ABSTRACT
Aim: Nano-hydroxyapatite (nHA) is a good nanocarrier to load 223Ra, but the low specific activity (sp.act.) of 223Ra@nHA limits its application in medicine. Methods: We proposed a method for preparing nHA using PEG as a template, which significantly increases the sp.act of 223Ra@nHA and a new method to loaded 99mTc for in vivo tracking. Results: The nHA synthesized using PEG as a template was associated with higher sp.act for 223Ra in comparison to nHA with identical particle size and without PEG. The nHA load 99mTc-MDP was associated with higher labeling rate and stability in comparison to 99mTc. Conclusion: All these findings suggest that using PEG as a template and 99mTc-MDP could be the most effective of synthetic 223Ra/99mTc@nHA.
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Subject(s)
Bone Neoplasms , Durapatite , Particle Size , Radium , Durapatite/chemistry , Humans , Bone Neoplasms/drug therapy , Bone Neoplasms/diagnostic imaging , Radium/chemistry , Polyethylene Glycols/chemistry , Nanoparticles/chemistry , Technetium/chemistry , Cell Line, Tumor , Radiopharmaceuticals/chemistry , Animals , Technetium Tc 99m Medronate/chemistryABSTRACT
Imaging before 223Ra-dichloride (223Ra) therapy is crucial for selecting metastatic castration-resistant prostate cancer (mCRPC) patients with bone-only disease. The purpose of this study was to evaluate if baseline prostate-specific membrane antigen (PSMA) PET/CT (bPSMA) versus CT is associated with outcomes of 223Ra therapy. Methods: A secondary analysis of the data of a prospective observational study (NCT04995614) was performed. Patients received a maximum of 6 223Ra cycles and were retrospectively divided into the bPSMA or baseline CT (bCT) groups. All patients received baseline bone scintigraphy. Primary endpoints were alkaline phosphatase and prostate-specific antigen response. Secondary endpoints were overall survival (OS) and radiologic response. Results: Between 2017 and 2020, 122 mCRPC patients were included: 18 (14.8%) in the bPSMA group and 104 (85.2%) in the bCT group. All baseline characteristics were comparable. No significant differences in alkaline phosphatase or prostate-specific antigen response were found. The bCT group showed an OS significantly shorter than that of the bPSMA group (12.4 vs. 19.9 mo, P = 0.038). In 31 of 76 patients (40.1%) in the bCT group who also received posttherapy CT, lymph node or visceral metastases (soft-tissue involvement [STI]) were detected after 223Ra therapy, compared with 0 of 15 patients in the bPSMA group who received posttherapy PSMA PET/CT or CT. No significant difference in OS was found between patients in the bCT or posttherapy CT subgroup without STI (46/76) and the bPSMA group. Conclusion: bPSMA versus CT does not seem to impact biochemical response during 223Ra therapy in mCRPC patients. Nevertheless, patients in the bCT group had a significantly shorter OS, most likely due to underdetection of STI in this group. Therefore, replacing bCT with PSMA PET/CT appears to be a valuable screening method for identifying patients who will benefit most from 223Ra therapy.
Subject(s)
Positron Emission Tomography Computed Tomography , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Alkaline Phosphatase , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/diagnostic imaging , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Radiopharmaceuticals/therapeutic use , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Targeted alpha therapy is one of the most powerful therapeutical modalities available in nuclear medicine. It's therapeutic potency is based on the nuclides that emit one or several alpha particles providing strong and highly localized therapeutic effects. However, some of these radionuclides, like e.g.223Ra or 225Ac decay in cascades, where the radioactive progeny originating from the consecutive alpha-decays may leave the original vector and cause unwanted irradiation of non-target organs. This progeny, even if partially retained in target tissues by internalization processes, typically do not follow the fate of originally targeted radiopharmaceutical and potentially spread over body following their own biodistribution. In this study we aimed to estimate 211Pb/211Bi progeny fate from the 223Ra surface-labelled TiO2 nanoparticles in vitro and the fate of 211Pb in vivo in a mice model. RESULTS: In vitro stability studies have shown significant differences between the release of the mother 223Ra and its progeny (211Pb, 211Bi) in all the biological matrices that have been tested. The lowest released activities were measured in saline, resulting in less than 5 % of released activity for all nuclides. Contrary to that, the highest released activity of 223Ra of up to 10 % within 48 h was observed in 5 % solution of albumin. The released activity of its progeny; the 211Pb and 211Bi was in the range of 20-40 % in this test medium. Significantly higher released activities of 211Pb and 211Bi compared to 223Ra by at least 10 % was observed in each biological medium, except saline, where no significant differences were observed. The in vivo biodistribution studies results in a mice model, show similar pattern, where it was found that even after accumulation of nanoparticles in target tissues, approximately 10 % of 211Pb is continuously released into the blood stream within 24 h, followed by its natural accumulation in kidneys. CONCLUSION: This study confirms our assumption that the progeny formed in a chain alpha decay of a certain nuclide, in this case the 223Ra, can be released from its original vector, leave the target tissue, relocate and could be deposited in non-target organs. We did not observe complete progeny wash-out from its original target tissues in our model. This indicates strong dependence of the progeny hot atom fate after its release from the original radiopharmaceutical preparation on multiple factors, like their internalization and retention in cells, cell membranes, extracellular matrices, protein binding, etc. We hypothesize, that also the primary tumour or metastasis size, their metabolic activity may significantly influence progeny fate in vivo, directly impacting the dose delivered to non-target tissues and organs. Therefore a bottom-up approach should be followed and detailed pre-/clinical studies on the release and biodistribution of radioactive progeny originating from the chain alpha emitters should be preferably performed.
Subject(s)
Nanoparticles , Radiopharmaceuticals , Mice , Animals , Radiopharmaceuticals/therapeutic use , Tissue Distribution , Lead , Radioisotopes/therapeutic useABSTRACT
α-particle emitters are emerging as a potent modality for disseminated cancer therapy because of their high linear energy transfer and localized absorbed dose profile. Despite great interest and pharmaceutical development, there is scant information on the distribution of these agents at the scale of the α-particle pathlength. We sought to determine the distribution of clinically approved [223Ra]RaCl2 in bone metastatic castration-resistant prostate cancer at this resolution, for the first time to our knowledge, to inform activity distribution and dose at the near-cell scale. Methods: Biopsy specimens and blood were collected from 7 patients 24 h after administration. 223Ra activity in each sample was recorded, and the microstructure of biopsy specimens was analyzed by micro-CT. Quantitative autoradiography and histopathology were segmented and registered with an automated procedure. Activity distributions by tissue compartment and dosimetry calculations based on the MIRD formalism were performed. Results: We revealed the activity distribution differences across and within patient samples at the macro- and microscopic scales. Microdistribution analysis confirmed localized high-activity regions in a background of low-activity tissue. We evaluated heterogeneous α-particle emission distribution concentrated at bone-tissue interfaces and calculated spatially nonuniform absorbed-dose profiles. Conclusion: Primary patient data of radiopharmaceutical therapy distribution at the small scale revealed that 223Ra uptake is nonuniform. Dose estimates present both opportunities and challenges to enhance patient outcomes and are a first step toward personalized treatment approaches and improved understanding of α-particle radiopharmaceutical therapies.
Subject(s)
Bone Neoplasms , Prostatic Neoplasms , Male , Humans , Radiopharmaceuticals , Prostatic Neoplasms/radiotherapy , Prostatic Neoplasms/pathology , Bone and Bones/diagnostic imaging , Bone and Bones/pathology , Autoradiography , Bone Neoplasms/radiotherapy , Bone Neoplasms/secondaryABSTRACT
Objetivos Establecer biomarcadores basales en pacientes con cáncer de próstata metastásico resistente a la castración (CPMRC) tratados con Ra-223 que predigan una mejor supervivencia global (SG), así como valorar la toxicidad hematológica y la respuesta. Materiales y métodos Estudio retrospectivo multicéntrico en 151 pacientes con CPMRC tratados con Ra-223 entre 2013 y 2020. Se valoró la SG de acuerdo a: los niveles basales de hemoglobina (Hb), el antígeno prostático específico (PSA), la fosfatasa alcalina (FA), la escala de dolor de la OMS, el Eastern Cooperative Oncology Group (ECOG), el número de lesiones en gammagrafía ósea (GO), el uso de agentes de protección ósea y las dosis recibidas. Se determinó el grado de toxicidad hematológica y la respuesta basada en los cambios de la FA y el dolor pre y postratamiento. Resultados Mediana de SG de 24meses (IC95%: 16,5-31). En el 70% que recibieron tratamiento completo (5-6dosis) la mediana de SG fue de 34,9meses, versus 5,8 en el tratamiento incompleto (1-4dosis). La SG fue mayor en los pacientes con menor PSA, FA, Hb>13g/dl, menor número de metástasis óseas y ECOG 0-1. 52/151pacientes (34%) fallecieron durante el seguimiento. Cerca del 70% de los pacientes presentaron disminución del dolor, y el 66%, reducción de la FA. La mitad de los pacientes presentaron eventos adversos hematológicos leves, y solo el 5%, severos. Conclusiones Los pacientes con CPMRC tratados con Ra-223 que presentan biomarcadores basales como Hb>13g/ml, ECOG 0-1, PSA<20ng/ml y menor número de lesiones en GO muestran mejor SG, con un adecuado perfil de seguridad (AU)
Objectives Establish basal biomarkers in patients with bone metastatic castration-resistant prostate cancer (mCRPC) treated with Ra-223 that predicted a better overall survival (OS), assess hematology toxicity and treatment response. Materials and methods Retrospective multicenter study in 151 patients with mCRPC between 2013 and 2020. OS was assessed according to basal hemoglobin (Hb), PSA, alkaline phosphatase (AP), WHO pain scale, Eastern Cooperative Oncology Group (ECOG), number of metastatic lesions on bone scan (BS), use of protective bone agents and received. Hematological toxicities were evaluated. Treatment response was based on changes in FA and pain. Results Median OS was 24months (95%CI: 16.5-31). OS in 70% of patients who received complete Ra-223 treatment (5-6 doses) was 34.9m vs. 5.8m in patients with incomplete treatment (1-4 doses). OS was longer in patients with lower PSA and AP, Hb>13g/dL, lesser bone metastasis on GO and ECOG 0-1. 52/151 patients (34%) died during follow-up. Nearly 70% of patients experienced decrease in pain and 66% reduction on AP. Half of patients had mild hematological adverse effects and only 5% had severe. Conclusions mCRPC patients treated with Ra-223 who had Hb>13g/mL, ECOG 0-1, low AP, PSA<20ng/ml and lesser bone metastasis on BS shown a better OS with adequate safety profile (AU)