Micellar solution of [223Ra]RaCl2: Reaching renal excretion, potent efficacy in osteoblastic osteosarcoma in PDX model, biochemistry alterations and pharmacokinetics.

Despite the successful use of the radiopharmaceutical radium-223 dichloride ([223Ra]RaCl2) for targeted alpha therapy of castration-resistant prostate cancer patients with bone metastases, some short-term side effects, such as diarrhea and vomiting, have been documented, causing patient discomfort. Hence, we prepared a nanosized micellar solution of [223Ra]RaCl2 and evaluated its biodistribution, pharmacokinetics, and induced biochemical changes in healthy mice up to 96 h after intraperitoneal administration as an alternative to overcome the previous limitations. In addition, we evaluated the bone specificity of micellar [223Ra]RaCl2 in patient-derived xenografts in the osteosarcoma model. The biodistribution studies revealed the high bone-targeting properties of the micellar [223Ra]RaCl2. Interestingly, the liver uptake remained significantly low (%ID/g = 0.1-0.02) from 24 to 96 h after administration. In addition, the micellar [223Ra]RaCl2 exhibited a significantly higher uptake in left (%ID/g = 0.85-0.23) and right (%ID/g = 0.76-0.24) kidneys than in small (%ID/g = 0.43-0.06) and large intestines (%ID/g = 0.24-0.09) over time, suggesting its excretion pathway is primarily through the kidneys into the urine, in contrast to the non-micellar [223Ra]RaCl2. The micellar [223Ra]RaCl2 also had low distribution volume (0.055 ± 0.003 L) and longer elimination half-life (28 ± 12 days). This nanosystem was unable to change the enzymatic activities of alanine aminotransferase, aspartate aminotransferase, gamma GT, glucose, and liquiform lipase in the treated mice. Finally, microscopic examination of the animals' osteosarcoma tumors treated with micellar [223Ra]RaCl2 indicated regression of the tumor, with large areas of necrosis. In contrast, in the control group, we observed tumor cellularity and cell anaplasia, mitotic figures and formation of neoplastic extracellular bone matrix, which are typical features of osteosarcoma. Therefore, our findings demonstrated the efficiency and safety of nanosized micellar formulations to minimize the gastrointestinal excretion pathway of the clinical radiopharmaceutical [223Ra]RaCl2, in addition to promoting regression of the osteosarcoma. Further studies must be performed to assess dose-response outcomes and organ/tissue dosimetry for clinical translation.

Folic acid-functionalized graphene quantum dots: Synthesis, characterization, radiolabeling with radium-223 and antiviral effect against Zika virus infection.

The use of graphene quantum dots as biomedical devices and drug delivery systems has been increasing. The nano-platform of pure carbon has shown unique properties and is approved to be safe for human use. In this study, we successfully produced and characterized folic acid-functionalized graphene quantum dots (GQD-FA) to evaluate their antiviral activity against Zika virus (ZIKV) infection in vitro, and for radiolabeling with the alpha-particle emitting radionuclide radium-223. The in vitro results exhibited the low cytotoxicity of the nanoprobe GQD-FA in Vero E6 cells and the antiviral effect against replication of the ZIKV infection. In addition, our findings demonstrated that functionalization with folic acid doesn't improve the antiviral effect of graphene quantum dots against ZIVK replication in vitro. On the other hand, the radiolabeled nanoprobe 223Ra@GQD-FA was also produced as confirmed by the Energy Dispersive X-Ray Spectroscopy analysis. 223Ra@GQD-FA might expand the application of alpha targeted therapy using radium-223 in folate receptor-overexpressing tumors.

Nanomicelles of Radium Dichloride [223Ra]RaCl2 Co-Loaded with Radioactive Gold [198Au]Au Nanoparticles for Targeted Alpha-Beta Radionuclide Therapy of Osteosarcoma.

Alpha and beta particulate radiation are used for non-treated neoplasia, due to their ability to reach and remain in tumor sites. Radium-223 (223Ra), an alpha emitter, promotes localized cytotoxic effects, while radioactive gold (198Au), beta-type energy, reduces radiation in the surrounding tissues. Nanotechnology, including several radioactive nanoparticles, can be safely and effectively used in cancer treatment. In this context, this study aims to analyze the antitumoral effects of [223Ra]Ra nanomicelles co-loaded with radioactive gold nanoparticles ([198Au]AuNPs). For this, we synthesize and characterize nanomicelles, as well as analyze some parameters, such as particle size, radioactivity emission, dynamic light scattering, and microscopic atomic force. [223Ra]Ra nanomicelles co-loaded with [198Au]AuNPs, with simultaneous alpha and beta emission, showed no instability, a mean particle size of 296 nm, and a PDI of 0.201 (±0.096). Furthermore, nanomicelles were tested in an in vitro cytotoxicity assay. We observed a significant increase in tumor cell death using combined alpha and beta therapy in the same formulation, compared with these components used alone. Together, these results show, for the first time, an efficient association between alpha and beta therapies, which could become a promising tool in the control of tumor progression.

Radiolabeled nanomaterials for biomedical applications: radiopharmacy in the era of nanotechnology.

BACKGROUND: Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. Nanomedicine, a term for the application of nanotechnology in medical and health fields, uses nanoparticles for several applications such as imaging, diagnostic, targeted cancer therapy, drug and gene delivery, tissue engineering, and theranostics. RESULTS: Here, we overview the current state-of-the-art of radiolabeled nanoparticles for molecular imaging and radionuclide therapy. Nanostructured radiopharmaceuticals of technetium-99m, copper-64, lutetium-177, and radium-223 are discussed within the scope of this review article. CONCLUSION: Nanoradiopharmaceuticals may lead to better development of theranostics inspired by ingenious delivery and imaging systems. Cancer nano-theranostics have the potential to lead the way to more specific and individualized cancer treatment.

Single-center developing country analysis of radium-223 therapy in prostate cancer-preliminary results.

We reviewed the records of mCRPC patients treated with off-label use of Ra-223. Ra-223 efficiency in this non-study population was correlated to outcome measures overall survival (OS), progression-free survival (PFS), bone event-free survival, bone marrow failure (BMF), and disease-related biomarkers. There were no limits regarding the number of prior hormonal agents or chemotherapy received before or during Ra-223. Exclusion criteria consisted of baseline platelet counts below 50,000/mm3 and/or absolute neutrophil counts below 1,500/mm3. Twenty-eight patients received 130 cycles of Ra-223 between 2017 and 2018. The overall median OS was 15.6 months. However, in patients submitted to 4 or fewer cycles, the median OS was 9.1 months; in contrast, the median OS was 18.5 months in patients submitted to 5 or 6 cycles. There was a significant inverse correlation between the number of cycles and the occurrence of bone events (76.2% of the patients that completed 6 cycles did not present bone events, while 71.4% of the patients that had skeletal-related events were submitted to less than 6 cycles). 82.1% of the patients were submitted to concomitant therapies with no significant side effects. There was also a decrease in ALP and LDH levels throughout treatment. Radium-223 increased OS and decreased bone events, especially when patients were able to complete 5-6 cycles. The proper selection of patients is crucial to improve outcomes.

Overall survival prediction in metastatic castration-resistant prostate cancer treated with radium-223.

OBJECTIVE: Radium-223(223Ra) is indicated for patients (p) with metastatic castration resistant prostate cancer (mCRCP). OBJECTIVES: The aim of this study was to evaluate the role of baseline clinical variables associated with overall survival (OS) and toxicity of 223Ra. Its purpose was to identify the factors that can predict a better response to treatment and provide information regarding the most appropriate time for the application of 223Ra. MATERIALS AND METHODS: Prospective study in 40p with mCRPC treated with 223Ra. End points were OS, progression-free survival and time to progression. The follow-up parameters were: doses received, hemoglobin (Hb), absolute neutrophil count (ANC), platelet count (PC), prostate specific antigen (PSA), alkaline phosphatase (ALP), Visual Analogue Scale for pain, Eastern Cooperative Oncology Group (ECOG) and WHO's Cancer Pain Ladder. The use of other treatments was also evaluated. RESULTS: Median OS was 17.1 months(mo) (CI95%6.5-27.7); 26/40p received complete treatment of 223Ra, without reaching a median OS and 14p received incomplete treatment with a median OS 13.6mo(CI95%1.6-25.6). Median follow-up was 11.2mo (range:1.3-45.2). The univariate analysis showed that factors as VAS, ECOG, Hb and ALP values were independently associated with OS. First line treatment with 223Ra was started in 11/40p, while 19p had been heavily pre-treated and 13p received concomitant treatment. CONCLUSIONS: 223Ra therapy require an adequate selection of patients to obtain the greatest clinical benefit. Low basal Hb, hight basal ALP, bone marrow involvement and an altered ECOG were the main factors that decreased OS in our patients. 223Ra should be considered relatively early in the course of treatment. Available at. https://www.intbrazjurol.com.br/pdf/aop/2019-0343OA.pdf.

Overall survival prediction in metastatic castration-resistant prostate cancer treated with radium-223

ABSTRACT Objective Radium-223(223Ra) is indicated for patients (p) with metastatic castration resistant prostate cancer (mCRCP). Objectives The aim of this study was to evaluate the role of baseline clinical variables associated with overall survival (OS) and toxicity of 223Ra. Its purpose was to identify the factors that can predict a better response to treatment and provide information regarding the most appropriate time for the application of 223Ra. Materials and Methods Prospective study in 40p with mCRPC treated with 223Ra. End points were OS, progression-free survival and time to progression. The follow-up parameters were: doses received, hemoglobin (Hb), absolute neutrophil count (ANC), platelet count (PC), prostate specific antigen (PSA), alkaline phosphatase (ALP), Visual Analogue Scale for pain, Eastern Cooperative Oncology Group (ECOG) and WHO's Cancer Pain Ladder. The use of other treatments was also evaluated. Results Median OS was 17.1 months(mo) (CI95%6.5-27.7); 26/40p received complete treatment of 223Ra, without reaching a median OS and 14p received incomplete treatment with a median OS 13.6mo(CI95%1.6-25.6). Median follow-up was 11.2mo (range:1.3-45.2). The univariate analysis showed that factors as VAS, ECOG, Hb and ALP values were independently associated with OS. First line treatment with 223Ra was started in 11/40p, while 19p had been heavily pre-treated and 13p received concomitant treatment. Conclusions 223Ra therapy require an adequate selection of patients to obtain the greatest clinical benefit. Low basal Hb, hight basal ALP, bone marrow involvement and an altered ECOG were the main factors that decreased OS in our patients. 223Ra should be considered relatively early in the course of treatment.

Is interim 18F-fluoride PET/CT a predictor of outcomes after radium-223 therapy?

OBJECTIVE: To determine whether an interim 18F-fluoride positron-emission tomography/computed tomography (PET/CT) study performed after the third cycle of radium-223 dichloride (223RaCl2) therapy is able to identify patients that will not respond to treatment. MATERIALS AND METHODS: We retrospectively reviewed 34 histologically confirmed cases of hormone-refractory prostate cancer with bone metastasis in patients submitted to 223RaCl2 therapy. All of the patients underwent baseline and interim 18F-fluoride PET/CT studies. The interim study was performed immediately prior to the fourth cycle of 223RaCl2. The skeletal tumor burden-expressed as the total lesion fluoride uptake above a maximum standardized uptake value of 10 (TLF10)-was calculated for the baseline and the interim studies. The percent change in TLF10 between the baseline and interim studies (%TFL10) was calculated as follows: %TFL10 = interim TLF10 - baseline TLF10 / baseline TLF10. End points were overall survival, progression-free survival, and skeletal-related events. RESULTS: The mean age of the patients was 72.4 ± 10.2 years (range, 43.3-88.8 years). The %TLF10 was not able to predict overall survival (p = 0.6320; hazard ratio [HR] = 0.753; 95% confidence interval [CI]: 0.236-2.401), progression-free survival (p = 0.5908; HR = 1.248; 95% CI: 0.557-2.797) nor time to a bone event (p = 0.5114; HR = 1.588; 95% CI: 0.399-6.312). CONCLUSION: The skeletal tumor burden on an interim 18F-fluoride PET/CT, performed after three cycles of 223RaCl2, is not able to predict overall survival, progression-free survival, or time to bone event, and should not be performed to monitor response at this time.

OBJETIVO: Avaliar se o PET/CT interim com fluoreto-18F após a terceira dose da terapia com dicloreto de rádio-223 (223Ra) é capaz de identificar pacientes que não responderão ao tratamento. MATERIAIS E MÉTODOS: Revisamos, retrospectivamente, 34 pacientes com diagnóstico histológico de câncer de próstata refratários a hormonioterapia e com metástases ósseas que foram submetidos a 223Ra. Todos os pacientes foram submetidos a PET/CT com fluoreto-18F antes de iniciar o tratamento (basal) e imediatamente antes da quarta dose de 223Ra (interim). A carga tumoral esquelética (TLF10) foi calculada em ambos os exames da PET/CT com fluoreto-18F de cada paciente e foi determinada a alteração percentual na TLF10 entre eles (%TFL10 = TLF10 interim - TLF10 basal / TLF10 basal). Foram avaliados a sobrevida global, a sobrevida livre de progressão e o tempo para um evento ósseo. RESULTADOS: A idade média dos pacientes foi 72,4 ± 10,2 anos (variação: 43,3-88,8 anos). A %TLF10 não foi capaz de predizer a sobrevida global (p = 0,6320; HR = 0,753; intervalo de confiança [IC] 95%: 0,236-2,101), a sobrevida livre de progressão (p = 0,5908; HR = 1,248; IC 95%: 0,557-2,797) nem o tempo para um evento ósseo (p = 0,5114; HR = 1,588; IC 95%: 0,399-6,312). CONCLUSÃO: A carga tumoral esquelética da PET/CT com fluoreto-18F realizada após três doses de 223Ra não é capaz de predizer sobrevida global, sobrevida livre de progressão ou tempo até um evento ósseo, e não deve ser realizada para monitorar a resposta ao tratamento desses pacientes, nesse momento.

Is interim 18F-fluoride PET/CT a predictor of outcomes after radium-223 therapy? / O PET/CT interim com fluoreto-18F é capaz de predizer desfechos após a terapia com rádio-223?

Abstract Objective: To determine whether an interim 18F-fluoride positron-emission tomography/computed tomography (PET/CT) study performed after the third cycle of radium-223 dichloride (223RaCl2) therapy is able to identify patients that will not respond to treatment. Materials and Methods: We retrospectively reviewed 34 histologically confirmed cases of hormone-refractory prostate cancer with bone metastasis in patients submitted to 223RaCl2 therapy. All of the patients underwent baseline and interim 18F-fluoride PET/CT studies. The interim study was performed immediately prior to the fourth cycle of 223RaCl2. The skeletal tumor burden-expressed as the total lesion fluoride uptake above a maximum standardized uptake value of 10 (TLF10)-was calculated for the baseline and the interim studies. The percent change in TLF10 between the baseline and interim studies (%TFL10) was calculated as follows: %TFL10 = interim TLF10 - baseline TLF10 / baseline TLF10. End points were overall survival, progression-free survival, and skeletal-related events. Results: The mean age of the patients was 72.4 ± 10.2 years (range, 43.3-88.8 years). The %TLF10 was not able to predict overall survival (p = 0.6320; hazard ratio [HR] = 0.753; 95% confidence interval [CI]: 0.236-2.401), progression-free survival (p = 0.5908; HR = 1.248; 95% CI: 0.557-2.797) nor time to a bone event (p = 0.5114; HR = 1.588; 95% CI: 0.399-6.312). Conclusion: The skeletal tumor burden on an interim 18F-fluoride PET/CT, performed after three cycles of 223RaCl2, is not able to predict overall survival, progression-free survival, or time to bone event, and should not be performed to monitor response at this time.

Resumo Objetivo: Avaliar se o PET/CT interim com fluoreto-18F após a terceira dose da terapia com dicloreto de rádio-223 (223Ra) é capaz de identificar pacientes que não responderão ao tratamento. Materiais e Métodos: Revisamos, retrospectivamente, 34 pacientes com diagnóstico histológico de câncer de próstata refratários a hormonioterapia e com metástases ósseas que foram submetidos a 223Ra. Todos os pacientes foram submetidos a PET/CT com fluoreto-18F antes de iniciar o tratamento (basal) e imediatamente antes da quarta dose de 223Ra (interim). A carga tumoral esquelética (TLF10) foi calculada em ambos os exames da PET/CT com fluoreto-18F de cada paciente e foi determinada a alteração percentual na TLF10 entre eles (%TFL10 = TLF10 interim - TLF10 basal / TLF10 basal). Foram avaliados a sobrevida global, a sobrevida livre de progressão e o tempo para um evento ósseo. Resultados: A idade média dos pacientes foi 72,4 ± 10,2 anos (variação: 43,3-88,8 anos). A %TLF10 não foi capaz de predizer a sobrevida global (p = 0,6320; HR = 0,753; intervalo de confiança [IC] 95%: 0,236-2,101), a sobrevida livre de progressão (p = 0,5908; HR = 1,248; IC 95%: 0,557-2,797) nem o tempo para um evento ósseo (p = 0,5114; HR = 1,588; IC 95%: 0,399-6,312). Conclusão: A carga tumoral esquelética da PET/CT com fluoreto-18F realizada após três doses de 223Ra não é capaz de predizer sobrevida global, sobrevida livre de progressão ou tempo até um evento ósseo, e não deve ser realizada para monitorar a resposta ao tratamento desses pacientes, nesse momento.

Metastatic castration-resistant prostate cancer and the challenge of a patient with chronic kidney disease in hemodialysis

At a time when the population shows increasing longevity, entities such as cancer and chronic kidney disease (CKD) are more frequently connected. In the United States, approximately 6% of the patients on hemodialysis have cancer. The challenge to manage oncologic patients with CKD in a hemodialytic program represents a great shortage of available information on the choice of the best drug, timing, dosage adjustments, dialysis method, and treatment safety. We present the case of a patient with prostate cancer and terminal CKD in hemodialysis, and the treatment sequence after the development of resistance to hormonal blockade therapy, which included docetaxel, enzalutamide, and radium-223.

Metastatic castration-resistant prostate cancer and the challenge of a patient with chronic kidney disease in hemodialysis.

At a time when the population shows increasing longevity, entities such as cancer and chronic kidney disease (CKD) are more frequently connected. In the United States, approximately 6% of the patients on hemodialysis have cancer. The challenge to manage oncologic patients with CKD in a hemodialytic program represents a great shortage of available information on the choice of the best drug, timing, dosage adjustments, dialysis method, and treatment safety. We present the case of a patient with prostate cancer and terminal CKD in hemodialysis, and the treatment sequence after the development of resistance to hormonal blockade therapy, which included docetaxel, enzalutamide, and radium-223.

Optimizing the treatment of metastatic castration-resistant prostate cancer: a Latin America perspective.

Prostate cancer is a significant burden and cause of mortality in Latin America. This article reviews the treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) and provides consensus recommendations to assist Latin American prostate cancer specialists with clinical decision making. A multidisciplinary expert panel from Latin America reviewed the available data and their individual experience to develop clinical consensus opinions for the use of life-prolonging agents in mCRPC, with consideration given to factors influencing patient selection and treatment monitoring. There is a lack of level 1 evidence for the best treatment sequence or combinations in mCRPC. In this context, consensus recommendations were provided for the use of taxane-based chemotherapies, androgen receptor axis-targeted agents and targeted alpha therapy, for patients in Latin America. Prostate-specific antigen (PSA) changes alone, during treatment, should be treated with caution; PSA may not be a suitable biomarker for radium-223. Bone scans and computed tomography are the standard imaging modalities in Latin America. Imaging should be prompted during treatment where symptomatic decline and/or significant worsening of laboratory evaluations are reported, or where a course of therapy has been completed and another antineoplastic agent is under consideration. Recommendations and guidance for treatment options in Latin America are provided in the context of country-level variable access to approved agents and technologies for treatment monitoring. Patients should be treated with the purpose of prolonging overall survival and preserving quality of life through increasing the opportunity to administer all available life-prolonging therapies when appropriate.

SEOM clinical guidelines for the treatment of metastatic prostate cancer (2017).

Androgen deprivation treatment was the only treatment available for metastatic prostate cancer until recently, with docetaxel as the only treatment with a proven survival benefit in castration-resistant prostate cancer (CRPC). Several drugs have been approved in the castration-resistant disease (sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, radium-223). More recently, docetaxel and abiraterone have been moved to the hormone-sensitive disease setting, achieving better patient survival. The purpose of this article is to define the state of the art in the treatment of prostate carcinoma.

SEOM Clinical Guideline for bone metastases from solid tumours (2016).

Bone metastases are common in many advanced solid tumours, being breast, prostate, thyroid, lung, and renal cancer the most prevalent. Bone metastases can produce skeletal-related events (SREs), defined as pathological fracture, spinal cord compression, need of bone irradiation or need of bone surgery, and hypercalcaemia. Patients with bone metastases experience pain, functional impairment and have a negative impact on their quality of life. Several imaging techniques are available for diagnosis of this disease. Bone-targeted therapies include zoledronic acid, a potent biphosfonate, and denosumab, an anti-RANKL monoclonal antibody. Both reduce the risk and/or delay the development of SREs in several types of tumours. Radium 233, an alpha-particle emitter, increases overall survival in patients with bone metastases from resistant castration prostate cancer. Multidisciplinary approach is essential and bone surgery and radiotherapy should be integrated in the treatment of bone metastases when necessary. This SEOM Guideline reviews bone metastases pathogenesis, clinical presentations, lab tests, imaging techniques for diagnosis and response assessment, bone-targeted agents, and local therapies, as radiation and surgery, and establishes recommendations for the management of patients with metastases to bone.