Bone Seeking Research Articles

From palliative therapy to prolongation of survival: (223)RaCl2 in the treatment of bone metastases.

Patients with hormone-refractory prostate cancer often have multiple bone metastases. The resulting bone pain is associated with reduced life quality, increased cost of therapy and impairment of overall survival. Trials with bone-targeting β-emitters have mostly showed an effect on alleviation of bone pain along with prolongation in survival, documented in only a limited number of patients. A randomized phase III trial (ALSYMPCA) using the α-emitter (223)RaCl2 (Xofigo®) showed for the first time, a longer overall survival of 3.6 months in treated patients as a sign of an antitumor effect. The time to first skeletal-related events was also significantly longer in the therapy group compared with placebo. Because of the short range of α-emitter, the bone marrow toxicity of radium therapy is low, and so this radionuclide could also be a candidate for combination with chemotherapy. The elimination of (223)RaCl2 is mainly through the gastrointestinal tract and side effects are mainly in this area. The procedure is similar to treatment with other bone-seeking agents and consists of six administrations of 50 kBq/kg bodyweight Xofigo®, repeated every 4 weeks. At present Xofigo® is only approved for hormone-refractory prostate cancer.

Preparation and biological evaluation of 175Yb-BPAMD as a potential agent for bone pain palliation therapy

Due to the promising results of 4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD) complexes in human studies, in this study, new therapeutic complex of 175Yb-BPAMD was investigated. The effect of various parameters on the labelling yield of 175Yb-BPAMD, stability tests, partition coefficient and hydroxyapatite binding of the complex were studied. Biodistribution studies (SPECT imaging and sacrifice) were performed after injection of the complex to rats and compared with the biodistribution of the 175Yb cation and other 175Yb bone-seeking agents. Totally, 175Yb-BPAMD has interesting characteristics compared to the other 175Yb bone-seeking agents and can be considered as a potential agent for bone pain palliation.

Abstract P6-16-02: Treatment of skeletal metastatic breast cancer with bone seeking matrix metalloproteinase inhibitors

Abstract Background. Breast to bone metastasis is a common event during breast cancer progression. The resultant lesions are painful and currently, despite medical advances, are incurable. The progression of bone metastatic breast cancer is critically dependent on interactions with the surrounding microenvironment. Therefore, identifying the underpinning molecular mechanisms is vital for the development of new therapies. Rationale. Gene expression analysis and validation in human and murine specimens of bone metastases revealed matrix metalloproteinases, such as MMP-2, are highly expressed in the bone metastatic microenvironment. Genetic ablation of MMP-2 demonstrated the importance of this MMP in driving the growth of the osteolytic bone metastatic breast cancer by regulating the bioavailability of transforming growth factor β (TGFβ). These data support the rationale for the development of a highly specific MMP-2 inhibitor for the eradication of active bone metastatic breast cancer. Methods. Given that previous broad-spectrum MMP inhibitor (MMPI) trials were unsuccessful due to dose limiting systemic side effects, we utilized a novel chemical approach to synthesize bone seeking MMP inhibitors (BMMPIs) on a bisphosphonic backbone, with specificity for MMP-2 in the nanomolar range (IC50=140 nM). In vitro, we tested the effect of BMMPIs at varying doses (1nM-100μM) on the viability of the major cellular components of the cancer-bone microenvironment, namely breast cancer cells (PyMT, 4T1), osteoblasts (MC3T3) and osteoclasts (primary monocytes and RAW 264.7). In vivo, mice were intratibially inoculated with either luciferase expressing 4T1 or PyMT (1x105) cells. Mice (n=10/group) then received vehicle, zoledronate (1 mg/kg) or BMMPIs (1 mg/kg). Tumor growth was determined via luminescence quantitation. Cancer induced bone disease was measured ex vivo by μCT, Xray and histomorphometry. MMP activity in vivo and ex vivo was determined via specific activatable MMP probes. Results. BMMPIs significantly impacted the viability of breast cancer cells and osteoclasts in vitro (p<0.05) compared to control. In vivo BMMPIs significantly reduced the growth of bone metastatic breast cancer compared to control and the standard of care bisphosphonate, zoledronate. MMP activity was also lower in the BMMPI treated groups (using tumor burden to normalize values). μCT/Xray/Histomorphometry analysis also illustrated the significant beneficial effects of the BMMPIs in reducing the size of osteolytic lesions (up to 80% by μCT; p<0.05). Conclusions. MMP-2 specific BMMPIs prevent bone metastatic breast cancer growth by impacting cancer cell viability and cancer induced osteolysis. Given that bisphosphonates are well tolerated in the clinical setting, we predict that BMMPIs could be translated to the clinical setting for the treatment and eradication of bone metastatic breast cancer. Citation Format: Tauro M, Laghezza A, Tortorella P, Lynch CC. Treatment of skeletal metastatic breast cancer with bone seeking matrix metalloproteinase inhibitors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-16-02.

Changes in T cell immunity in patients with metastatic castration resistant prostate treated with Radium-223 treatment.

295 Background: The bone seeking calcium mimetic, Radium223 (Ra223), emits high energy alpha particle that cause irreparable double strand DNA breaks in osseous metastases. Ra223 improves survival in patients with bone-predominant metastatic castration resistant prostate cancer (mCRPC). The effect of Ra223 on the host immune system, and T cell immunity in particular, is unknown. Methods: Eligible patients include men with mCRPC, osseous metastases and a clinical indication for Ra223 were eligible. Blood samples were collected at the following time points: prior to the first, second, and fourth treatments (tx) and 4 weeks after the sixth dose. Peripheral blood mononuclear cells (PBMCs) were purified and stained with a cocktail of antibodies to surface and effector immune molecules. Some PBMCs were stimulated and stained for intracellular cytokines (IFN-g, TNF-a, IL-13, IL-17, and IL-21). Stained cells were analyzed by flow cytometry. Results: A total seven patients completed at least two sample collections. The median number of prior lines of therapy was three. Median age was 71 (55-79). Median PSA was 78 (2-351). Effector memory (EM) CD8+ T cells were divided into two subsets expressing high and low levels of the IL-7 receptor alpha chain (IL-7Ra) with distinct cellular characteristics including perforin expression. The frequency of IL-7Rahigh and low EM CD8+ T cells expressing programmed death protein 1 (PD-1) was decreased after Ra223 treatment (pre vs. post, median (%) ± interquartile range, 14.3 ± 12.9 vs. 7.2 ± 20.9, P = 0.03; 16.7 ± 28.8 vs. 14.1 ± 37.8, P = 0.015 by Wilcoxon matched-pairs signed rank test). A similar finding was observed in the frequency of memory CD4+ T cells expressing PD-1 after the treatment (median (%) ± interquartile range, 7.2 ± 7.7 vs. 3.9 ± 3.4, P= 0.03). Conclusions: In this preliminary cohort of patients, Ra223 tx was associated with decrease in PD-1 expression by effector T cells. Further investigations of an immune mechanism of Ra223 mediated antitumor activity are warranted.

Preparation and characterization of polyphosphoester coated nanoparticles having a potential for delivery of hydrophobic drugs to bone

Event Abstract Back to Event Preparation and characterization of polyphosphoester coated nanoparticles having a potential for delivery of hydrophobic drugs to bone Yuya Hirano1* and Yasuhiko Iwasaki2, 3* 1 Kansai university, Graduate School of Science and Engineering, Japan 2 Kansai university, Faculty of Chemistry, Materials and Bioengineering, Japan 3 Kansai university, ORDIST, Japan Introduction: Bone is the most common metastatic site of epithelial cancers. Chemotherapy is the currentry most reliable treatment for bone metastasis. To improve the efficacy of the chemotherapy, several nanoparticles (NPs) have been proposed. Particularly, the nanoparticles bering bisphosphonates are usefule to deliver drugs to bone substrates[1]. We have recently proposed poly(ethylene phosphate) as a bone seeking polymer because the polymer shows higher affinity to hydroxyapatite (HAp) compared with bisphosphonates[2]. In the present study, we prepared poly (L-lactic acid) (PLLA) NPs coated with poly(ethylene phosphate) to obtain a drug carrier to specifically deliver chemotherapeutics to bone. Materials and Methods: Cholesteryl-terminated poly(ethylene sodium phosphate) (CH-PEP-Na) was synthesized according to a previously described method[3]. PLLA was dissolved in chloroform and the solution was dropped into the aqueous solution containing CH-PEP-Na at 0oC. The mixture was sonicated using a probe-type sonicator and chloroform was then evaporated under reduced pressure. PLLA NPs coated poly(ethylene glycol) (PEG) were prepared as a control. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to characterize prepared NPs. Cytotoxicity assay using MC3T3-E1 cells and hemolysis test were also carried out. To evaluate affinity of PEP-Na coated NPs to HAp, fluorophore-conjugated NPs were prepared, and contacted with HAp and calculated adsorption constant (KHAp). Results: PEP-Na coated NPs had approximately 100 nm in diameter and spherical shape as shown in Fig.1. NPs prepared by using PEG had similar size and morphology. Cytotoxicity and hemolytic activity of NPs were similar to those of negative control. Fig. 2 shows binding isotherms of NPs on HAp microparticles. KHAp of PEP-Na and PEG coated NPs suspended in PBS(-) calculated using Langmuir equation were 1.42×107 M-1 and 3.29×106 M-1, respectively. Discussion: The NPs coated PEP-Na could have a good dispersibility due to a spherical morphology and negative ζ-potential. The results of cytotoxicity assay using MC3T3-E1 cells and hemolysis test revealed that PEP-Na coated NPs had biocompatibility. The KHAp value of PEP-Na coated NPs in PBS (-) was higher than that of PEG coated NPs in PBS (-) and was similar to that of alendronate (1.6×107 M-1), so it was shown that PEP-Na coated NPs had high HAp-affinity. Conclusion: In the present study, we prepared poly(ethylene phosphate) coated PLLA NPs. Particle size of the NPs was about 100 nm, moreover, we revealed the NPs had excellent biocompatibility and HAp-affinity. The NPs could also encapsulate hydrophobic fluorephore. It is expected from our results that the NPs could incorporate hydrophobic drugs and deliver them to bone.

Novel 188Re multi-functional bone-seeking compounds: Synthesis, biological and radiotoxic effects in metastatic breast cancer cells

IntroductionRadiolabeled bisphosphonates (BPs) have been used for bone imaging and delivery of β− emitting radionuclides for bone pain palliation. As a β− emitter, 188Re has been considered particularly promising for bone metastases therapy. Aimed at finding innovative bone-seeking agents for systemic radiotherapy of bone metastases, we describe herein novel organometallic compounds of the type fac-[188Re(CO)3(k3-L)], (L=BP-containing chelator), their in vitro and in vivo stability, and their cellular damage in MDAMB231 cells, a metastatic breast cancer cell line. MethodsAfter synthesis and characterization of the novel organometallic compounds of the type fac-[188Re(CO)3(k3-L)] their radiochemical purity and in vitro stability was assessed by HPLC. In vivo stability and pharmacokinetic profile were evaluated in mice and the radiocytotoxic activity and DNA damage were assessed by MTT assay and by the cytokinesis-block micronucleus (CBMN) assay, respectively. ResultsAmong all complexes, 188Re3 was obtained with high radiochemical purity (>95%) and high specific activity and presented high in vitro and in vivo stability. Biodistribution studies of 188Re3 in Balb/c mice showed fast blood clearance, high bone uptake (16.1±3.3% IA/g organ, 1h p.i.) and high bone-to-blood and bone-to-muscle radioactivity ratios, indicating that it is able to deliver radiation to bone in a very selective way. The radiocytotoxic effect elicited by 188Re3 in the MDAMB231 cells was dependent on its concentration, and was higher than that induced by identical concentrations of [188ReO4]−. Additionally, 188Re3 elicited morphological changes in the cells and induced DNA damage by the increased number of MN observed. ConclusionAltogether, our results demonstrate that 188Re3 could be considered an attractive candidate for further preclinical evaluation for systemic radionuclide therapy of bone metastases considering its ability to deliver radiation to bone in a very selective way and to induce radiation damage.

The role of 18F–NaF PET/CT in metastatic bone disease

AimTo investigate the role of 18F–NaF PET/CT and compare it with 99m Tc-MDP whole body bone scintigraphy and 18F-FDG PET/CT in detecting the extent of metastatic bone disease and to present our first experience with 18F–NaF PET/CT in our country. Materials and methodsA total of 37 histopathologically proven cancer patients (22 male, 15 female) with bone metastasis detected on Tc-99m MDP whole body bone scan were prospectively enrolled Cebeci, following ethics committee approval. 18F–NaF PET/CT was performed to the participants in Ankara University Medical Faculty Nuclear Medicine Department for evaluation of symptomatic skeletal sites which were negative on Tc-99m MDP whole body bone scan. A lesion based comparison was made between 18F–NaF PET/CT and Tc-99m MDP whole body bone scan for each patient and between 18F–NaF PET/CT and 18F-FDG PET/CT in 12/37 patients. ResultsThe number of lesions demonstrated by 99m Tc-MDP bone scan and 18F–NaF PET/CT was equal in 4/37 (%11) of the cases. 18F–NaF PET/CT showed a greater number of pathological foci in 89% of participants. 18F–NaF PET/CT was able to show both lytic and blastic lesions and small lesions were better visualized due to the advantage of sectional imaging with much better resolution and higher target/background ratio. 18F–NaF PET/CT demonstrated a greater number of metastases in 10/12 (83%) of the patients when compared to 18F-FDG PET/CT. In the other two patients, bone metastasis could be demonstrated only by 18F–NaF PET/CT. The uptake of 18F-FDG was variable in blastic lesions and cranial bone involvement was missed by 18F-FDG PET/CT in some cases due to physiological brain metabolism. ConclusionAlthough further prospective clinical studies in specific cancer populations are indicated to set the place of 18F–NaF PET/CT in diagnostic scheme, the results of this pilot study from our country support the superiority of 18F–NaF PET/CT in investigation of bone metastasis over 99mTc-MDP bone scan and 18F-FDG PET/CT in various malignancies. 18F–NaF PET/CT is coming forward as a single step bone seeking study, considering all the advantages, but especially potential of detecting occult metastases and reliably directing patient management.

Estimated human absorbed dose of 177Lu–BPAMD based on mice data: Comparison with 177Lu–EDTMP

In this work, the absorbed dose of human organs for 177Lu–BPAMD was evaluated based on biodistribution studies into the Syrian mice by RADAR method and was compared with 177Lu–EDTMP as the only clinically used Lu-177 bone-seeking agent. The highest absorbed dose for both 177Lu–BPAMD and 177Lu–EDTMP is observed on the bone surface with 8.007 and 4.802mSv/MBq. Generally, 177Lu–BPAMD has considerable characteristics compared with 177Lu–EDTMP and can be considered as a promising agent for the bone pain palliation therapy.

Estimated human absorbed dose of a new 153Sm bone seeking agent based on biodistribution data in mice: Comparison with 153Sm-EDTMP

PurposeThe main goal in radiotherapy is to deliver the absorbed dose within the target organs in highest possible amount, while the absorbed dose of the other organs, especially the critical organs, should be kept as low as possible. In this work, the absorbed dose to human organs for a new 153Sm bone-seeking agent was investigated. Methods153Sm-(4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (153Sm-BPAMD) complex was successfully prepared. The biodistribution of the complex was investigated in male Syrian mice up to 48 h post injection. The human absorbed dose of the complex was estimated based on the biodistribution data of the mice by radiation absorbed dose assessment resource (RADAR) method. The target to non-target absorbed dose ratios for 153Sm-BPAMD were compared with these ratios for 153Sm-EDTMP. ResultsThe highest absorbed dose for 153Sm-BPAMD was observed in bone surface with 5.828 mGy/MBq. The dose ratios of the bone surface to the red marrow and to the total body for 153Sm-BPAMD were 5.3 and 20.0, respectively, while these ratios for 153Sm-EDTMP were 4.4 and 18.3, respectively. This means, for a given dose to the bone surface as the target organ, the red marrow (as the main critical organ) and the total body would receive lesser absorbed dose in the case of 153Sm-BPAMD. ConclusionsGenerally, the human absorbed dose estimation of 153Sm-BPAMD indicated that all other tissues approximately received insignificant absorbed dose in comparison with bone surface and therefore can be regarded as a new potential agent for bone pain palliation therapy.

Preliminary absorbed dose evaluation of two novel 153Sm bone-seeking agents for radiotherapy of bone metastases: comparison with 153Sm-EDTMP

AbstractAimThe amount of energy deposited on any organ by ionising radiation termedabsorbed dose, plays an important role in evaluating the risks associated with the administration of radiopharmaceuticals. In this research work, the absorbed dose received by human organs for153Sm-TTHMP and153Sm-PDTMP was evaluated based on biodistribution studies on the Syrian rats.Materials and methods153Sm-TTHMP and153Sm-PDTMP were successfully prepared with radiochemical purity of higher than 99%. The biodistribution of the complexes was investigated within the Syrian rats up to 48 hours post injection. The human absorbed dose of the complexes was estimated by the radiation dose assessment resource method.ResultsThe highest absorbed dose for153Sm-TTHMP and153Sm-PDTMP was observed in the trabecular bone with 1·085 and 1·826 mGy/MBq, respectively. The bone to other critical organ dose ratio for153Sm-PDTMP is significantly greater than153Sm-TTHMP. Also, the bone/red marrow dose ratio for these complexes is comparable with this ratio for153Sm-EDTMP, as the most clinically used Sm-153 bone pain palliative radiopharmaceutical.FindingsAccording to the considerable bone absorbed dose against the insignificant absorbed dose of non-target organs, these complexes can be used as potential bone pain palliative agents in clinical applications.

Studies on the Labeling of Ethylenediaminetetramethylene Phosphonic Acid, Methylene Diphosphonate, Sodium Pyrophosphate and Hydroxyapatite with Lutetium-177 for use in Nuclear Medicine.

For the treatment of skeletal metastasis, a therapeutic radionuclide tagged with a bone seeking ligand is required, while for radiation synovectomy (RS), a therapeutic radionuclide irreversibly attached to pre-formed particles of appropriate size is required. Radio lanthanides are mostly therapeutic, and ligands containing phosphate groups are predominantly bone seekers. Exploiting these facts, number of new therapeutic radiopharmaceuticals could be developed. Labeling of four phosphate containing materials was pursued in the present study. It was hypothesized that various 177Lu-labeled bone-seeking complexes such as 177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP), 177Lu-methylene diphosphonate (MDP) and 177Lu-pyrophosphate (PYP) could be developed as agents for palliative radiotherapy of bone pain due to skeletal metastases, and 177Lu-Hydroxyapatite (HA) could be developed as an agent for radiosynovectomy of small joints. Lyophilized kit vials of EDTMP, MDP and sodium pyrophosphate (Na-PYP) were formulated. HA particles were synthesized locally and purity was checked by high-performance liquid chromatography (HPLC). 177Lu was labeled with EDTMP, MDP, PYP, and HA and the behavior of all was studied by radio-thin layer chromatography (TLC) radio-HPLC and radio-electrophoresis. Radio-TLC confirmed the labeling. HPLC analysis too verified the labeling. Radio-electrophoresis results depicted peaks for 177Lu-MDP, 177Lu-EDTMP and 177Lu-PYP at 3.37 ± 0.06 cm, 5.53 ± 0.15 cm and 7.03 ± 0.06 cm respectively confirming negative charge on each specie as all migrated toward positive anode. All 3 methods verified the labeling. The study demonstrated that EDTMP, MDP and PYP form stable complexes with 177Lu in injectable solution form. HA particulates could too be labeled with 177Lu with high radiochemical yields (>98%) in suspension form. Former three could be utilized as bone-pain palliation agents for the treatment of bone metastases, and the later could be applied for the treatment of Rheumatoid arthritis of small joints. The study has also indicated the possibility of developing other numerous radiolanthanide analogs with the potentials of possible use in radiation therapy.

Metastatic Bone Pain Palliation using (177)Lu-Ethylenediaminetetramethylene Phosphonic Acid.

177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using 177Lu-EDTMP for MBP palliation. 177Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. 177Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. 177Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients with bone metastasis.

MP46-19 MICRODISTRIBUTION OF ALPHA PARTICLE EMITTING RADIUM-223 DICHLORIDE IN MODELS OF PROSTATE CANCER BONE METASTASIS

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2015MP46-19 MICRODISTRIBUTION OF ALPHA PARTICLE EMITTING RADIUM-223 DICHLORIDE IN MODELS OF PROSTATE CANCER BONE METASTASIS Diane Abou, David Ulmert, Robert Hobbs, Ryan Riddle, and Daniel Thorek Diane AbouDiane Abou More articles by this author , David UlmertDavid Ulmert More articles by this author , Robert HobbsRobert Hobbs More articles by this author , Ryan RiddleRyan Riddle More articles by this author , and Daniel ThorekDaniel Thorek More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1582AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Radium-223 dichloride (Xofigo, Bayer HealthCare Pharmaceuticals) is a first in class alpha particle emitter producing a survival benefit for patients with late stage bone metastatic castrate resistant prostate cancer (bmCRPC). Dosed at 45 kBq per kg every 4 weeks for 6 total injections, the bone seeking radionuclide delivers 4 high-energy alpha particles across a path length of only several cell diameters. Mechanism of action for the survival benefit is not fully understood, hampering our ability to best utilize this novel therapy. We tested 223Ra in naïve and bone metastatic models of disease, to define the whole body and sub-organ distribution of the radionuclide. Our results shed light on important considerations for pre- and clinical evaluation of 223Ra for personalized radiotherapy. METHODS Animals were dosed with 45 kBq per kg of clinical grade 223Ra. Whole body distribution was monitored by gamma counting in multiple skeletally-mature murine models. Organ and whole body retention were assessed at 1, 4 and 24 h. Detailed 223Ra microdistribution was assessed by cross-modality imaging of whole body and long bone autoradiography, histochemistry and alpha-camera imaging of whole-mount, undecalcified tissues. Uptake dependence and radiobiological effect of 223Ra on bone morphology were evaluated by 10 μm isotropic resolution μCT (SkyScan). RESULTS In contrast to previous preclinical work, our distribution studies recapitulate the planar scintigraphy results in man (Carrasquillo et al., EJNMMI, 2013), with 223Ra accumulation observed in bowel, stomach, and spleen. In particular, whole-body autoradiography demonstrated the radioisotope bound to the contents of the digestive organs. Kinetic analysis revealed rapid clearance from the blood, and delayed clearance from kidney and intestine. In the bone, 223Ra predominantly localized to the growth plates; largely sparing the marrow cavity. In bone metastatic models, including the osteoblastic LNCaP, 223Ra uptake was significantly lower than that in the epiphyseal plate (Figure). CONCLUSIONS Here we provide greater understanding of the in vivo biological fate of this radiopharmaceutical, with significant implications for enhanced dosing strategies in bmCRPC. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e551 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Diane Abou More articles by this author David Ulmert More articles by this author Robert Hobbs More articles by this author Ryan Riddle More articles by this author Daniel Thorek More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

MP46-20 CARMUSTINE AND SELENITE COMBINATION THERAPY EFFECTIVELY INHIBITS CASTRATION RESISTANT PROSTATE CANCER IN PRECLINICAL MODELS

INTRODUCTION AND OBJECTIVES: Radium-223 dichloride (Xofigo, Bayer HealthCare Pharmaceuticals) is a first in class alpha particle emitter producing a survival benefit for patients with late stage bone metastatic castrate resistant prostate cancer (bmCRPC). Dosed at 45 kBq per kg every 4 weeks for 6 total injections, the bone seeking radionuclide delivers 4 high-energy alpha particles across a path length of only several cell diameters. Mechanism of action for the survival benefit is not fully understood, hampering our ability to best utilize this novel therapy. We tested Ra in naive and bone metastatic models of disease, to define the whole body and sub-organ distribution of the radionuclide. Our results shed light on important considerations for preand clinical evaluation of Ra for personalized radiotherapy. METHODS: Animals were dosed with 45 kBq per kg of clinical grade Ra. Whole body distribution was monitored by gamma counting in multiple skeletally-mature murine models. Organ and whole body retention were assessed at 1, 4 and 24 h. Detailed Ra microdistribution was assessed by cross-modality imaging of whole body and long bone autoradiography, histochemistry and alpha-camera imaging of whole-mount, undecalcified tissues. Uptake dependence and radiobiological effect of Ra on bone morphology were evaluated by 10 mm isotropic resolution mCT (SkyScan). RESULTS: In contrast to previous preclinical work, our distribution studies recapitulate the planar scintigraphy results in man (Carrasquillo et al., EJNMMI, 2013), with Ra accumulation observed in bowel, stomach, and spleen. In particular, whole-body autoradiography demonstrated the radioisotope bound to the contents of the digestive organs. Kinetic analysis revealed rapid clearance from the blood, and delayed clearance from kidney and intestine. In the bone, Ra predominantly localized to the growth plates; largely sparing the marrow cavity. In bone metastatic models, including the osteoblastic LNCaP, Ra uptake was significantly lower than that in the epiphyseal plate (Figure). CONCLUSIONS: Here we provide greater understanding of the in vivo biological fate of this radiopharmaceutical, with significant implications for enhanced dosing strategies in bmCRPC.

Preparation and biological evaluation of 166Ho-BPAMD as a potential therapeutic bone-seeking agent

In this work 166Ho-(4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (166Ho-BPAMD) complex was prepared successfully with sufficient radiochemical purity of >94 % and specific activity of 244 GBq/mmol at the optimized conditions. The complex demonstrated significant stability at room temperature and in human serum at least for 24 h. Hydroxyapatite (HA) binding assay demonstrated that even at the small amount of HA, >10 mg, above 98 % of the complex is bound to HA. At the pH 7.4, LogP0/w was −1.73 ± 0.02. Both planar imaging and biodistribution studies showed major accumulation of the labelled compound in the bone tissue.

Hormonal therapy and chemotherapy for advanced prostate cancer

료 등 다양한 기전의 치료방법이 승인되어 사용되고 있다. The management of advanced prostate cancer has evolved rapidly. Androgen deprivation therapy, through surgical or medical castration, is the cornerstone of first-line therapy for hormone-naive metastatic prostate cancer. Recently reported results of clinical trials have given answers to questions regarding the best therapeutic agents and strategies, and these have broadened the scope of evidence-based therapy in this field. Although hormone therapy is very effective, the majority of patients eventually develop resistance to hormonal manipulation, leading to so-called castration-resistant prostate cancer. For castration-resistant prostate cancer, docetaxel-based chemotherapy had been the only approved agent to show a survival benefit for several years. However, over the last five years, significant advances in the field have led to the approval of several new agents with different mechanisms of action, such as the new androgen pathway inhibitors abiraterone and enzalutamide, a new cytotoxic agent, cabazitaxel, and new bone-seeking agents such as radium-223, which have all been associated with improved quality of life and pain palliation and an increase in survival. Herein, recent developments in hormone therapy and chemotherapy for advanced prostate cancer are reviewed and some of the trials with important results are summarized. As treatment options have expanded and developed rapidly, the selection of the most appropriate agent and administration method through multidisciplinary management is much more important than simply giving newly approved agents to maximize the clinical outcome for patients with advanced, especially castration-resistant, prostate cancer.

Radio-Synthesis, and In-vivo Skeletal Localization of 177Lu- zoledronic Acid as Novel Bone Seeking Therapeutic Radiopharmaceutical

Radiocomplextion of zoledronic acid (ZL), a potent bisphosphonate with Lutetium-177, was investigated. The 177Lu-ZL complex was assessed for its radiochemical purity, in vitro stability and bone uptake by scintigrpahic images. A stable 177Lu-ZL complex was observed with > 99.0±0.5% radiochemical yield and remained stable for more than 7 hours in vitro by mixing 12mg ZL, 5mCi activity of 177LuCl3 produced by thermal neutron irradiation (~1.2× 1014 n.cm-2s-1) of enriched Lu2O3 samples in Pakistan Research Reactor-1 (PARR-I), at pH 7-8. Radiochemical purity was determined by PC, ITLC and HPLC. The biodistribution of 177Lu-ZL in rabbit was studied by SPECT imaging. The 177Lu-ZL showed significant uptake in the bone, which was scintigrpahically confirmed after whole body scanning. Due to better physical properties of 177Lu as compared to Sm-153 and acceptable biodistribution of the compound, 177Lu-ZL seemed to be an interesting new candidate for bone pain palliation therapy of skeletal metastases.

Production, biodistribution, and dosimetry of (47)Sc-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid as a bone-seeking radiopharmaceutical.

In this study 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) was used as the polyaminophosphonic acid carrier ligand and the therapeutic potential of the bone seeking radiopharmaceutical 47Sc-DOTMP was assessed by measuring its dosage–dependent skeletal uptake and then the absorbed radiation dose of human organs was estimated. Because of limited availability of 47Sc we performed some preliminary studies using 46Sc. 46Sc was produced with a specific activity of 116.58 MBq/mg (3.15 mCi/mg) and radionuclide purity of 98%. 46Sc-DOTMP was prepared and an activity of 1.258 MBq (34 μCi) at a chelant-to-metal ratio of 60:1 was administered to five groups of mice with each group containing 3 mice that were euthanized at 4, 24, 48, 96 and 192 h post administration. The heart, lungs, liver, spleen, kidneys, intestine, skin, muscle, and a femur were excised, weighed, and counted. The data were analyzed to determine skeletal uptake and source organ residence times and cumulated activities for 47Sc-DOTMP. 46Sc-DOTMP complex was prepared in radiochemical purity about 93%. In vitro stability of complex was evaluated at room temperature for 48 h. Biodistribution studies of complex in mice were studied for 7 days. The data were analyzed to estimate skeletal uptake and absorbed radiation dose of human organs using biodistribution data from mice. By considering the results, 47Sc-DOTMP is a possible therapeutic agent for using in palliation of bone pain due to metastatic skeletal lesions from several types of primary cancers in prostate, breast, etc.

A comparative study of trans- and cis-isomers of a bone-seeking agent, DO2A2P

The macrocyclic bone-seeking agent, DO2A2P, bears a cyclen core and two pairs of peripheral phosphonate and carboxylate groups. The geometric disposition of the peripheral functionalities gives arise to a pair of geometric isomers: cis-DO2A2P and trans-DO2A2P. In order to compare the biological behavior of the isomer pair, cis-DO2A2P was synthesized. Both isomers were successfully radiolabeled with 177Lu, which might potentiate their applications in both radiotherapy and imaging of bone diseases. Through a set of biological assays including the hydroxyapatite binding, in vitro stability, and in vivo distribution, we demonstrated that the geometric pair of DO2A2P had virtually identical biological properties.

Detection of breast cancer microcalcification using 99mTc-MDP SPECT or Osteosense 750EX FMT imaging

BackgroundIn previous work, we demonstrated the presence of hydroxyapetite (type II microcalcification), HAP, in triple negative MDA-MB-231 breast cancer cells. We used 18F-NaF to detect these types of cancers in mouse models as the free fluorine, 18F−, binds to HAP similar to bone uptake. In this work, we investigate other bone targeting agents and techniques including 99mTc-MDP SPECT and Osteosense 750EX FMT imaging as alternatives for breast cancer diagnosis via targeting HAP within the tumor microenvironment. MethodsThirteen mice were injected subcutaneously in the right flank with 106 MDA-MB-231 cells. When the tumor size reached ~0.6cm3, mice (n=9) were injected with ~37MBq of 99mTc-MDP intravenously and then imaged one hour later in a NanoSPECT/CT or injected intravenously with 4nmol/g of Osetosense 750EX and imaged 24hours later in an FMT (n=4). The imaging probe concentration in the tumor was compared to that of muscle. Following SPECT imaging, the tumors were harvested, sectioned into 10μm slices, and underwent autoradiography or von Kossa staining to correlate 99mTc-MDP binding with HAP distribution within the tumor. The SPECT images were normalized to the injected dose and regions-of-interest (ROIs) were drawn around bone, tumor, and muscle to obtain the radiotracer concentration in these regions in units of percent injected dose per unit volume. ROIs were drawn around bone and tumor in the FMT images as no FMT signal was observed in normal muscle. ResultsUptake of 99mTc-MDP was observed in the bone and tumor with little or no uptake in the muscle with concentrations of 11.34±1.46 (mean±SD), 2.22±0.95, and 0.05±0.04%ID/cc, respectively. Uptake of Osteosense 750EX was also observed in the bone and tumor with concentrations of 0.35±0.07 (mean±SD) and 0.04±0.01picomoles, respectively. No FMT signal was observed in the normal muscle. There was no significant difference in the bone-to-tumor ratio between the two modalities (5.1±2.3 for SPECT and 8.8±2.2 for FMT) indicating that there is little difference in tumor uptake between these two agents. ConclusionThis study provides evidence of the accessibility of HAP within the breast tumor microenvironment as an in vivo imaging target for bone-seeking agents. SPECT imaging using 99mTc-MDP can be rapidly translated to the clinic. FMT imaging using Osteosense 750EX is not currently approved for clinical use and is limited to animal research.