Enhanced antitumour response of gold nanostar-mediated photothermal therapy in combination with immunotherapy in a mouse model of colon carcinoma.

OBJECTIVES: This study investigated the potential of combining PTT with dendritic cell (DC)-based immunotherapy and anti-PD-L1 immune checkpoint blockade (ICB) therapy against colorectal cancer and elucidated the underlying mechanisms. METHODS: The CT26 tumour-bearing mice were divided into seven treatment groups: control, atezolizumab (A), dendritic cells (DC), pAuNSs-mediated PTT (PTT), PTT combined with atezolizumab (PTT + A), PTT combined with dendritic cells (PTT + DC), and PTT combined with dendritic cells and atezolizumab (PTT + DC + A). Therapeutic efficacy was monitored. RESULTS: PTT upregulated most immune cell membrane receptor genes, including PD-L1, and downregulated genes associated with antigen presentation and T cell activation. Although the PTT + A and PTT + DC treatments showed partial tumour growth retardation, the combination of PTT with DCs and atezolizumab (PTT + DC + A) exhibited the most significant antitumour effect, with a complete remission rate of 50% and prolonged survival. On day 14, tumour samples from non-responsive mice revealed insufficient recruitment of T cells as the reason for uncured tumours. Notably, mice cured with PTT + DC and PTT + DC + A treatments showed no detectable lung nodules. CONCLUSION: This study demonstrated that the combination of PTT with DC-based immunotherapy and atezolizumab effectively overcomes the non-sensitive nature of CT26 tumours. These findings highlight the potential of this combination approach for colorectal cancer treatment.

Site-specific Conjugation of 6 DOTA Chelators to a CA19-9-targeting scFv-Fc Antibody for Imaging and Therapy.

Antibodies conjugated with diagnostic/therapeutic radionuclides are attractive options for inoperable cancers lacking accurate imaging methods and effective therapeutics, such as pancreatic cancer. Hence, we have produced an antibody radionuclide conjugate termed TE-1132 comprising a α-CA19-9 scFv-Fc that is site-specifically conjugated at each C-terminus to 3 DOTA chelators via a cysteine-containing peptide linker. The smaller scFv-Fc size facilitates diffusivity within solid tumors, whereas the chelator-to-antibody ratio of six enabled 177Lu-radiolabeled TE-1132 to exhibit high radioactivity up to 520 MBq/nmol. In mice bearing BxPC3 tumors, immuno-SPECT/CT imaging of [111In]In-TE-1132 and the biodistribution of [177Lu]Lu-TE-1132 showed selective tumor accumulation. Single and multiple doses of [177Lu]Lu-TE-1132 effectively inhibited the BxPC3 tumor growth and prolonged the survival of mice with no irreversible body weight loss or hematopoietic damage. The adequate pharmacokinetic parameters, prominent tumor accumulation, and efficacy with good safety in mice encourage the further investigation of theranostic TE-1132 for treating pancreatic cancer.

PDT-active upconversion nanoheaters for targeted imaging guided combinatorial cancer phototherapies with low-power single NIR excitation.

A versatile nanoformulation is designed by anchoring human transferrin protein (Tf) on fluoromagnetic upconverting nanoheaters, NaGdF4:Yb,Er (UCNP), loaded with Rose Bengal (RB), for multimodal imaging guided synergistic photothermal (PTT) and photodynamic therapy (PDT) at the targeted tumor site. The NIR excitation of the UCNP-RB Forster Resonance Energy Transfer (FRET) pair results in the reactive oxygen species (ROS) generation for PDT, whereas the non-radiative transitions in Er result in the heat required for PTT. The intravenously injected theranostic agent (UCNP@Tf-RB) enabled; (1) combinatorial PTT and PDT of 4T1 tumors with minimal systemic toxicity, (2) dual targeted (passive and active) tumor accumulation, (3) dual-modal imaging (MRI/photothermal), and, (4) excellent stability and biocompatibility. The in vitro therapy data corroborates the MRI findings that Tf conjugation resulted in actively targeted tumor accumulation via over-expressed transferrin receptors (TfR) on 4T1 cells. Real-time photothermal imaging enabled visualization of the tumor while receiving the therapy. The UCNP@Tf-RB, for synergistic PTT-PDT, and UCNP@Tf, for PTT only, caused rapid suppression of tumor with a tumor-growth inhibition index (TGII) of ~0.91, and 0.79, respectively. Histopathological examination demonstrated minimal damage to non-targeted tissues and caused significant damage to the tumor. This theranostic methodology enhances anti-cancer therapeutic efficiency, and announces the potential for pre-clinical cancer therapy.

Radiometal-Labeled Chitosan Microspheres as Transarterial Radioembolization Agents against Hepatocellular Carcinoma.

Transarterial radioembolization (TARE) is an emerging treatment for patients with unresectable hepatocellular carcinoma (HCC). This study successfully developed radiometal-labeled chitosan microspheres (111In/177Lu-DTPA-CMS) with a diameter of 36.5 ± 5.3 µm for TARE. The radiochemical yields of 111In/177Lu-DTPA-CMS were greater than 90% with high radiochemical purities (>98%). Most of the 111In/177Lu-DTPA-CMS were retained in the hepatoma and liver at 1 h after intraarterial (i.a.) administration. Except for liver accumulation, radioactivity in each normal organ was less than 1% of the injected radioactivity (%IA) at 72 h after injection. At 10 days after injection of 177Lu-DTPA-CMS (18.6 ± 1.3 MBq), the size of the hepatoma was significantly reduced by around 81%, while that of the rats in the control group continued to grow. This study demonstrated the effectiveness of 177Lu-DTPA-CMS in the treatment of N1-S1 hepatoma. 111In/177Lu-DTPA-CMS have the potential to be a superior theranostic pair for the treatment of clinical hepatoma.

Brachytherapy Approach Using 177Lu Conjugated Gold Nanostars and Evaluation of Biodistribution, Tumor Retention, Dosimetry and Therapeutic Efficacy in Head and Neck Tumor Model.

Brachytherapy can provide sufficient doses to head and neck squamous cell carcinoma (HNSCC) with minimal damage to nearby normal tissues. In this study, the ß--emitter 177Lu was conjugated to DTPA-polyethylene glycol (PEG) decorated gold nanostars (177Lu-DTPA-pAuNS) used in surface-enhanced Raman scattering and photothermal therapy (PTT). The accumulation and therapeutic efficacy of 177Lu-DTPA-pAuNS were compared with those of 177Lu-DTPA on an orthotopic HNSCC tumor model. The SPECT/CT imaging and biodistribution studies showed that 177Lu-DTPA-pAuNS can be accumulated in the tumor up to 15 days, but 177Lu-DTPA could not be detected at 24 h after injection. The tumor viability and growth were suppressed by injected 177Lu-DTPA-pAuNS but not nonconjugated 177Lu-DTPA, as evaluated by bioluminescent imaging. The radiation-absorbed dose of the normal organ was the highest in the liver (0.33 mSv/MBq) estimated in a 73 kg adult, but that of tumorsphere (0.5 g) was 3.55 mGy/MBq, while intravenous injection of 177Lu-DTPA-pAuNS resulted in 1.97 mSv/MBq and 0.13 mGy/MBq for liver and tumorsphere, respectively. We also observed further enhancement of tumor-suppressive effects by a combination of 177Lu-DTPA-pAuNS and PTT compared to 177Lu-DTPA-pAuNS alone. In conclusion, 177Lu-DTPA-pAuNS may be considered as a potential radiopharmaceutical agent for HNSCC brachytherapy.

Automated Synthesis and Initial Evaluation of (4'-Amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase.

Background: Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4'-amino-5',8'-difluoro-1'H-spiro[piperidine-4,2'-quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation. Methods: An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [18F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution (V t), and area under the curve (AUC) based on the [18F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues. Results: At the end of synthesis, the yield of [18F]FBAT was 2.2-3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125-137 GBq/µmol. In vitro, [18F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [18F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [18F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [18F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16 ± 0.18, 1.53 ± 0.25, 1.41 ± 0.21, and 1.90 ± 0.12, respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution (V t, mL/cm3), and K i (influx rate) of [18F]FBAT were 1.9 ± 0.21- and 1.4 ± 0.22-fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain K i of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and V t values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS. Conclusion: An automated robotic method was established for radiosynthesis of [18F]FBAT, and the preliminary in vitro and in vivo results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI.

Development of Radiofluorinated Nicotinamide/Picolinamide Derivatives as Diagnostic Probes for the Detection of Melanoma.

Regarding the increased incidence and high mortality rate of malignant melanoma, practical early-detection methods are essential to improve patients' clinical outcomes. In this study, we successfully prepared novel picolinamide-benzamide (18F-FPABZA) and nicotinamide-benzamide (18F-FNABZA) conjugates and determined their biological characteristics. The radiochemical yields of 18F-FPABZA and 18F-FNABZA were 26 ± 5% and 1 ± 0.5%, respectively. 18F-FPABZA was more lipophilic (log P = 1.48) than 18F-FNABZA (log P = 0.68). The cellular uptake of 18F-FPABZA in melanotic B16F10 cells was relatively higher than that of 18F-FNABZA at 15 min post-incubation. However, both radiotracers did not retain in amelanotic A375 cells. The tumor-to-muscle ratios of 18F-FPABZA-injected B16F10 tumor-bearing mice increased from 7.6 ± 0.4 at 15 min post-injection (p.i.) to 27.5 ± 16.6 at 3 h p.i., while those administered with 18F-FNABZA did not show a similarly dramatic increase throughout the experimental period. The results obtained from biodistribution studies were consistent with those derived from microPET imaging. This study demonstrated that 18F-FPABZA is a promising melanin-targeting positron emission tomography (PET) probe for melanotic melanoma.

Evaluation of Radioiodinated Fluoronicotinamide/Fluoropicolinamide-Benzamide Derivatives as Theranostic Agents for Melanoma.

Malignant melanoma is the most harmful type of skin cancer and its incidence has increased in this past decade. Early diagnosis and treatment are urgently desired. In this study, we conjugated picolinamide/nicotinamide with the pharmacophore of 131I-MIP-1145 to develop 131I-iodofluoropicolinamide benzamide (131I-IFPABZA) and 131I-iodofluoronicotiamide benzamide (131I-IFNABZA) with acceptable radiochemical yield (40 ± 5%) and high radiochemical purity (>98%). We also presented their biological characteristics in melanoma-bearing mouse models. 131I-IFPABZA (Log P = 2.01) was more lipophilic than 131I-IFNABZA (Log P = 1.49). B16F10-bearing mice injected with 131I-IFNABZA exhibited higher tumor-to-muscle ratio (T/M) than those administered with 131I-IFPABZA in planar γ-imaging and biodistribution studies. However, the imaging of 131I-IFNABZA- and 131I-IFPABZA-injected mice only showed marginal tumor uptake in A375 amelanotic melanoma-bearing mice throughout the experiment period, indicating the high binding affinity of these two radiotracers to melanin. Comparing the radiation-absorbed dose of 131I-IFNABZA with the melanin-targeted agents reported in the literature, 131I-IFNABZA exerts lower doses to normal tissues on the basis of similar tumor dose. Based on the in vitro and in vivo studies, we clearly demonstrated the potential of using 131I-IFNABZA as a theranostic agent against melanoma.

Investigation of biodistribution and tissue penetration of PEGylated gold nanostars and their application for photothermal cancer treatment in tumor-bearing mice.

Gold nanostars (AuNSs), with unique physicochemical properties, are thought to be a promising agent for photothermal therapy (PTT). In this study, we prepared PEGylated gold nanostars (pAuNSs) using the HEPES-reduction method. The high photothermal conversion efficiency (∼80%) and photothermal stability of pAuNSs were demonstrated in vitro and in vivo. 111In-DTPA-pAuNSs were prepared as a radioactive surrogate for the biodistribution studies of pAuNSs. In both microSPECT/CT images and the biodistribution study, the tumor-to-muscle (T/M) ratio reached a maximum at 24 h post intravenous injection of 111In-DTPA-pAuNSs. The high linear correlation between the 111In radioactivity and the gold content in the tumors (R2 0.86-0.99) indicated that 111In-DTPA-pAuNSs were appropriate for noninvasively tracking pAuNSs in vivo after systemic administration. Histological examination after silver enhancement staining clearly illustrated that the accumulated pAuNSs in the tumors were mainly located on the luminal surface of vessels. The mice bearing a SKOV-3 xenograft exhibited remarkable therapeutic efficacy with negligible organ damage after receiving pAuNS-mediated photothermal therapy. Our findings suggested that pAuNSs, together with their radioactive surrogate 111In-DTPA-pAuNSs, are promising for applications in image-guided photothermal therapy.

Evaluation of the Biological Behavior of a Gold Nanocore-Encapsulated Human Serum Albumin Nanoparticle (Au@HSANP) in a CT-26 Tumor/Ascites Mouse Model after Intravenous/Intraperitoneal Administration.

Colorectal cancer is one of the major causes of cancer-related death in Taiwan and worldwide. Patients with peritoneal metastasis from colorectal cancer have reduced overall survival and poor prognosis. Hybrid protein-inorganic nanoparticle systems have displayed multifunctional applications in solid cancer theranostics. In this study, a gold nanocore-encapsulated human serum albumin nanoparticle (Au@HSANP), which is a hybrid protein-inorganic nanoparticle, and its radioactive surrogate 111In-labeled Au@HSANP (111In-Au@HSANP), were developed and their biological behaviors were investigated in a tumor/ascites mouse model. 111In-Au@HSANP was injected either intravenously (iv) or intraperitoneally (ip) in CT-26 tumor/ascites-bearing mice. After ip injection, a remarkable and sustained radioactivity retention in the abdomen was noticed, based on microSPECT images. After iv injection, however, most of the radioactivity was accumulated in the mononuclear phagocyte system. The results of biodistribution indicated that ip administration was significantly more effective in increasing intraperitoneal concentration and tumor accumulation than iv administration. The ratios of area under the curve (AUC) of the ascites and tumors in the ip-injected group to those in the iv-injected group was 93 and 20, respectively. This study demonstrated that the ip injection route would be a better approach than iv injections for applying gold-albumin nanoparticle in peritoneal metastasis treatment.

In Vivo and in Vitro Demonstration of Gold Nanorod Aided Photothermal Presoftening of B16F10 Melanoma for Efficient Chemotherapy Using Doxorubicin Loaded Graphene Oxide.

A combined photothermal therapy (PTT) and chemotherapy (chemo) were performed in vitro on B16F10 melanoma cells and in vivo using melanoma bearing C57BL/6 mice. The 785 nm (100 mW) irradiated gold nanorods (AuNRs) were used as the PT agent, and electrostatically conjugated Doxorubicin (Dox) to a nanocarrier graphene oxide (GO) worked as the chemotherapeutic. Selection of dosage was optimized from the individual viability studies, and finally a combined therapeutic (AuNR (100 ppm), GO (125, and 250 ppm), Dox (0.0058, and 0.00058 ppm)), was delivered in vitro. PTT, followed by chemo, sequentially, resulted in <10% viability, whereas simultaneous PTT with chemo resulted in a viability of ∼40% for the melanoma cells. Flow cytometry indicated optical inhomogeneity in the cells that internalized GO, and AuNR; however, the Dox amount was identical within the cells treated with or without PTT. Confocal microscopy revealed that GO+Dox was internalized, and Dox was distributed uniformly within the cells irrespective of the treatment protocol. In vivo results in melanoma bearing C57BL/6 mice resembled the in vitro data closely. The tumor growth inhibition index was highest at 0.78 for the group receiving sequential treatment, followed by 0.61 for those receiving simultaneous treatment, where the control group had a score of 0. For the sequential treatment, presoftening of the cells with PTT, followed by the chemo resulted in significantly improved toxicity of the treatment, whereas simultaneous PTT with chemo results were dominated by the Dox alone.

Presence of Gold Nanoparticles in Cells Associated with the Cell-Killing Effect of Modulated Electro-Hyperthermia.

The efficacy of gold nanoparticle (AuNP)-assisted radiofrequency (RF)-induced hyperthermia employing the Kanzius device remains controversial. Different from the Kanzius device, modulated electro-hyperthermia (mEHT) utilizes the capacitive-impedance coupled 13.56 MHz radiofrequency (RF) current and has been approved for clinical cancer treatment. In this study, we investigated the heating characteristics of spherical-, urchin-, and rod-like AuNPs of a similar 50 nm size upon exposure to a 13.56 MHz radiofrequency using the LabEHY-105CL, an in vivo mEHT device. We found that, regardless of the AuNPs' sphere-, urchin- or rod-like shape, purified gold nanoparticle solution would not promote heat generation. The temperature elevation during radiofrequency irradiation was solely attributed to the ionic background of the solution. The AuNPs present in the medium (≤25 ppm) showed no effect on selective cell killing of malignant cells, whereas the AuNPs incorporated in the cells diminished the cell selectivity as well as cell death and acted as protectors in mEHT cancer treatment. Our study suggested that (1) the temperature elevation induced by 50 nm AuNPs in the 13.56 MHz radiofrequency field was negligible and was shape-independent, and (2) the presence of AuNPs would alter the cell-killing effect of modulated electro-hyperthermia.

Synthesis and biological evaluation of 2-(3,4-dimethoxyphenyl)-6-(2-[18F]fluoroethoxy)benzothiazole ([18F]FEDBT) for PET imaging of breast cancer.

Given the ever-present demand for improved PET radiotracer in oncology imaging, we have synthesized 2-(3,4-dimethoxyphenyl)-6-(2-[18F]fluoroethoxy)benzothiazole ([18F]FEDBT), a fluorine-18-containing fluoroethylated benzothiazole to explore its utility as a PET imaging tracer. [18F]FEDBT was prepared via kryptofix-mediated nucleophilic substitution of the tosyl group precursor. Fractionated ethanol-based solid-phase (SPE cartridge-based) purification afforded [18F]FEDBT in 60% radiochemical yield (EOB), with radiochemical purity in excess of 98% and the specific activity was 35GBq/µmol. The radiotracer displayed clearly higher cellular uptake ratio in various breast cancer cell lines MCF7, MDA-MB-468 and MDA-MB-231. However, both biodistribution and microPET studies have showed an higher abdominal accumulation of [18F]FEDMBT and the tumor/muscle ratio of 1.8 was observed in the MDA-MB-231 xenograft tumors mice model. Further the lipophilic improvement is needed for the reducement of hepatobilliary accumulation and to promote the tumor uptake for PET imaging of breast cancer.

Preparation and characterization of a novel Al(18)F-NOTA-BZA conjugate for melanin-targeted imaging of malignant melanoma.

Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. Previous studies have demonstrated the specific binding ability of benzamide moiety to melanin. In this study, we developed a novel (18)F-labeled NOTA-benzamide conjugate, Al(18)F-NOTA-BZA, which can be synthesized in 30min with a radiochemical yield of 20-35% and a radiochemical purity of >95%. Al(18)F-NOTA-BZA is highly hydrophilic (logP=-1.96) and shows good in vitro stability. Intravenous administration of Al(18)F-NOTA-BZA in two melanoma-bearing mouse models revealed highly specific uptake in B16F0 melanotic melanoma (6.67±0.91 and 1.50±0.26%ID/g at 15 and 120min p.i., respectively), but not in A375 amelanotic melanoma (0.87±0.21 and 0.24±0.09%ID/g at 15 and 120min p.i., respectively). The clearance from most normal tissues was fast. A microPET scan of Al(18)F-NOTA-BZA-injected mice also displayed high-contrast tumor images as compared with normal organs. Owing to the favorable in vivo distribution of Al(18)F-NOTA-BZA after intravenous administration, the estimated absorption dose was low in all normal organs and tissues. The melanin-specific binding ability, sustained tumor retention, fast normal tissues clearance and thelow projected human dosimetry supported that Al(18)F-NOTA-BZA is a very promising melanin-specific PET probe for melanin-positive melanoma.

Synthesis and characterization of a novel radioiodinated phenylacetamide and its homolog as theranostic agents for malignant melanoma.

Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. This study reports the preparation and biological characterizations of N-(2-(diethylamino)ethyl)-2-(3-(123/131)I-iodo-4- hydroxyphenyl)acetamide and N-(2-(diethylamino)ethyl)-3-(3-(123/131)I-iodo-4-hydroxyphenyl)propanamide (123/131)I-IHPA and 123/131I-IHPP) as novel melanin-specific theranostic agents. These two tracers were hydrophilic, exhibited good serum stability and high binding affinity to melanin. In vitro and in vivo studies revealed rapid, high and tenacious uptakes of both 131I-IHPA and 131I-IHPP in melanotic B16F0 cell line and in C57BL/6 mice bearing B16F0 melanoma, but not in amelanonic A375 cell line and tumors. Small-animal SPECT imaging also clearly delineate B16F0 melanoma since 1 h postinjection of 123I-IHPA and 123I-IHPP in tumor-bearing mice. Owing to the favorable biodistribution of 131I-IHPA and 131I-IHPP after intravenous administration, the estimated absorption dose was low in most normal organs and relatively high in melanotic tumor. The melanin-specific binding ability, sustained tumor retention, fast normal tissues clearance and acceptable projected human dosimetry supported that these two tracers are promising theranostic agents for melanin-positive melanoma.

Synthesis and evaluation of ¹²³/¹³¹I-Iochlonicotinamide as a novel SPECT probe for malignant melanoma.

Malignant melanoma expresses a highly aggressive metastasis. Early diagnosis of malignant melanoma is important for patient survival. Radiolabeled benzamides and nicotinamides have been reported to be attractive candidates for malignant melanoma diagnosis as they bind to melanin, a characteristic substance that displays in malignant melanoma, and show high tumor accumulation and retention. Herein, we designed and synthesized a novel (123/131)I-labeled nicotinamide derivative that specifically binds to melanin. (123/131)I-Iochlonicotinamide was prepared with good radiochemical yield (50-70%, decay corrected) and high specific radioactivity (50-80 GBq/µmol). (131)I-Iochlonicotinamide exhibited good in vitro stability (radiochemical purity >95% after a 24-h incubation) in human serum. High uptake of (123/131)I-Iochlonicotinamide in B16F0 melanoma cells compared to that in A375 amelanotic cells demonstrated its selective binding to melanin. Intravenous administration of (123/131)I-Iochlonicotinamide in a melanoma-bearing mouse model revealed high uptake in melanotic melanoma and high tumor-to-muscle ratio. MicroSPECT scan of (123/131)I-Iochlonicotinamide injected mice also displayed high contrast tumor imaging as compared with normal organs. The radiation-absorbed dose projection for the administration of (131)I-Iochlonicotinamide to human was based on the results of biodistribution study. The effective dose appears to be approximately 0.44 mSv/MBq(-1). The specific binding of (123/131)I-Iochlonicotinamide to melanin along with a prolonged tumor retention and acceptable projected human dosimetry suggest that it may be a promising theranostic agent for treating malignant melanoma.

Synthesis and biological evaluation of technetium-99m labeled galactose derivatives as potential asialoglycoprotein receptor probes in a hepatic fibrosis mouse model.

Two galactose derivatives, a monovalent (99m)Tc-MAMA-MGal galactoside and a divalent (99m)Tc-MAMA-DGal galactoside, were synthesized and radiolabeled in high radiochemical purity (>98%). Dynamic microSPECT imaging and biodistribution study of two traces in normal and liver fibrosis mice showed that the (99m)Tc-MAMA-DGal revealed higher specific binding to asialoglycoprotein receptors in liver and then rapidly excreted via both hepatobiliary system and renal clearance. The results suggest that (99m)Tc-MAMA-DGal may be used as SPECT probes for noninvasive evaluation of asialoglycoprotein receptor-related liver dysfunction.

Simultaneous imaging of temporal changes of NF-κB activity and viable tumor cells in Huh7/NF-κB-tk-luc2/rfp tumor-bearing mice.

Few studies have reported that the effect of sorafenib on advanced human hepatocellular carcinoma (HCC) is taking place via the inhibition of NF-κB signal transduction. Here we constructed a human HCC Huh7 stable clone with NF-κB-responsive element to drive dual reporter genes, herpes simplex virus thymidine kinase (tk) and firefly luciferase (luc2), and co-transfected with a third red fluorescent protein (rfp) gene, renamed as Huh7/NF-κB-tk-luc2/rfp cells, and combined with bioluminescent imaging (BLI) and red fluorescent protein imaging (RFPI) to monitor the effect of sorafenib on NF-κB activation and tumor inhibition. The results show that sorafenib could suppress the NF-κB-DNA binding activity, and the expression of downstream effector proteins. Notably, the relative photon fluxes obtained from RFPI and BLI, which represent the viable tumor cells and cells with NF-κB activation, decreased after sorafenib treatment by 50 to 65%, and 87.5 to >90%, respectively, suggesting that NF-κB activation is suppressed in viable HCC cells by sorafenib. Simultaneous molecular imaging of the temporal change of NF-κB activity and of viable cells in the same Huh7/NF-κB-tk-luc2/rfp tumors of the animal may reflect the real status of NF-κB activity and the viable tumor cells at the time of imaging.

Evaluation of (131/123)I-5-iodo-2'-deoxycytidine as a novel proliferation probe in a tumor mouse model.

This study evaluated a radioiodinated deoxycytidine analog, (131)I-5-iodo-2'-deoxycytidine ([(131)I]ICdR), as a novel proliferation probe and compared it with (131)I-5-iodo-2'-deoxyuridine ([(131)I]IUdR) in a NG4TL4 sarcoma-bearing mouse model. As an imaging agent, the biological characteristics of [(123)I]IUdR is not satisfactory due to its metabolic instability and short biological half-life in vivo. With [(123)I]ICdR/SPECT it was possible to clearly delineate the tumor lesion at 1h post-injection (tumor-to-muscle ratio 7.74) in tumor-bearing mice. The results of biodistribution were consistent with those observed in scintigraphic imaging. This study demonstrated that [(131)I]ICdR is a more promising SPECT probe than [(131)I]IUdR for imaging proliferation.

The utilization of radionuclide myocardial perfusion imaging and cardiac catheterization under Taiwan's universal health insurance program.

This study examines the utilization patterns of myocardial perfusion imaging (MPI) and cardiac catheterization (CC) under Taiwan's national health insurance program. This study used the longitudinal health insurance database with 1,000,000 people were randomly selected from the national health insurance research database. This study obtained data from these patients with coronary artery disease (CAD) and comparison with the utilization of MPI or CC between 2005 and 2009. The incidence of CAD did not significantly change, while the prevalence of CAD, utilization of MPI, and the utilization of CC for the CAD patients increased annually. There were the most CAD patients in Northern Taiwan (43.5%), followed by Southern, Central, and Eastern Taiwan. The utilizations of both of MPI (12.7 per 100 CAD patients) and CC (10.6 per 100 CAD patients) were most frequent in Northern Taiwan followed by Southern, Central, and Eastern Taiwan. However, the MPI/CC ratio was 1.20 in Northern Taiwan, followed by Southern, Central, and Eastern Taiwan (0.88, 0.64, and 0.52, respectively, P = 0.0008). The use of MPI was higher than CC only in Northern Taiwan. MPI may be underutilized to serve the role of gatekeeper for CC in the other regions.