Gann Ting

Nanotargeted Radionuclides for Cancer Nuclear Imaging and Internal Radiotherapy

Current progress in nanomedicine has exploited the possibility of designing tumor-targeted nanocarriers being able to deliver radionuclide payloads in a site or molecular selective manner to improve the efficacy and safety of cancer imaging and therapy. Radionuclides of auger electron-, α-, β-, and γ-radiation emitters have been surface-bioconjugated or after-loaded in nanoparticles to improve the efficacy and reduce the toxicity of cancer imaging and therapy in preclinical and clinical studies. This article provides a brief overview of current status of applications, advantages, problems, up-to-date research and development, and future prospects of nanotargeted radionuclides in cancer nuclear imaging and radiotherapy. Passive and active nanotargeting delivery of radionuclides with illustrating examples for tumor imaging and therapy are reviewed and summarized. Research on combing different modes of selective delivery of radionuclides through nanocarriers targeted delivery for tumor imaging and therapy offers the new possibility of large increases in cancer diagnostic efficacy and therapeutic index. However, further efforts and challenges in preclinical and clinical efficacy and toxicity studies are required to translate those advanced technologies to the clinical applications for cancer patients.

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 of188Re-Lipiodol as a radiopharmaceutical for the treatment of hepatic tumours in humans. Twelve male rats with hepatic tumours were killed at 1 h, 24 h and 48 h after injection of approximately 7.4 MBq of188Re-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 122.9 h. 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 31.7 h. The ratio of tumour concentration to the normal liver tissue concentration was 5.15 at 1 h and rose to 7.7 at 24 h and 10.84 at 48 h. The level of radioactivity in the lung was high at 1 h, 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 that188Re-Lipiodol should be considered as a potential radiopharmaceutical for the intra-arterial treatment of hepatic tumours.

Diagnostic and therapeutic evaluation of 111In-vinorelbine-liposomes in a human colorectal carcinoma HT-29/luc-bearing animal model

Colorectal carcinoma is a highly prevalent and common cause of cancer in Taiwan. There is still no available cure for this malignant disease. To address this issue, we applied the multimodality of molecular imaging to explore the efficacy of diagnostic and therapeutic nanoradiopharmaceuticals in an animal model of human colorectal adenocarcinoma [colorectal cancer (CRC)] that stably expresses luciferase (luc) as a reporter. In this study, an in vivo therapeutic efficacy evaluation of dual-nanoliposome (100 nm in diameter) encaged vinorelbine (VNB) and (111)In-oxine on HT-29/luc mouse xenografts was carried out. HT-29/luc tumor cells were transplanted subcutaneously into male SCID mice. Multimodality of molecular imaging approaches including bioluminescence imaging (BLI), gamma scintigraphy, whole-body autoradiography (WBAR) and in vivo tumor growth tracing, histopathology and biochemistry/hematology analyses were applied on xenografted SCID mice to study the treatments with 6% polyethylene glycol (PEG) of (111)In-NanoX/VNB-liposomes. In vivo tumor growth tracing and BLI showed that tumor volume could be completely inhibited by the combination therapy with (111)In-VNB-liposomes and by chemotherapy with NanoX/VNB-liposomes (i.e., without Indium-111) (P<.01). The nuclear medicine images of gamma scintigraphy and WBAR also revealed the conspicuous inhibition of tumor growth by the combination therapy with (111)In-VNB-liposomes. Animal body weights, histopathology and biochemistry/hematology analyses were used to confirm the safety and feasibility of radiopharmaceuticals. A synergistic therapeutic effect on CRC xenografted SCID mice was proven by combining an Auger electron-emitting radioisotope (Indium-111) with an anticancer drug (VNB). This study further demonstrates the beneficial potential applications of multimodality molecular imaging as part of the diagnostic and therapeutic approaches available for the evaluation of new drugs and other strategic approaches to disease treatment.

Therapeutic Efficacy Evaluation of 111In-Labeled PEGylated Liposomal Vinorelbine in Murine Colon Carcinoma with Multimodalities of Molecular Imaging

In our previous studies using combined radioisotopes with chemotherapeutic liposomal drugs (i.e., 111In-labeled polyethylene glycol (PEG)ylated liposomal vinorelbine) we have reported possible therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this chemotherapy has a therapeutic effect as good as that of combination therapy. The goal of this study was to investigate the real therapeutic effectiveness of 6 mol% PEG 111In-vinorelbine liposomes via the elevation of the radiation dosage and reduction in the concentration of chemotherapeutic agents. Methods: Murine colon carcinoma cells transfected with dual-reporter genes (CT-26/tk-luc) were xenografted into BALB/c mice. The biodistribution was estimated to determine the drug profile and targeting efficiency of 111In-vinorelbine liposomes. Bioluminescence imaging and 18F-FDG small-animal PET were applied to monitor the therapeutic response after drug administration. The survival in vivo was estimated and linked with the toxicologic and histopathologic analyses to determine the preclinical safety and feasibility of the nanomedicine. Results: Effective long-term circulation of radioactivity in the plasma was achieved by 6 mol% PEG 111In-vinorelbine liposomes, and this dose showed significantly lower uptake in the reticuloendothelial system than that of 0.9 mol% PEG 111In-vinorelbine liposomes. Selective tumor uptake was represented by cumulative deposition, and the maximum accumulation was at 48 h after injection. The combination therapy exhibited an additive effect for tumor growth suppression as tracked by caliper measurement, bioluminescence imaging, and small-animal PET. Furthermore, an improved survival rate and reduced tissue toxicity were closely correlated with the toxicologic and histopathologic results. Conclusion: The results demonstrated that the use of 6 mol% PEG 111In-vinorelbine liposomes for passively targeted tumor therapy displayed an additive effect with combined therapy, not only by prolonging the circulation rate because of a reduction in the phagocytic effect of the reticuloendothelial system but also by enhancing tumor uptake. Thus, this preclinical study suggests that 6 mol% PEG 111In-vinorelbine liposomes have the potential to increase the therapeutic index and reduce the toxicity of the passively nanotargeted chemoradiotherapies.

Rhenium-188 microspheres: a new radiation synovectomy agent.

SUMMARYRadiation synovectomy is efficacious in controlling the symptoms of rheumatoid arthritis. However, the procedure is not widely used because of concerns about leakage of radiopharmaceuticals from the treated joints. Leakage can be minimized by selecting particles of an appropriate size. In this study, we labelled microspheres with 188Re and analysed its biodistribution after intra-articular injection in rabbits with antigen-induced arthritis. Gamma camera imaging was performed to quantify the mean retention of 188Re in the knees. The mean retention of 188Re was 98.7, 94.6 and 93.6% at 1, 24 and 48 h, respectively. The biodistribution data revealed very low radioactivity in all organs at different times, which suggests the leakage of radiotracer from the knee was negligible. Our preliminary results indicate that 188Re microspheres are a potentially effective radiopharmaceutical for radiation synovectomy.

Effect of reaction conditions on preparations of rhenium-188 hydroxyethylidene diphosphonate complexes.

Rhenium-186 (Re-186) hydroxyethylidene diphosphonate (HEDP) has been shown to localize in metastatic foci within bone in a manner similar to Tc-99m bone-seeking agents. Usually, in the preparation of diagnostic Tc-99m radiopharmaceuticals, the concentration of Tc is at trace level (10(-8) M). However, large amounts of carrier are included in the preparation of Re-186 radiopharmaceuticals (10(-4) M), which may significantly affect the preparation of Re-HEDP. In this study, Re-188 was used as an Re tracer. The effects of pH and concentrations of Re carrier on the preparation of Re-HEDP were investigated. Re-188-Sn-HEDP was prepared by reconstitution of a kit of lyophilized HEDP mixture, and tin chloride with a radioactive solution of perrhenate in saline. The total concentration of Re present in this work ranged from 10(-8) to 10(-3) M. The results showed that high labeling efficiency was obtained for each preparation. Although the chemical behaviors of the Re-188 HEDP complexes, with and without carrier, were similar, the biodistribution patterns of carrier free Re-188 HEDP in rats were found to differ from the biodistribution patterns of carrier-added Re-188 HEDP.

Biodistribution study of [123I] ADAM in mice: correlation with whole body autoradiography

Iodine-123 labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([(123)I] ADAM) has been suggested as a promising serotonin transporter (SERT) imaging agent. Much research has been accomplished, mainly focusing on the SERT binding sites in the central nervous system (CNS). However, the biodistribution of [(123)I] ADAM using whole body autoradiography (WBAR) has never been previously described, to the best of our knowledge. In this study, we assayed the biodistribution of [(123)I] ADAM in tissues/organs removed from mice, and measured their radioactivity with a scintillation counter (SC). The results showed that the liver has the highest uptake. On the other hand, the WBAR clearly demonstrated that [(123)I] ADAM was bound to SERT-rich sites including those in the brain stem, lung, adrenal glands and intestinal mucosa. This radiotracer also accumulated in the liver, kidney, and thyroid. The results from both methods were compared; each has its own complementary role in the biodistribution studies. The SC method revealed the total amount of radiotracer accumulation in each organ, and the WBAR demonstrated more anatomical details of the radiotracers distribution. The whole body distribution results of the radioligand using both methods explore the usage of this novel radioligand for most possible SERT binding sites, not only in the CNS but also in the peripheral nervous system and neuroendocrine tissues. These findings suggest that [(123)I] ADAM is a potentially useful imaging agent for SERT.

Preparation and biodistribution of yttrium-90 Lipiodol in rats following hepatic arterial injection

In this study, we labelled Lipiodol with yttrium-90 and analysed the biodistribution in rats after intrahepatic arterial injection. An RP-18 column (E. Merck) was used to separate90Y from strontium-90.90Y was retained on the column, which had been pretreated with yttrium-selective extraction reagent, di(2-ethylhexyl) phosphate, while90Sr was washed out. A hexadentate nitrogen-donor chelating ligandN,N,N′,N′-tetrakis(2-ben-zymidazolylmethyl)-1,2-ethanediamine (EDTB) was synthesized by condensation of 1,2-benzenediamine and ethylene diamine tetra-acetic acid (EDTA). Lipiodol was covalently conjugated with EDTB. The final product was obtained by eluting the retained90Y from the RP-18 column with EDTB-Lipiodol. Sixteen male rats (Sprague-Dawley) were sacrificed at 1 h, 24 h, 48 h and 72 h (four rats at each time) after injection of approximately 0.1 mCi90Y Lipiodol via the hepatic artery. Samples of liver, spleen, muscle, lung, kidney, bone, whole blood and testis were obtained and counted to calculate the tissue concentrations. In addition, labelling efficiency and in vitro stability were determined by ITLC methods. We found that at 1 h after intrahepatic injection, most of the radiotracer was retained in the liver, but it was eliminated gradually over a few days. The radioactivity level in the lung was fair at 1 h and remained at roughly the same level throughout the study. Radioactivity in the kidney and spleen reached a relatively high level at 24 h, but declined rapidly. Bone uptake was low initially but showed an increase between 24 h and 72 h. Low concentrations of radioactivity were noted in the muscle, testis and whole blood. In the study of in vitro stability, radiochemical purity and labelling efficiency were higher than 90%, indicative of good stability. These initial results indicate that Lipiodol may be a possible carrier agent for90Y The retention of90Y-Lipiodol in the normal liver is high initially; however, elimination occurs over a period of a few days. Future studies should assess the biodistribution of90Y Lipiodol in an animal model with liver cancer.

Comparison of various rhenium-188-labeled diphosphonates for the treatment of bone metastases

In the past, many diphosphonates were introduced as bone scan radiopharmaceuticals. In addition, diphosphonates have been labeled with beta-emitted isotopes and developed into useful therapeutic drugs for bone metastases. However, it is not clear which diphosphonate is the best choice when labeling with Re-188. In this study, we labeled methylene diphosphonate (MDP), hydroxyethylidene diphosphonate (HEDP), and hydroxymethane diphosphonate (HDP) with Re-188. Each radiopharmaceutical was further evaluated in two conditions (with and without carrier). Twenty-four rabbits were used (four in each group) for the analysis of the biodistributions and bone uptakes of these radiopharmaceuticals to assess their potential for clinical applicability. Four hours after intravenous injection of approximately 37 MBq (1 mCi) Re-188-labeled diphosphonate preparations, whole body scans were performed using a large-field gamma camera equipped with a high resolution collimator. Bone-to-soft tissue ratios (B/S ratio) were calculated using a computer program. Our data showed that Re-188 HEDP with carrier (10(-4) M carrier) could accumulate in the skeletal system whereas very little absorption by bone was observed in the rabbits that were injected with carrier-free Re-188 HEDP. In addition, no significant bone uptake was demonstrated for Re-188 MDP or Re-188 HDP, with or without carrier. The B/S ratio was 25.06 in the Re-188 HEDP with carrier group but less than 3 in the other groups. In conclusion, HEDP is the best choice among these three bone-seeking drugs when labeled with Re-188. But, it is necessary to add carrier when preparing Re-188 HEDP for the treatment of bone metastases.

Histologic study of effects of radiation synovectomy with Rhenium-188 microsphere

Rhenium-188 microsphere is a relatively new radiation synovectomy agent developed for the treatment of rheumatoid arthritis. It has been shown that the levels of unwanted extra-articular radiation are negligible with this agent. A histologic study was conducted to assess the effect of radiation synovectomy on synovium and articular cartilage after intra-articular injection of various doses of Re-188 microspheres into the knee joints of rabbits. Intra-articular injection of Re-188 microspheres into rabbit knee joints resulted in mild reactive inflammation and thrombotic occlusion of vessels which subsided rapidly. Sclerosis of subsynovium could be seen 12 weeks after injection. No evidence of damage to articular cartilage was noted. There was no significant difference in the articular pattern after injection of 0.3 or 0.6 mCi Re-188 microspheres. This study suggests that a treatment dose of Re-188 microspheres causes transient inflammation of synovium without any detectable damage to the articular cartilage of knee joint.