Rhenium Sulfide Nanoparticles as a Biosafe Spectral CT Contrast Agent for Gastrointestinal Tract Imaging and Tumor Theranostics in Vivo.

Spectral computed tomography (CT) imaging as a novel imaging technique shows promising prospects in the accurate diagnosis of various diseases. However, clinically iodinated contrast agents suffer from poor signal-to-noise ratio, and emerging heavy-metal-based CT contrast agents arouse great biosafety concern. Herein, we show the fabrication of rhenium sulfide (ReS2) nanoparticles, a clinic radiotherapy sensitizer, as a biosafe spectral CT contrast agent for the gastrointestinal tract imaging and tumor theranostics in vivo by teaching old drugs new tricks. The ReS2 nanoparticles were fabricated in a one-pot facile method at room temperature, and exhibited sub-10 nm size, favorable monodispersity, admirable aqueous solubility, and strong X-ray attenuation capability. More importantly, the proposed nanoparticles possess an outstanding spectral CT imaging ability and undoubted biosafety as a clinic therapeutic agent. Besides, the ReS2 nanoparticles possess appealing photothermal performance due to their intense near-infrared absorption. The proposed nano-agent not only guarantees obvious contrast enhancement in gastrointestinal tract spectral CT imaging in vivo, but also allows effective CT imaging-guided tumor photothermal therapy. The proposed "teaching old drugs new tricks" strategy shortens the time and cuts the cost required for clinical application of nano-agents based on existing clinical toxicology testing and trial results, and lays down a low-cost, time-saving, and energy-saving method for the development of multifunctional nano-agents toward clinical applications.

Synthesis, characterization and pre-clinical evaluation of (99m) Tc-tricarbonyl complexes as potential myocardial perfusion imaging agents.

Myocardial perfusion imaging is an established Nuclear Medicine investigation. Current myocardial perfusion imaging agents sestamibi and tetrofosmin have number of drawbacks; low heart uptake coupled with uptake into the surrounding tissues leads to a poorer image quality. There is a need for continued research into designing and evaluating potentially superior myocardial imaging agents. Tri-carbonyl-technetium and rhenium complexes were prepared by combination with mono-dentate and bi-dentate ligands. Complexes were characterized by HPLC, MAS, nuclear magnetic resonance, infrared, single-crystal X-ray diffraction and partition coefficient determinations. (99m) Tc(CO)3 complexes were administered intravenously to Sprague Dawley rats, and tissue distribution studies were carried out at 15 min and 1 h p.i. Radiochemical purity was assessed as >90%. 1-10-phenanthroline, 2,2'-bipyridine and imidazole complexes gave the highest heart uptake. The percentage injected dose per gram (n = 3) at 1 h for 1-10-phenanthroline/imidazole was blood 0.21 ± 0.01, heart 1.12 ± 0.11, kidney 3.61 ± 1.13, liver 0.62 ± 0.06, lung 0.28 ± 0.12, spleen 0.24 ± 0.05, small intestine contents 1.87 ± 0.92; and for 2,2'-bipyridine /imidazole was blood 0.23 ± 0.02, heart 1.07 ± 0.18, kidney 3.31 ± 1.28, liver 0.56 ± 0.09, lung 0.14 ± 0.02, spleen 0.2 ± 0.1, small intestine content 1.05 ± 0.48. Further investigation to evaluate more complexes based on 1,10-phenanthroline, 2,2'-bipyridine and imidazole derivatives could potentially lead to agents with an increased heart uptake and faster clearance from the liver and gastrointestinal tract.

Preparation and biodistribution of 188Re-labeled folate conjugated human serum albumin magnetic cisplatin nanoparticles (188Re-folate-CDDP/HSA MNPs) in vivo.

BACKGROUND: The purpose of this study was to develop intraperitoneal hyperthermic therapy based on magnetic fluid hyperthermia, nanoparticle-wrapped cisplatin chemotherapy, and magnetic particles of albumin. In addition, to combine the multiple-killing effects of hyperthermal targeting therapy, chemotherapy, and radiotherapy, the albumin-nanoparticle surfaces were linked with radionuclide (188)Re-labeled folic acid ligand ((188)Re-folate-CDDP/HSA). METHODS: Human serum albumin was labeled with (188)Re using the pre-tin method. Reaction time and optimal conditions of labeling were investigated. The particles were intravenously injected into mice, which were sacrificed at different time points. Radioactivity per gram of tissue of percent injected dose (% ID/g) was measured in vital organs. The biodistribution of (188)Re-folate-CDDP/HAS magnetic nanoparticles was assessed. RESULTS: Optimal conditions for (188)Re-labeled folate-conjugated albumin combined with cisplatin magnetic nanoparticles were: 0.1 mL of sodium gluconate solution (0.3 mol/L), 0.1 mL of concentrated hydrochloric acid with dissolved stannous chloride (10 mg/mL), 0.04 mL of acetic acid buffer solution (pH 5, 0.2 mol/L), 30 mg of folate-conjugated albumin combined with cisplatin magnetic nanoparticles, and (188)ReO(4) eluent (0.1 mL). The rate of (188)Re-folate-CDDP-HSA magnetic nanoparticle formation exceeded 90%, and radiochemical purity exceeded 95%. The overall labeling rate was 83% in calf serum at 37°C. The major uptake tissues were the liver, kidney, intestine, and tumor after the (188)Re-folate-CDDP/HSA magnetic nanoparticles were injected into nude mice. Uptake of (188)Re-folate-CDDP/HSA magnetic nanoparticles increased gradually after injection, peaked at 8 hours with a value of 8.83 ± 1.71, and slowly decreased over 24 hours in vivo. CONCLUSION: These results indicate that (188)Re-folate-CDDP/HSA magnetic nanoparticles can be used in radionuclide-targeted cancer therapy. Surface-modified albumin nanoparticles with folic acid ligand-labeled radionuclide ((188)Re) were successfully prepared, laying the foundation for a triple-killing effect of thermotherapy, chemotherapy, and radiation therapy.

Patient-specific radiation dosimetry for radionuclide therapy of liver tumors with intrahepatic artery rhenium-188 lipiodol.

A clinically practical algorithm has been developed for the treatment of liver cancer by the administration of rhenium-188 ((188)Re)-labeled lipiodol via the hepatic artery. This algorithm is based on the "maximum tolerated-activity" paradigm for radionuclide therapy. A small "scout" activity of (188)Re-labeled lipiodol is administered to the patient before the actual therapeutic administration. At approximately 3 hours after administration, the activities in the normal liver, liver tumors, lungs, and total body are measured by gamma camera imaging using the conjugate-view method, with first-order corrections for attenuation (using a (188)Re transmission scan) and scatter (using the "dual-window" method). At the same time, peripheral blood samples are counted, and the activity concentrations in whole blood are calculated. The blood activity concentrations are then converted to red marrow activity concentrations and then total red marrow activity using anatomic data from Standard Man anthropomorphic models. Next, the cumulated activities in the normal liver, liver tumors, lungs, red marrow, and total body are calculated using the measured activities in the respective source regions and conservatively assuming elimination of activity only by physical decay in situ. The absorbed doses to the therapy-limiting normal tissues, liver, lung, and red marrow, are then calculated using the Medical Internal Radiation Dose Committee schema, adjusting the pertinent S factors for differences in total body and organ masses between the patient and the anthropomorphic model and including the dose contribution from the liver tumors. Finally, based on maximum tolerated absorbed doses of 3,000, 1,200, and 150 rad (cGy) to liver, lung, and red marrow, the respective absorbed doses per unit administered activity are used to calculate the therapy activity. Although not required for treatment planning, tumor absorbed dose may also be estimated. This algorithm has been automated using an Excel (Microsoft, Redmond, WA) spreadsheet.

Assessment of 186Re chelate-conjugated bisphosphonate for the development of new radiopharmaceuticals for bones.

INTRODUCTION: The preferable pharmacokinetics of rhenium-186 (186Re)-monoaminemonoamidedithiol-conjugated or 186Re-mercaptoacetyltriglycine-conjugated bisphosphonates (BPs) suggested that the molecular design would be applicable to other radionuclides such as 68Ga, 99mTc, 153Sm and 177Lu. In this study, a key factor affecting the pharmacokinetics of a chelate-conjugated BP was investigated to estimate the validity and the applicability of molecular design. METHODS: Chemically inert and well-characterized tricarbonyl[186Re][(cyclopentadienylcarbonyl amino)-acetic acid]rhenium ([186Re]CpTR-Gly) was conjugated with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate and purified by high-performance liquid chromatography (HPLC) to prepare [186Re](1-{3-[tricarbonyl(cyclopentadienylcarbonyl amino)-acetylamido]-1-hydroxy-1-phosphono-propyl}-phosphonic acid)rhenium ([186Re]CpTR-Gly-APD). Plasma stability, plasma protein binding, hydroxyapatite (HA) binding and the pharmacokinetics of [186Re]CpTR-Gly-APD were compared with those of 186Re 1-hydroxyethylidene-1,1-diphosphonate (HEDP). The effect of HEDP coadministration and preadministration on the pharmacokinetics of [186Re]CpTR-Gly-APD was also determined. RESULTS: The HPLC-purified [186Re]CpTR-Gly-APD showed higher plasma stability, higher HA binding, higher bone accumulation and lower plasma protein binding than did 186Re-HEDP. However, HA binding of [186Re]CpTR-Gly-APD decreased to levels slightly higher than that of 186Re-HEDP at similar HEDP concentrations. Bone accumulation of [186Re]CpTR-Gly-APD also decreased to levels similar to that of 186Re-HEDP when [186Re]CpTR-Gly-APD was coinjected with HEDP equivalent to that in 186Re-HEDP. In contrast, HEDP pretreatment did not impair bone accumulation of the two 186Re-labeled compounds. However, a delay in blood clearance and an increase in renal radioactivity levels were observed particularly with 186Re-HEDP. CONCLUSIONS: Although 186Re-HEDP possessed HA binding and bone accumulation similar to those of [186Re]CpTR-Gly-APD, the specific activity of 186Re-labeled BPs was found to play a crucial role in bone accumulation and blood clearance. Thus, the molecular design of chelate-conjugated BP would be useful for the development of bone-seeking radiopharmaceuticals with a variety of radionuclides by selecting chelating molecules that provide high specific activities.

Locoreginal radioimmunotherapy with 186Re-labeled monoclonal antibody in treating small peritoneal carcinomatosis of colon cancer in mice in comparison with 131I-counterpart.

The efficacy of locoregional radioimmunotherapy (RIT) in treating peritoneal tumors of colon cancer of <2 mm in diameter was examined at maximum tolerated doses, focusing the comparison between 186Re and 131I labeled to an anti-colorectal cancer IgG1. Estimated radiation doses to tumors were considerably higher with 186Re-RIT than with 131I-RIT. The advantage of 186Re-RIT decreased with decreasing tumor size, but 186Re-RIT delivered 1.6-times higher radiation to tumors of 1 mm. Consequently, 186Re-RIT attained better survival of mice than 131I-RIT or chemotherapy with 5-fluorouracil did. Therefore, locoregional 186Re-RIT may be an option in an adjuvant setting of colon cancer with high risk of peritoneal dissemination.

A model-based method for the prediction of whole-body absorbed dose and bone marrow toxicity for 186Re-HEDP treatment of skeletal metastases from prostate cancer.

In high-activity rhenium-186 hydroxyethylidene diphosphonate ((186)Re-HEDP) treatment of bone metastatic disease from prostate cancer the dose-limiting factor is haematological toxicity. In this study, we examined the correlation of the injected activity and the whole-body absorbed dose with treatment toxicity and response. Since the best response is likely to be related to the maximum possible injected activity limited by the whole-body absorbed dose, the relationship between pre-therapy biochemical and physiological parameters and the whole-body absorbed dose was studied to derive an algorithm to predict the whole-body absorbed dose prior to injection of the radionuclide. The whole-body retention of radioactivity was measured at several time points after injection in a cohort of patients receiving activities ranging between 2,468 MBq and 5,497 MBq. The whole-body absorbed dose was calculated by fitting a sequential series of exponential phases to the whole-body time-activity data and by integrating this fit over time to obtain the whole-body cumulated activity. This was then converted to absorbed dose using the Medical Internal Radiation Dose (MIRD) committee methodology. Treatment toxicity was estimated by the relative decrease in white cell (WC) and platelet (Plt) counts after the injection of the radionuclide, and by their absolute nadir values. The criterion for a treatment response was a 50% or greater decrease in prostate-specific antigen (PSA) value lasting for 4 weeks. Alkaline phosphatase (AlkPh), chromium-51 ethylene diamine tetra-acetate ((51)Cr-EDTA) clearance rate and weight were measured before injection of the radionuclide. The whole-body absorbed dose showed a significant correlation with WC and Plt toxicity ( P=0.005 and 0.003 for the relative decrease and P=0.006 and 0.003 for the nadir values of WC and Plt counts respectively) in a multivariate analysis which included injected activity, whole-body absorbed dose, pre-treatment WC and Plt baseline counts, PSA and AlkPh values, and the pre-treatment Soloway score. The injected activity did not show any correlation with WC or Plt toxicity, but it did correlate with PSA response ( P=0.005). These results suggest that the administration of higher activities would be likely to generate a better response, but that the quantity of activity that can be administered is limited by the whole-body absorbed dose. We have derived and evaluated a model that estimates the whole-body absorbed dose on an individual patient basis prior to injection. This model uses the level of injected activity and pre-injection measurements of AlkPh, weight and (51)Cr-EDTA clearance. It gave good estimates of the whole-body absorbed dose, with an average difference between predicted and measured values of 15%. Furthermore, the whole-body absorbed dose predicted using this algorithm correlated with treatment toxicity. It could therefore be used to administer levels of activity on a patient-specific basis, which would help in the optimisation of targeted radionuclide therapy. We believe that algorithms of this kind, which use pre-injection biochemical and physiological measurements, could assist in the design of escalation trials based on a toxicity-limiting whole-body absorbed dose, rather than using the more conventional activity escalation approach.

[Radiotherapy with (186)Re-lipiodol II for primary liver cancer patients].

OBJECTIVE: To analyze the biodistribution of (186)Re-lipiodol (RL) in patients with primary liver cancer (PLC) after hepatic arterial injection in attempt to assess the potential of RL as a radiopharmaceutical for the treatment of PLC. METHODS: RL was synthesized from (186)Rhenium and Lipiodol by a series of physical and chemical procedures. Doses of RL ranged from 1 110 MBq to 2 220 MBq per patient depending on the volume of tumor. Quantitative gamma camera imaging (ECT) and gamma counting of serum and urine were used to obtain data for dosimetry estimation. Serum tumor marker (AFP) level and shrinkage of tumor were used to evaluate the therapeutic efficacy of RL. RESULTS: In the hepatic tumor, RL was selectively retained and radioactivity was very high throughout this study. The ratio of tumor concentration to the normal liver tissue concentration (T/NT ratio) was 10 - 14 at 48 hours after injection of RL. The main side effects of this therapy were transient fever and anorexia. No unacceptable toxicity was observed. In 100% of the patients, the therapy resulted in a significant decrease of AFP level and reduction of tumor volume. CONCLUSION: The biodistribution and imaging results demonstrated RL localized selectively in tumor, and that RL may be a potential internal radiopharmaceutical agent for the treatment of primary liver cancer.

Radiolabelling of Lipiodol with generator-produced 188Re for hepatic tumor therapy.

In this study we prepared and analyzed the biodistribution of 188Re-labelled Lipiodol ([188Re]-Lipiodol) in rats after intrahepatic arterial injection. EDTB was synthesized by condensation of 1,2-benzenediamine and ethylenediaminetetraacetic acid (EDTA). The labelling efficiency of [188Re] Lipiodol was determined to be greater than 97% by ITLC developed with n-hexane. Following incubation of the [188Re] Lipiodol with an equal volume of serum at 37 degrees C for 48 h, ITLC indicated good in vitro stability. Approximately 7.4 MBq [188Re] Lipiodol was injected in each rat via the hepatic artery and samples of liver, spleen, muscle, lung, kidney, bone, whole blood and testis were obtained. [188Re] Lipiodol tissue concentrations showed that after 1 h intrahepatic injection most of the radiotracer was retained in the liver, and was eliminated slowly with a biological half-life of 33.5 h. Radioactvity levels in the lung, kidney and blood were moderate at 1 h, and declined rapidly over time. In the spleen, muscle, testis and bone, radiation levels were insignificant. These initial results indicate that -188Re- Lipiodol may be a potential radiopharmaceutical agent for the treatment of liver tumors.

Biodistribution of rhenium-188 Lipiodol infused via the hepatic artery of rats with hepatic tumours.

The purpose of this study was to analyse the biodistribution of rhenium-188 Lipiodol in rats with hepatic tumours following intrahepatic arterial injection to assess the potential of 188Re-Lipiodol as a radiopharmaceutical for the treatment of hepatic tumours in humans. Twelve male rats with hepatic tumours were killed at 1h, 24h and 48h after injection of approximately 7.4MBq of 188Re-Lipiodol via the hepatic artery. Samples of various organs were obtained and counted to calculate the tissue concentration. Radioactivity in the hepatic tumours was very high throughout this study, with a biological half-life of 122.9h. Radioactivity in the normal liver tissue was also high, but was significantly lower than in the tumour. The biological half-life in the normal liver tissue was 31.7h. The ratio of tumour concentration to the normal liver tissue concentration was 5.15 at 1h and rose to 7.7 at 24h and 10.84 at 48h. The level of radioactivity in the lung was high at 1h, and declined rapidly over time. The level of radioactivity in the kidney was moderate throughout the study. The radiation concentrations in muscle, spleen, testis, bone and whole blood were insignificant. We conclude that 188Re-Lipiodol should be considered as a potential radiopharmaceutical for the intra-arterial treatment of hepatic tumours.

Direct radiolabeling of monoclonal antibodies with generator-produced rhenium-188 for radioimmunotherapy: labeling and animal biodistribution studies.

The use of 188Re from an alumina-based 188W/188Re generator has been investigated for antibody radiolabeling. It was found that, with simple labeling techniques, 188Re can be used immediately after elution. The direct radiolabeling of intact antibodies with 188Re is described. Lyophilized antibody preparations have been reconstituted with 188Re taken directly from the generator at specific activities of up to 15 mCi of 188Re per mg of antibody. Radiolabeling yields of 90 to 98% have been obtained, with the incorporation rate being dependent upon time and the relative concentrations of the reagents. It was determined that the conjugates were immunoreactive and stable when challenged by serum in vitro, with 188Re-immunoglobulin G showing adequate resistance to reoxidation with no transfer of 188Re to serum protein. 188Re-antibody conjugates were shown to clear from the blood faster than the corresponding 131I-labeled antibody, giving rise to good tumor/nontumor ratios at 24 to 72 h postinjection, while serum samples taken from the animals have shown that the circulating 188Re remained bound to immunoglobulin G. The combination of the technologies of the 188W/188Re generator, the direct labeling methodology, and the use of single-vial lyophilized antibody makes the use of 188Re-radiolabeled monoclonal antibodies a simple and convenient method of cancer radioimmunotherapy with a beta-emitting radionuclide.