RESUMEN
BACKGROUND: Diffusing alpha-emitters radiation therapy (DaRT) is a novel brachytherapy technique that leverages the diffusive flow of 224Ra progeny within the tumor volume over the course of the treatment. Cell killing is achieved by the emitted alpha particles that have a short range in tissue and high linear energy transfer. The current proposed absorbed dose calculation method for DaRT is based on a diffusion-leakage (DL) model that neglects absorbed dose from beta particles. PURPOSE: This work aimed to couple the DL model with dose point kernels (DPKs) to account for dose from beta particles as well as to consider the non-local deposition of energy. METHODS: The DaRT seed was modeled using COMSOL multiphysics and the DL model was implemented to extract the spatial information of the diffusing daughters. Using Monte-Carlo (MC) methods, DPKs were generated for 212Pb, 212Bi, and their progenies since they were considered to be the dominant beta emitters in the 224Ra radioactive decay chain. A convolution operation was performed between the integrated number densities of the diffusing daughters and DPKs to calculate the total absorbed dose over a 30-day treatment period. Both high-diffusion and low-diffusion cases were considered. RESULTS: The calculated DPKs showed non-negligible energy deposition over several millimeters from the source location. An absorbed dose >10 Gy was deposited within a 1.8 mm radial distance for the low diffusion case and a 2.2 mm radial distance for the high diffusion case. When the DPK method was compared with the local energy deposition method that solely considered dose from alpha particles, differences above 1 Gy were found within 1.3 and 1.8 mm radial distances from the surface of the source for the low diffusion and high diffusion cases, respectively. CONCLUSIONS: The proposed method enhances the accuracy of the dose calculation method used for the DaRT technique.
Asunto(s)
Partículas alfa , Método de Montecarlo , Radiometría , Dosificación Radioterapéutica , Partículas alfa/uso terapéutico , Difusión , Braquiterapia/métodos , Radioisótopos de Plomo/uso terapéutico , Bismuto/uso terapéutico , Humanos , Partículas beta/uso terapéutico , Planificación de la Radioterapia Asistida por Computador/métodosRESUMEN
We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212Pb, an in vivo generator of alpha-emitting 212Bi and 212Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212Pb-TCMC-YS5. We characterized 212Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) 212Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi 212Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Radioinmunoterapia , Masculino , Animales , Humanos , Radioinmunoterapia/métodos , Plomo , Partículas alfa , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radioisótopos de Plomo/uso terapéutico , Proteína Cofactora de MembranaRESUMEN
Two radiopharmaceutical preparations were developed on the basis of artificial targeted polypeptide ZHER2 specific to HER2/neu tumor marker and radionuclides 177Lu (ZHER2-HSA-chelator-177Lu) or 212Pb (ZHER2-HSA-chelator-212Pb). The objective was to evaluate in vitro the cytotoxic activity of the targeted radiopharmaceuticals using two cultured human breast cancer cell lines with different expression of HER2/neu: SK-BR3 (high expression of HER2/neu) and MCF-7 (low expression of HER2/neu). It was shown that the cytotoxic effect of both preparations was significantly higher against the SK-BR-3 cells. The cytotoxicity correlated with the incubation period (it was higher after 72 h than after 24 h) and was significantly more pronounced in comparison with activity of radionuclide salts without a specific ligand. In vivo preclinical study of these pharmaceuticals seems to be very promising in animals with xenografted tumors showing high expression of HER2/neu marker.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/radioterapia , Inmunotoxinas/uso terapéutico , Radioisótopos de Plomo/uso terapéutico , Lutecio/uso terapéutico , Radioisótopos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Radioisótopos de Plomo/química , Células MCF-7 , Terapia Molecular Dirigida/métodos , Radiofármacos/uso terapéutico , Especificidad por SustratoRESUMEN
Alpha-particle emitting radionuclides continue to be the subject of medical research because of their high energy and short range of action that facilitate effective cancer therapies. Radium-224 (224Ra) is one such candidate that has been considered for use in combating micrometastatic disease. In our prior studies, a suspension of 224Ra-labeled calcium carbonate (CaCO3) microparticles was designed as a local therapy for disseminated cancers in the peritoneal cavity. The progenies of 224Ra, of which radon-220 (220Rn) is the first, together contribute three of the four alpha particles in the decay chain. The proximity of the progenies to the delivery site at the time of decay of the 224Ra-CaCO3 microparticles can impact its therapeutic efficacy. In this study, we show that the diffusion of 220Rn was reduced in labeled CaCO3 suspensions as compared with cationic 224Ra solutions, both in air and liquid volumes. Furthermore, free-floating lead-212 (212Pb), which is generated from released 220Rn, had the potential to be re-adsorbed onto CaCO3 microparticles. Under conditions mimicking an in vivo environment, more than 70% of the 212Pb was adsorbed onto the CaCO3 at microparticle concentrations above 1 mg/mL. Further, the diffusion of 220Rn seemed to occur whether the microparticles were labeled by the surface adsorption of 224Ra or if the 224Ra was incorporated into the bulk of the microparticles. The therapeutic benefit of differently labeled 224Ra-CaCO3 microparticles after intraperitoneal administration was similar when examined in mice bearing intraperitoneal ovarian cancer xenografts. In conclusion, both the release of 220Rn and re-adsorption of 212Pb are features that have implications for the radiotherapeutic use of 224Ra-labeled CaCO3 microparticles. The release of 220Rn through diffusion may extend the effective range of alpha-particle dose deposition, and the re-adsorption of the longer lived 212Pb onto the CaCO3 microparticles may enhance the retention of this nuclide in the peritoneal cavity.
Asunto(s)
Carbonato de Calcio/química , Radioisótopos de Plomo/uso terapéutico , Neoplasias Ováricas/radioterapia , Radón/uso terapéutico , Animales , Apoptosis , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias Ováricas/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.
Asunto(s)
Radioisótopos de Plomo/uso terapéutico , Neoplasias , Radiofármacos/uso terapéutico , Bismuto , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Medicina de Precisión , Radioisótopos , Distribución TisularRESUMEN
BACKGROUND: New treatments combating bone and extraskeletal metastases are needed for patients with metastatic castration-resistant prostate cancer. The majority of metastases overexpress prostate-specific membrane antigen (PSMA), making it an ideal candidate for targeted radionuclide therapy. OBJECTIVE: The aim of this study was to test a novel liquid 224Ra/212Pb-generator for the rapid preparation of a dual-alpha targeting solution. Here, PSMA-targeting ligands are labelled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, natural bone-seeking 224Ra targeting sclerotic bone metastases and 212Pb-chelated PSMA ligands targeting PSMA-expressing tumour cells are obtained. METHODS: Two PSMA-targeting ligands, the p-SCN-Bn-TCMC-PSMA ligand (NG001), specifically developed for chelating 212Pb, and the most clinically used DOTA-based PSMA-617 were labelled with 212Pb. Radiolabelling and targeting potential were investigated in situ, in vitro (PSMA-positive C4-2 human prostate cancer cells) and in vivo (athymic mice bearing C4-2 xenografts). RESULTS: NG001 was rapidly labelled with 212Pb (radiochemical purity >94% at concentrations of ≥15 µg/ml) using the liquid 224Ra/212Pb-generator. The high radiochemical purity and stability of [212Pb]Pb- NG001 were demonstrated over 48 hours in the presence of ascorbic acid and albumin. Similar binding abilities of the 212Pb-labelled ligands were observed in C4-2 cells. The PSMA ligands displayed comparable tumour uptake after 2 hours, but NG001 showed a 3.5-fold lower kidney uptake than PSMA- 617. Radium-224 was not chelated and, hence, showed high uptake in bones. CONCLUSION: A fast method for the labelling of PSMA ligands with 212Pb in the 224Ra/212Pb-solution was developed. Thus, further in vivo studies with dual tumour targeting by alpha-particles are warranted.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Radioisótopos de Plomo/uso terapéutico , Antígeno Prostático Específico/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Radio (Elemento)/uso terapéutico , Torio/uso terapéutico , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Ligandos , Masculino , Ratones , Ratones Desnudos , Radiofármacos/uso terapéuticoRESUMEN
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
Diffusing alpha-emitters radiation therapy ('DaRT') is a new cancer-treatment modality, which enables treating solid tumors by alpha particles. The treatment utilizes implantable seeds embedded with a low activity of radium-224. Each seed continuously emits the short-lived alpha-emitting daughters of radium-224, which spread over several mm around it, creating a 'kill region' of high alpha-particle dose. DaRT is presently tested in clinical trials, starting with locally advanced and recurrent squamous cell carcinoma (SCC) of the skin and head and neck, with promising results with respect to both efficacy and safety. This work aims to provide a simple model which can serve as a zero-order approximation for DaRT dosimetry, allowing for calculating the macroscopic alpha particle dose of a point source, as a basis for more realistic source geometries. The model consists of diffusion equations for radon-220, lead-212 and bismuth-212, with the other short-lived daughters in local secular equilibrium. For simplicity, the medium is assumed to be homogeneous, isotropic and time-independent. Vascular effects are accounted for by effective diffusion and clearance terms. To leading order, the alpha particle dose can be described by simple analytic expressions, which shed light on the underlying physics. The calculations demonstrate that, for a reasonable choice of model parameters, therapeutic alpha-particle dose levels are obtained over a region measuring 4-7 mm in diameter for sources carrying a few [Formula: see text]Ci of radium-224. The model predictions served as the basis for treatment planning in the SCC clinical trial, where treatments employing DaRT seeds carrying 2 [Formula: see text]Ci of radium-224 and spaced 5 mm apart resulted in â¼[Formula: see text] complete response of the treated tumors with no observed radiation-induced toxicity. The promising results of the SCC clinical trial indicate that in spite of its approximate nature, the simple diffusion-based dosimetry model provides a quantitative starting point for DaRT treatment planning.
Asunto(s)
Partículas alfa/uso terapéutico , Braquiterapia/métodos , Neoplasias de Cabeza y Cuello/radioterapia , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Bismuto/uso terapéutico , Difusión , Fraccionamiento de la Dosis de Radiación , Humanos , Cinética , Radioisótopos de Plomo/uso terapéutico , Radioisótopos/uso terapéutico , Radiometría , Radio (Elemento)/uso terapéutico , Radón/uso terapéutico , Torio/uso terapéuticoRESUMEN
PURPOSE: Targeted alpha therapy (TAT) takes advantage of the short-range and high-linear energy transfer of α-particles and is increasingly used, especially for the treatment of metastatic lesions. Nevertheless, dosimetry of α-emitters is challenging for the very same reasons, even for in vitro experiments. Assumptions, such as the uniformity of the distribution of radionuclides in the culture medium, are commonly made, which could have a profound impact on dose calculations. In this study we measured the spatial distribution of α-emitting 212 Pb coupled to an anti-VCAM-1 antibody (212 Pb-αVCAM-1) and its evolution over time in the context of in vitro irradiations. METHODS: Two experimental setups were implemented without cells to measure α-particle count rates and energy spectra in culture medium containing 15 kBq of 212 Pb-α-VCAM-1. Silicon detectors were placed above and below cell culture dishes for 20 h. One of the dishes had a 2.5-µm-thick mylar-base allowing easy detection of the α-particles. Monte Carlo simulations were performed to analyze experimental spectra. Experimental setups were modeled and α-energy spectra were simulated in the silicon detectors for different decay positions in the culture medium. Simulated spectra were then used to deconvolute experimental spectra to determine the spatial distribution of 212 Pb-αVCAM-1 in the medium. This distribution was finally used to calculate the dose deposition in cell culture experiments. RESULTS: Experimental count rates and energy spectra showed differences in measurements taken at the top and the bottom of dishes and temporal variations that did not follow 212 Pb decay. The radionuclide spatial distribution was shown to be composed of a uniform distribution and concentration gradients at the top and the bottom, which were subjected to temporal variations that may be explained by gravity and electrostatic attraction. The absorbed dose in cells calculated from this distribution was compared with the dose expected for a uniform and static distribution and found to be 1.75 times higher, which is highly significant to interpret biological observations. CONCLUSIONS: This study demonstrated that accurate dosimetry of α-emitters requires the experimental determination of radionuclide spatial and temporal distribution and highlighted that in vitro assessment of dose for TAT cannot only rely on a uniform distribution of activity in the culture medium. The reliability and reproducibility of future experiments should benefit from specifically developed dosimetry tools and methods.
Asunto(s)
Partículas alfa/uso terapéutico , Inmunoconjugados/uso terapéutico , Radioisótopos de Plomo/uso terapéutico , Dosis de Radiación , Molécula 1 de Adhesión Celular Vascular/inmunología , Inmunoconjugados/inmunología , Método de Montecarlo , Dosificación RadioterapéuticaRESUMEN
Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematologic malignancy. Despite new treatments and protocols, including high-dose chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. α-radioimmunotherapy (α-RIT) represents an attractive treatment strategy because of the high-linear-energy transfer and short pathlength of α-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of α-RIT with 212Pb-daratumumab (anti-hCD38), in both in vitro and in vivo models, as well as an antimouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of the RPMI8226 cell line with an increasing activity (0.185-3.7 kBq/mL) of 212Pb-isotypic control or 212Pb-daratumumab was evaluated. Biodistribution was performed in vivo by SPECT/CT imaging and after death. Dose-range-finding and acute toxicity studies were conducted. Because daratumumab does not bind the murine CD38, biodistribution and dose-range finding were also determined using an antimurine CD38 antibody. To evaluate the in vivo efficacy of 212Pb-daratumumab, mice were engrafted subcutaneously with 5 × 106 RPMI8226 cells. Mice were treated 13 d after engraftment with an intravenous injection of 212Pb-daratumumab or control solution. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after 3 d of incubation with 212Pb-daratumumab, compared with 212Pb-isotypic control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of daratumumab. No toxicity was observed with 212Pb-daratumumab up to 370 kBq because of lack of cross-reactivity. Nevertheless, acute toxicity experiments with 212Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of 212Pb-daratumumab. Marked tumor growth inhibition compared with controls was observed, with a median survival of 55 d for 277.5 kBq of 212Pb-daratumumab instead of 11 d for phosphate-buffered saline. Conclusion: These results showed 212Pb-daratumumab to have efficacy in xenografted mice, with significant tumor regression and increased survival. This study highlights the potency of α-RIT in MM treatment.
Asunto(s)
ADP-Ribosil Ciclasa 1/metabolismo , Radioisótopos de Plomo/uso terapéutico , Mieloma Múltiple/radioterapia , Radioinmunoterapia , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Transformación Celular Neoplásica , Humanos , Ratones , Mieloma Múltiple/diagnóstico por imagen , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Distribución TisularRESUMEN
PURPOSE: The aims of this study were to develop a prostate-specific membrane antigen (PSMA) ligand for labelling with different radioisotopes of lead and to obtain an approximation of the dosimetry of a simulated 212Pb-based alpha therapy using its 203Pb imaging analogue. METHODS: Four novel Glu-urea-based ligands containing the chelators p-SCN-Bn-TCMC or DO3AM were synthesized. Affinity and PSMA-specific internalization were studied in C4-2 cells, and biodistribution in C4-2 tumour-bearing mice. The most promising compound, 203Pb-CA012, was transferred to clinical use. Two patients underwent planar scintigraphy scans at 0.4, 4, 18, 28 and 42 h after injection, together with urine and blood sampling. The time-activity curves of source organs were extrapolated from 203Pb to 212Pb and the calculated residence times of 212Pb were forwarded to its unstable daughter nuclides. QDOSE and OLINDA were used for dosimetry calculations. RESULTS: In vitro, all ligands showed low nanomolar binding affinities for PSMA. CA09 and CA012 additionally showed specific ligand-induced internalization of 27.4 ± 2.4 and 15.6 ± 2.1 %ID/106 cells, respectively. The 203Pb-labelled PSMA ligands were stable in serum for 72 h. In vivo, CA012 showed higher specific uptake in tumours than in other organs, and particularly showed rapid kidney clearance from 5.1 ± 2.5%ID/g at 1 h after injection to 0.9 ± 0.1%ID/g at 24 h. In patients, the estimated effective dose from 250-300 MBq of diagnostic 203Pb-CA012 was 6-7 mSv. Assuming instant decay of daughter nuclides, the equivalent doses projected from a therapeutic activity of 100 MBq of 212Pb-CA012 were 0.6 SvRBE5 to the red marrow, 4.3 SvRBE5 to the salivary glands, 4.9 SvRBE5 to the kidneys, 0.7 SvRBE5 to the liver and 0.2 SvRBE5 to other organs; representative tumour lesions averaged 13.2 SvRBE5 (where RBE5 is relative biological effectiveness factor 5). Compared to clinical experience with 213Bi-PSMA-617 and 225Ac-PSMA-617, the projected maximum tolerable dose was about 150 MBq per cycle. CONCLUSION: 212Pb-CA012 is a promising candidate for PSMA-targeted alpha therapy of prostate cancer. The dosimetry estimate for radiopharmaceuticals decaying with the release of unstable daughter nuclides has some inherent limitations, thus clinical translation should be done cautiously.
Asunto(s)
Partículas alfa/uso terapéutico , Antígenos de Superficie/metabolismo , Glutamato Carboxipeptidasa II/metabolismo , Radioisótopos de Plomo/uso terapéutico , Animales , Línea Celular Tumoral , Humanos , Marcaje Isotópico , Ligandos , Ratones , RadiometríaRESUMEN
The use of targeted radionuclide therapy for cancer is on the rise. While beta-particle-emitting radionuclides have been extensively explored for targeted radionuclide therapy, alpha-particle-emitting radionuclides are emerging as effective alternatives. In this context, fundamental understanding of the interactions and dosimetry of these emitted particles with cells in the tumor microenvironment is critical to ascertaining the potential of alpha-particle-emitting radionuclides. One important parameter that can be used to assess these metrics is the S-value. In this study, we characterized several alpha-particle-emitting radionuclides (and their associated radionuclide progeny) regarding S-values in the cellular and tumor-metastasis environments. The Particle and Heavy Ion Transport code System (PHITS) was used to obtain S-values via Monte Carlo simulation for cell and tumor metastasis resulting from interactions with the alpha-particle-emitting radionuclides, lead-212 (212Pb), actinium-225 (225Ac) and bismuth-213 (213Bi); these values were compared to the beta-particle-emitting radionuclides yttrium-90 (90Y) and lutetium-177 (177Lu) and an Auger-electron-emitting radionuclide indium-111 (111In). The effect of cellular internalization on S-value was explored at increasing degree of internalization for each radionuclide. This aspect of S-value determination was further explored in a cell line-specific fashion for six different cancer cell lines based on the cell dimensions obtained by confocal microscopy. S-values from PHITS were in good agreement with MIRDcell S-values (cellular S-values) and the values found by Hindié et al. (tumor S-values). In the cellular model, 212Pb and 213Bi decay series produced S-values that were 50- to 120-fold higher than 177Lu, while 225Ac decay series analysis suggested S-values that were 240- to 520-fold higher than 177Lu. S-values arising with 100% cellular internalization were two- to sixfold higher for the nucleus when compared to 0% internalization. The tumor dosimetry model defines the relative merit of radionuclides and suggests alpha particles may be effective for large tumors as well as small tumor metastases. These results from PHITS modeling substantiate emerging evidence that alpha-particle-emitting radionuclides may be an effective alternative to beta-particle-emitting radionuclides for targeted radionuclide therapy due to preferred dose-deposition profiles in the cellular and tumor metastasis context. These results further suggest that internalization of alpha-particle-emitting radionuclides via radiolabeled ligands may increase the relative biological effectiveness of radiotherapeutics.
Asunto(s)
Partículas alfa/uso terapéutico , Partículas beta/uso terapéutico , Neoplasias/radioterapia , Actinio/uso terapéutico , Partículas alfa/efectos adversos , Partículas beta/efectos adversos , Bismuto/uso terapéutico , Relación Dosis-Respuesta en la Radiación , Humanos , Radioisótopos de Plomo/uso terapéutico , Lutecio/uso terapéutico , Metástasis de la Neoplasia , Neoplasias/patología , Radioisótopos/uso terapéutico , Radioisótopos de Itrio/uso terapéuticoRESUMEN
Refinement of treatment regimens enlisting targeted α-radiation therapy (TAT) is an ongoing effort. Among the variables to consider are the target molecule, radionuclide, dosage, and administration route. The panitumumab F(ab')2 fragment targeting epidermal growth factor receptor tolerated modification with the TCMC chelate as well as radiolabeling with 203Pb or 212Pb. Good specific activity was attained when the immunoconjugate was labeled with 212Pb (9.6 ± 1.4 mCi/mg). Targeting of LS-174T tumor xenografts with the 203Pb-panitumumab F(ab')2 demonstrated comparable amounts of uptake to the similarly radiolabeled panitumumab IgG. A dose escalation study was performed to determine an effective working dose for both intraperitoneal (i.p.) and intravenous (i.v.) injections of 212Pb-panitumumab F(ab')2. Therapeutic efficacy, with modest toxicity, was observed with 30 µCi given i.p. Results for the i.v. administration were not as definitive and the experiment was repeated with a higher dose range. From this study, 20 µCi given i.v. was selected as the effective working dose. A subsequent therapy study combined gemcitabine or paclitaxel with i.v. 212Pb-panitumumab F(ab')2, which increased the median survival (MS) of LS-174T tumor-bearing mice to 208 and 239 d, respectively. Meanwhile, the MS of mice treated with i.v. 212Pb-panitumumab F(ab')2 alone was 61 and 11 d for the untreated group of mice. In conclusion, the panitumumab F(ab')2 fragment whether given by i.p. or i.v. injection, is a viable candidate as a delivery vector for TAT of disseminated i.p. disease.
Asunto(s)
Partículas alfa , Anticuerpos Monoclonales/administración & dosificación , Neoplasias del Colon/terapia , Receptores ErbB/antagonistas & inhibidores , Radioisótopos de Plomo/uso terapéutico , Radioinmunoterapia , Administración Intravenosa , Animales , Apoptosis , Proliferación Celular , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Receptores ErbB/inmunología , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Inyecciones Intraperitoneales , Ratones , Ratones Desnudos , Panitumumab , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Targeted α-therapy (TAT) could be delivered early to patients who are at a high-risk for developing brain metastases, targeting the areas of the vasculature where tumor cells are penetrating into the brain. We have utilized a Monte Carlo model representing brain vasculature to calculate physical dose and DNA damage from the α-emitters 225Ac and 212Pb. The micron-scale dose distributions from all radioactive decay products were modeled in Geant4, including the eV-scale interactions using the Geant4-DNA models. These interactions were then superimposed on an atomic-scale DNA model to estimate strand break yields. In addition to 225Ac having a higher dose per decay than 212Pb, it also has a double strand break yield per decay that is 4.7⯱â¯0.5 times that of 212Pb. However, the efficacy of both nuclides depends on retaining the daughter nuclei at the target location in the brain vasculature. The relative biological effectiveness (RBE) of 225Ac and 212Pb are similar when the entire decay chains are included, with maxima of 2.7⯱â¯0.6 and 2.5⯱â¯0.5 (respectively), and RBE values of about 2 to a depth of 80⯵m. If the initial daughter is lost, the RBE of 212Pb is completely reduced to 1 or lower and the RBE of 225Ac is approximately 2 only for the first 40⯵m.
Asunto(s)
Actinio/uso terapéutico , Partículas alfa/uso terapéutico , Radioisótopos de Plomo/uso terapéutico , Daño del ADN , Método de Montecarlo , Efectividad Biológica RelativaRESUMEN
PURPOSE: One-year monitoring of patients receiving intraperitoneal (IP) Pb-TCMC-trastuzumab to provide long-term safety and outcome data. A secondary objective was to study 7 tumor markers for correlation with outcome. METHODS: Eighteen patients with relapsed intra-abdominal human epidermal growth factor receptor-2 expressing peritoneal metastases were treated with a single IP infusion of Pb-TCMC-trastuzumab, delivered <4 h after 4 mg/kg IV trastuzumab. Seven tumor markers were studied for correlation with outcome. RESULTS: Six dose levels (7.4, 9.6, 12.6, 16.3, 21.1, 27.4 MBq/m) were well tolerated with early possibly agent-related adverse events being mild, transient, and not dose dependent. These included asymptomatic, abnormal laboratory values. No late renal, liver, cardiac, or other toxicity was noted up to 1 year. There were no clinical signs or symptoms of an immune response to Pb-TCMC-trastuzumab, and assays to detect an immune response to this conjugate were negative for all tested. Tumor marker studies in ovarian cancer patients showed a trend of decreasing Cancer antigen 72-4 (CA 72-4) aka tumor-associated glycoprotein 72 (TAG-72) and tumor growth with increasing administered radioactivity. Other tumor markers, including carbohydrate antigen (CA125), human epididymis protein 4 (HE-4), serum amyloid A (SAA), mesothelin, interleukin-6 (IL-6), and carcinoembryonic antigen (CEA) did not correlate with imaging outcome. CONCLUSIONS: IP Pb-TCMC-trastuzumab up to 27 MBq/m seems safe for patients with peritoneal carcinomatosis who have failed standard therapies. Serum TAG-72 levels better correlated to imaging changes in ovarian cancer patients than the more common tumor marker, CA125.
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Isotiocianatos/química , Radioisótopos de Plomo/uso terapéutico , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Ováricas/mortalidad , Neoplasias Peritoneales/mortalidad , Radioinmunoterapia/mortalidad , Trastuzumab/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Evaluación de Resultado en la Atención de Salud , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/terapia , Pronóstico , Tasa de SupervivenciaRESUMEN
A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85°C (45min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.
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Radioisótopos de Plomo/aislamiento & purificación , Radioisótopos de Plomo/uso terapéutico , Neoplasias/radioterapia , Péptidos/aislamiento & purificación , Péptidos/uso terapéutico , Radiofármacos/aislamiento & purificación , Radiofármacos/uso terapéutico , Animales , Cromatografía Líquida de Alta Presión/instrumentación , Compuestos Heterocíclicos con 1 Anillo/aislamiento & purificación , Humanos , Radioisótopos de Plomo/farmacocinética , Melanoma Experimental/diagnóstico por imagen , Melanoma Experimental/radioterapia , Ratones , Ratones Endogámicos C57BL , Neoplasias/diagnóstico por imagen , Péptidos/farmacocinética , Radiofármacos/farmacocinética , Radioterapia Guiada por Imagen/métodos , Nanomedicina Teranóstica , Distribución TisularRESUMEN
INTRODUCTION: Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer. METHODS: mAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with 212Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of 212Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with 212Pb-376.96 or the irrelevant isotype-matched 212Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70MBq 212Pb-376.96 or 212Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies. RESULTS: 212Pb-376.96 was obtained in high yield and purity (>98%); Kd values ranged from 10.6-26.6nM for ovarian cancer cells, with 104-105 binding sites/cell. 212Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control 212Pb-F3-C25; combining 212Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24h after i.p. injection of 212Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2 ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for 212Pb-376.96 and 212Pb-F3-C25. Tumor-bearing mice treated with 212Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with 212Pb-F3-C25 or non-treated controls. CONCLUSION: These results support additional RIT studies with 212Pb-376.96 for future evaluation in patients with ovarian cancer.
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Antígenos B7/inmunología , Epítopos/inmunología , Radioisótopos de Plomo/uso terapéutico , Neoplasias Ováricas/radioterapia , Radioinmunoterapia/métodos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Diferenciación Celular , Línea Celular Tumoral , Supervivencia Celular , Transformación Celular Neoplásica , Femenino , Humanos , Ratones , Neoplasias Ováricas/patologíaRESUMEN
When radioisotopes are injected to human body, instantly free radicals are generated due to the interaction of ionizing radiation with water and fluids present in the body. The vehicle carrying radionuclides into human body should therefore be designed in a way which could also eliminate or reduce such possibilities. For the first time we have used free radical scavenger hesperidin, a polyphenolic compound having a benzo-γ-pyrone with a benzene ring moiety for extraction of no-carrier added (NCA) 200,203Pb and 200,201,202Tl. We have modified CA beads by incorporation of a polyphenol (hesperidin) (CA-Hes). This tailor made beads were characterized and tested for their efficacy towards extraction of no-carrier-added lead and thallium radioisotopes from 40MeV α particle irradiated Hg2Cl2 target.
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Radioisótopos de Plomo/administración & dosificación , Radiofármacos/administración & dosificación , Radioisótopos de Talio/administración & dosificación , Alginatos/administración & dosificación , Composición de Medicamentos/métodos , Ácido Glucurónico/administración & dosificación , Hesperidina/administración & dosificación , Ácidos Hexurónicos/administración & dosificación , Humanos , Radioisótopos de Plomo/aislamiento & purificación , Radioisótopos de Plomo/uso terapéutico , Microscopía Electrónica de Rastreo , Cintigrafía/métodos , Radiofármacos/aislamiento & purificación , Radiofármacos/uso terapéutico , Radioisótopos de Talio/aislamiento & purificación , Radioisótopos de Talio/uso terapéuticoRESUMEN
UNLABELLED: Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity, and tumor response of intraperitoneal (212)Pb-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) in patients with human epidermal growth factor receptor type 2 (HER-2)-expressing malignancy. METHODS: In a standard 3 + 3 phase 1 design for dose escalation, (212)Pb-TCMC-trastuzumab was delivered intraperitoneally less than 4 h after administration of trastuzumab (4 mg/kg intravenously) to patients with peritoneal carcinomatosis who had failed standard therapies. RESULTS: Five dosage levels (7.4, 9.6, 12.6, 16.3, and 21.1 MBq/m(2)) showed minimal toxicity at more than 1 y for the first group and more than 4 mo for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow, 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n = 3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion, and no specific uptake in major organs were observed in 24 h. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24 h (decay-corrected to injection time) and 500 Bq/mL (decay-corrected to collection time). Non-decay-corrected cumulative urinary excretion was 6% or less in 24 h (2.3 half-lives). Dose rate measurements performed at 1 m from the patient registered less than 5µSv/h (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Antidrug antibody assays performed on serum from the first 4 cohorts were all negative. CONCLUSION: Five dose levels of intraperitoneal (212)Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent-related toxicity, consistent with the dosimetry calculations.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Radioisótopos de Plomo/uso terapéutico , Radioinmunoterapia/métodos , Radiometría/métodos , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dosis de Radiación , Receptor ErbB-2/metabolismo , Factores de Tiempo , TrastuzumabRESUMEN
Radio-resistant hypoxic tumor cells are significant contributors to the locoregional recurrences and distant metastases that mark failure of radiotherapy. Due to restricted tissue oxygenation, chronically hypoxic tumor cells frequently become necrotic and thus there is often an association between chronically hypoxic and necrotic tumor regions. This simulation study is the first in a series to determine the feasibility of hypoxic cell killing after first targeting adjacent areas of necrosis with either an α- or ß-emitting radioimmunoconjugate.