RESUMEN
Background: Targeted α particle therapy using long-lived in vivo α particle generators is cytotoxic to target tissues. However, the redistribution of released radioactive daughters through the circulation should be considered. A mathematical model was developed to describe the physicochemical kinetics of 212Pb-labeled pharmaceuticals and its radioactive daughters. Materials and Methods: A bolus of 212Pb-labeled pharmaceuticals injected in a developed compartmental model was simulated. The contributions of chelated and free radionuclides to the total released energy were investigated for different dissociation fractions of 212Bi for different chelators, for example, 36% for DOTA. The compartmental model was applied to describe a 212Bi retention study and to assess the stability of the 212Bi-1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (212Bi-DOTAM) complex after ß- decay of 212Pb. Results: The simulation of the injection showed that α emissions contribute 75% to the total released energy, mostly from 212Po (72%). The simulation of the 212Bi retention study showed that (16 ± 5)% of 212Bi atoms dissociate from the 212Bi-DOTAM complexes. The fractions of energies released by free radionuclides were 21% and 38% for DOTAM and DOTA chelators, respectively. Conclusion: The developed α particle generator model allows for simulating the radioactive kinetics of labeled and unlabeled pharmaceuticals being released from the chelating system due to a preceding disintegration.
Asunto(s)
Partículas alfa , Quelantes , Humanos , Quelantes/química , Plomo , Radioisótopos/química , Modelos Teóricos , Preparaciones Farmacéuticas , RadiofármacosRESUMEN
Relapse of chronic lymphocytic leukaemia and non-Hodgkin's lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy with 212Pb-NNV003 presented in this study combines cytotoxic α-particles from 212Pb, with the anti-CD37 antibody NNV003, targeting B-cell malignancies. The goal of this study was to explore 212Pb-NNV003 for treatment of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma in preclinical mouse models.An anti-proliferative effect of 212Pb-NNV003 was observed in both chronic lymphocytic leukaemia (MEC-2) and Burkitt's lymphoma (Daudi) cells in vitro. In biodistribution experiments, accumulation of 212Pb-NNV003 was 23%ID/g and 16%ID/g in Daudi and MEC-2 tumours 24 h post injection. In two intravenous animal models 90% of the mice treated with a single injection of 212Pb-NNV003 were alive 28 weeks post cell injection. Median survival times of control groups were 5-9 weeks. There was no significant difference between different specific activities of 212Pb-NNV003 with regards to therapeutic effect or toxicity. For therapeutically effective activities, a transient haematological toxicity was observed. This study shows that 212Pb-NNV003 is effective and safe in preclinical models of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma, warranting future clinical testing.
Asunto(s)
Radioisótopos de Plomo/uso terapéutico , Leucemia Linfoide/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Animales , Antígenos de Neoplasias , Antineoplásicos Inmunológicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cetuximab/uso terapéutico , Femenino , Humanos , Leucemia Linfoide/metabolismo , Linfoma no Hodgkin/metabolismo , Ratones , Ratones SCID , Radiometría , Tetraspaninas/antagonistas & inhibidoresRESUMEN
Somatostatin analogues have been examined as a treatment for somatostatin receptor overexpressing tumors for years; specifically, octreotate (TATE) and octreotide (TOC). Several versions of these analogues coupled to beta or gamma nuclides are currently used as imaging agents, as treatments with peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumors or are being explored in preclinical and clinical settings. Our study describes the use of 212Pb-DOTAMTATE, the octreotate analogue, in combination with 212Pb, the parent of an alpha emitter. Preclinical studies demonstrated tumor targeting of 212Pb-DOTAMTATE of >20% ID/g up to 24 hours post drug injection. The addition of kidney protection agents, including l-lysine and l-arginine decreases drug accumulation in the kidneys and the addition of ascorbic acid to the chelation mixture reduces oxidation of the drug product. 212Pb-DOTAMTATE displays a favorable toxicity profile with single-dose injections of 20 µCi showing 100% survival and with nontoxic cumulative doses up to 45 µCi, when fractionated into three smaller doses of 15 µCi. In an initial efficacy study, a single 10 µCi injection of 212Pb-DOTAMTATE extended the mean survival 2.4-fold. Efficacy was enhanced by giving three treatment cycles of 212Pb-DOTAMTATE and reducing the time between injections to two weeks. Efficacy was optimized further by the addition of a chemo-sensitizing agent, 5-fluorouracil, given in combination with three cycles of 10 µCi 212Pb-DOTAMTATE. These conditions led to 79% of the animals being tumor free at the end of the 31-week study suggesting that 212Pb-DOTAMTATE alone or in combination with a chemotherapeutic may have positive clinical implications.