mujer (56,9Kg).

Bone-seeking radiopharmaceuticals like the ethylenediaminetetramethylene phosphonic acid (EDTMP) labeled with beta--emitting radioisotopes have demonstrated their efficacy in the palliative treatment of skeletal metastasis. A biokinetic and dosimetric study of 177Lu-EDTMP in NIH mice was performed. The results obtained were extrapolated to human. We estimate the absorbed doses in organs for two models: an adult male and an adult female. 177Lu-EDTMP has a selective uptake in bone, a rapid elimination from blood and negligible uptake in non-skeletal tissues. The estimated dose in bone is between 14.7-15.3 cGy/mCi for men and between 19.6-20.4 cGy/mCi for women. Bone marrow toxicity represents the limiting factor in this kind of therapy, and to avoid exceed the maximum dose it can tolerate (200 cGy), it was found that the maximum safe activity of 177Lu-EDTMP to be injected to male (73.9 kg), corresponds to a value of 1.01 mCi/kg and a value of 1.25 mCi/kg for female (56.9 kg).

Ensayos in-vitro e in-vivo del péptido marcado 177Lu-DOTA-Sustancia P y evaluación de los cálculos dosimétricos en la etapa preclínica / Tests in-vitro and in vivo of 177Lu-DOTA-SP labeled peptide and evaluation of the dosimetric calculations in the preclinical stage

Introducción: El péptido Sustancia P (SP) es el ligando principal de los receptores de neurokininas tipo 1, los cuales se encuentran sobreexpresados en los gliomas malignos. Método: Se obtuvo 177Lu-DOTA-SP con elevada pureza radioquímica. Se realizaron biodistribuciones en ratones normales a diferentes tiempos. Se calcularon las dosis absorbidas para los diferentes órganos del ratón (cGy/uCi). Utilizando los métodos de escalación por tiempo (A) y extrapolación directa (B), se obtuvieron las dosis en los diferentes órganos humanos. Se calcularon las máximas dosis tolerables en función de los órganos críticos (mCi/kg). Resultados: La máxima actividad tolerable que puede ser inyectada sin producir toxicidad en riñones es 11,2 mCi/kg (hombre adulto) y 11,4 mCi/kg (mujer adulta) según el método A y de 47,2 mCi/kg y 56,2 mCi/kg, respectivamente según el método B. Conclusiones: Hasta el momento se pudo obtener 177Lu-DOTA-SP con Ae= 0,05mCi/ ug de péptido. La misma puede aumentarse utilizando el 177LuCl3 de mayor actividad específica.

Introduction: Substance P (SP) is the main ligand of neurokin type 1 receptors, which are consistently overexpressed in malignant gliomas. Method: 177Lu-DOTA-SP was obtained with high radiochemical purity. Biodistribution in normal mice at different times, were done. Absorbed doses were calculated for different mice organs (cGy/uCi). Absorbed doses in human organs were calculated using two different methods, time scaling (A) and data extrapolation (B). Maximum tolerated doses were calculated according to critical organs (mCi/kg). Results: Maximum tolerated dose that can be injected without kidney toxicity is 11,2 mCi/kg (adult man) and 11,4 mCi/kg (adult woman) according to method A and 47,2 mCi/kg, 56,2 mCi/kg, respectively according to method B. Conclusion: So far, 177Lu-DOTA-SP was achieved with a specific activity (S.a) of 0,05 mCi/ ug of peptide. This S.a can be increased using 177LuCl3 of higher specific activity.

Intracoronary radionuclide therapy with liquid 188Re-filled balloons; radiopharmaceutical and dosimetric studies

Percutaneous transluminal coronary angioplasty associated with radioactive liquid-filled balloons has demostrated to be useful to inhibit the growth of neointimal tissue. The present study pursued optimizing the relation risk/benefit during a procedure of brachytherapy with 188Re associated to angioplasty. Since the possibility of balloon rupture exists, to increase the security during the treatment different agents such as 188Re-DTPA, 188Re-Citrate and 188Re-EC vs 188ReO4 were evaluated. Dosimetric studies using Mirdose 3, after iv injection to Wistar rats, evaluation of a number of safety requirements in order to estimate radiation dose delivered to operating personnel and absorbed doses estimated by Monte Carlo method (PENELOPE). It is a safe procedure, both for the patient and the working staff; in case of ballon rupture the use of the above mentioned radiopharmaceuticals increases its security. 188Re beta emitor achieves a local dosis, diminishing the dose in healthy tissue.

Labeling of DOTA-Tyr3-octreotate with 177Lu - stability and biodistribution study

The labeling with 177Lu and quality control procedures to produced DOTA (1,4,7,10-N,N´,N´´,N´´´, tetraazaciclododecane tetraacetic acid) coupled octreotate labeled peptide was evaluated. The labeling was performed using 30µg of DOTA-Tyr3-octreotate and 500 and 1110 MBq of 177Lu, buffered with sodium acetate/acetic acid 0.4M pH 4.5 for 20 minutes at 100ºC. The radiochemical purity was determined by ITLC na HPLC. Biological distribution studies were performed on Nude mices with tumours (AR42J rat pancreatic tumour cells) by invasive method. The stability of the 177Lu-DOTA-Tyr3-octreotate was followed by 7 days, and in both labeling procedures, the radiochemical purity were superior than 98 percent. Biodistribution studies showed fast blood clearance and the kidneys were the critical organs. The uptake in tumour were significant after 24 hours and the labeled peptide showed high in vivo stability.

Respuesta analgésica y efectos secundarios en pacientes con metástasis osteoblásticas tratados con samario-153 etilendiaminotetrametilenfosfato / Samarium 153 EDTMP in the treatment of metastatic bone pain: evaluation of analgesic response and secondary effects

Background: Samarium153 EDTMP, a beta and gamma emitter, is used in the palliative therapy of painful bone metastases. Aim: To evaluate the analgesic effects and myelotoxicity of Samarium153 EDTMP in patients with prostate, breast and renal carcinoma. Patients and methods: Twenty patients with bone metastases (11 males), aged 65 years old as a mean, received a 1 to 2 mCi/kg intravenous dose of Samarium153 EDTMP, produced in Chile. Patients were followed thereafter during 4 to 40 weeks. Pain was assessed using a visual analogue scale. Results: Pain decreased from a score of 6.4 prior to treatment, to 2.7 at the fourth week of therapy and the effect lasted a mean of 12.5 weeks. Myelotoxicity was observed in 68percent of cases (WHO stage I in 21 percent, stage II in 37 percent, stage III in 11percent and no patients in stage IV). Platelets were the most affected series and neutrophils the least affected. Cell counts returned to normal between the sixth and eighth week. Seventy nine percent of patients decreased their basal analgesic therapy at the sixth week and 88percent did so at the eighth week. Forty one percent of these patients discontinued all analgesics. Conclusions: Samarium153 EDTMP is effective in the treatment of pain in patients with bone metastases and its myelotoxicity is low to moderate. It should be considered as a therapy for this type of pain, with the precaution of performing periodical bood counts