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Porphyrins coordinated with platinum(II) chemotherapeutic drugs are attractive for the development of photosensitizers for photodynamic therapy (PDT) of cancer. In this paper, inorganic and metal-organic nanocomposites were synthesized with cascade-responsive imaging and photochemical synergistic effects. After endo/lysosomal escape, the outer metal-organic frameworks were degraded, leading to the release of an excellent photosensitizer (tetrapyridylporphyrin, PtTPyP). Subsequently, doxorubicin (DOX), inserted in the adenosine triphosphate (ATP) aptamer-functionalized gold nanoparticles, was released under the stimulation of endogenous ATP, synergistically enhancing cancer treatment. Fluorescence imaging allowed tracking of PtTPyP and DOX for real-time detection and on-demand therapy. This strategy endowed the nanocomposites with stability, responsiveness, effectiveness, and ease of synthesis, namely, sTREE strategy. Accordingly, our demonstration provided a promising and smart nanocarrier for imaging and drug delivery.

In view of the key roles played by noncovalent or weak interactions in biological processes, it is important to understand them at the molecular level. Based on the results of the thermodynamic, sp...

金沢大学疾患モデル総合研究センター, Alpha particle-emitting radionuclides have gained considerable attention for radionuclide therapy. Astatine-211 ( 211 At) is a promising alpha particle-emitting radionuclide. 211 At is a halogen that has similar chemical properties to iodine and exhibits a half-life of 7.2 h. However, direct labeling of proteins or peptides into the tyrosine residue with 211 At was shown to be impractical. Herein, we demonstrate a novel 211 At-labeling method using the RGD peptide as a model peptide. An 211 At-labeled RGD peptide, [ 211 At]c[RGDf(4-At)K], was prepared from a precursor with a tributylstannyl group on the phenylalanine residue in c(RGDfK) with a radiochemical yield of 63% and a radiochemical purity of >96%, and its potential for targeted radionuclide therapy was evaluated. Based on the results of biodistribution experiments, [ 125 I]c[RGDf(4-I)K] and [ 211 At]c[RGDf(4-At)K] showed high accumulation in the tumor and similar biodistribution. This study provides useful information for radiotheranostics between an 211 At-labeled peptide and the corresponding radioiodine-labeled peptide. © 2019 American Chemical Society., This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

金沢大学疾患モデル総合研究センター, [223Ra]RaCl2 is the first alpha-particle emitting radiopharmaceutical to be used for castration-resistant prostate cancer patients with bone metastases because of its excellent therapeutic effects. [223Ra]RaCl2 is excreted via the intestine into feces, and some is absorbed from the intestine into the blood, which may be undesirable in terms of the exposure to radiation. Recently, we showed that a complex of myo-inositol-hexakisphosphate (InsP6) with zinc is a useful decorporation agent against radiostrontium. In this study, we hypothesized that Zn-InsP6 could bind to not only strontium but also to radium, and could inhibit the absorption of radium from the intestine. In in vitro binding experiments, Zn-InsP6 showed a high binding affinity for radium. In in vivo biodistribution experiments by intravenous injection of [223Ra]RaCl2 after treatment of Zn-InsP6, mice treated with Zn-InsP6 showed significantly lower bone accumulation of radioactivity (34.82 ± 1.83%Dose/g) than the mice in the non-treatment control group (40.30 ± 2.78%Dose/g) at 48h postinjection. These results indicate that Zn-InsP6 bound radium in the intestine and inhibited the absorption of radium into the blood. Therefore, the insoluble Zn-InsP6 complex has high potential to decrease the side effects of [223Ra]RaCl2. © 2020, The Author(s).

Proteasome inhibitors are useful for biochemical research and clinical treatment. In our previous study, we reported that the 4N-coordinated platinum complexes with anthracenyl ring and heterocycle exhibited proteasome-inhibitory activity. In the present study, the structure–activity relationships and characterization of these complexes were determined for the elucidation of the role of aromatic ligands. Lineweaver–Burk analysis revealed that the chemical structure of heterocycles affects the binding mode of platinum complexes. Platinum complexes with anthracenyl ring and pyridine showed competitive inhibition, although platinum complexes with anthracenyl ring and phenanthroline showed non-competitive inhibition. The structure–activity relationships demonstrated that anthracenyl moiety plays a crucial role in proteasome-inhibitory activity. The platinum complexes with naphthyl or phenyl rings exhibited lower inhibitory activities than the platinum complex with anthracenyl ring. The reactivity with N-acetylcysteine varied according to the chemical structure of complexes.

Background/aim We have previously developed a novel bone-targeting platinum compound, 3Pt, and showed that it has strong inhibitory activity against osteosarcoma cells and orthotopic cell-line xenograft mouse models. In the present report, we compared the efficacy of 3Pt to cisplatinum (CDDP) in a CDDP-resistant relapsed osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. Patients and methods The tumor of a patient with osteosarcoma of the distal femur was treated with CDDP-based chemotherapy followed by surgery. The surgical specimen was used to establish a PDOX model. An osteosarcoma cell line was also established from the original patient tumor. Osteosarcoma cell viability was assessed with the WST-8 assay and the IC50 values were calculated. The PDOX models were randomized into three groups: untreated control, CDDP-treated group, and 3Pt-treated group. Tumor size and body weight were measured twice a week. Results 3Pt had a strong concentration-dependent cytocidal effect in vitro. The IC50 value of 3Pt was significantly lower than that of CDDP. On day 14 of the treatment, 3Pt caused a significantly greater tumor growth inhibition compared to the untreated control and CDDP-treated mice. Conclusion 3Pt is a promising clinical candidate for the treatment of recalcitrant osteosarcoma.

The new palladium(II) complex, [Pd(bpy)(AtC3)]2+, where bpy = 2,2′-bipyridine and AtC3 = N-(9-anthracenylmethyl)-1,3-propanediamine, was synthesized and characterized. The crystal structure of [Pd(...

C20H24Cl2N4Pt, monoclinic, P21/c (no. 14), a = 13.1119(7) Å, b = 13.5673(8) Å, c = 11.7167(5) Å, β = 99.714(7)°, V = 2054.43(19) Å3, Z = 4, R gt(F) = 0.0233, wR ref(F 2) = 0.0516, T = 103 K.

Platinum antitumour agents, containing aromatic rings, which are used for targeting DNA in effective therapies for the treatment of cancer. We have synthesized the title metallocomplex with an aromatic ligand and determined its crystal structure. In many cases, complexes of platinum and other metals have a symmetrical structure. In contrast, the platinum(II) complex with pyridine and N-(9-anthracenylmethyl)-1,2-ethanediamine as ligands (systematic name: cis-{N-[(anthracen-9-yl)methyl]ethane-1,2-diamine-κ2 N,N′}bis(pyridine-κN)platinum(II) dinitrate), [Pt(C5H5N)2(C17H18N2)](NO3)2, is asymmetric. Of the two pyridine ligands, only one is π-stacked with anthracene, resulting in an asymmetric structure. Moreover, the angle of orientation of each pyridine ligand is variable. Further examination of the packing motif confirms an intermolecular edge-to-face interaction.

金沢大学新学術創成研究機構, Platelet-derived growth factor receptor β (PDGFRβ) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRβ inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRβ. In this study, [125I]-1-(5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl)piperidin-4-amine ([125I]IIQP) and [125I]-N-3-iodobenzoyl-1-(2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl)-piperidin-4-amine ([125I]IB-IQP) were designed and synthesized, and their potential as PDGFRβ imaging agents was evaluated. In cellular uptake experiments, [125I]IIQP and [125I]IB-IQP showed higher uptake by PDGFRβ-positive cells than by PDGFRβ-negative cells, and the uptake in PDGFRβ-positive cells was inhibited by co-culture with PDGFRβ ligands. The biodistribution of both radiotracers in normal mice exhibited hepatobiliary excretion as the main route. In mice inoculated with BxPC3-luc (PDGFRβ-positive), the tumor uptake of radioactivity at 1h after the injection of [125I]IIQP was significantly higher than that after the injection of [125I]IB-IQP. These results indicated that [125I]IIQP can be a suitable PDGFRβ imaging agent. However, further modification of its structure will be required to obtain a more appropriate PDGFRβ-targeted imaging agent with a higher signal/noise ratio. © 2017., Embargo Period 12 months

Re-investigation of the reaction of phenylboronic acid (PhB(OH)2) with Alizarin Red S (ARS, H2L) was carried out using absorption and emission spectrophotometry to correct the currently proposed mechanism. Kinetic results obtained by both methods, which essentially show no significant differences, showed that the kinetic reactivity of ARS toward PhB(OH)2 was in the order H2L PhB(OH)3–. Acetic acid/acetate buffer accelerated the present reaction, though HEPES buffer did not. A detailed reaction mechanism involving the acceleration effect of the acetate buffer is proposed for the present reaction on the basis of a recent universal reaction mechanism.

Radioactive nuclides leak into the surrounding environment after nuclear power plant disasters, such as the Chernobyl accident and the Fukushima Daiichi Nuclear Power Plant disaster. Cesium-137 (137Cs) (t1/2=30.1 year), a water-soluble radionuclide with a long physical half-life, contaminates aquatic ecosystems and food products. In humans, 137Cs concentrates in muscle tissue and has a long biological half-life, indicating it may be harmful. myo-Inositol-hexakisphosphate (IP6) is a compound found in grain, beans, and oil seeds. IP6 has the ability to form insoluble complexes with metals, including lanthanum (La) and zinc (Zn). We hypothesized that La-IP6 and Zn-IP6 may promote the elimination of 137Cs from the body through the adsorption of La-IP6 and Zn-IP6 to 137Cs in the gastrointestinal tract. Therefore, in this study, we evaluated the adsorptive capacity of La-IP6 and Zn-IP6 complexes with 137Cs in vitro and in vivo. La-IP6 and Zn-IP6 complexes were stable in acidic solution (pH 1.2) at 37°C. In vitro binding assays indicated that La-IP6 and Zn-IP6 complexes adsorbed 137Cs, with the adsorption capacity of Zn-IP6 to 137Cs greater than that of La-IP6. To evaluate the usefulness of La-IP6 and Zn-IP6 in vivo, La-IP6 or Zn-IP6 was administrated to mice after intravenous injection of 137Cs. However, the biodistribution of 137Cs in the La-IP6 treated group and the Zn-IP6 treated group was nearly identical to the non-treated control group, indicating that La-IP6 and Zn-IP6 were not effective at promoting the elimination of 137Cs in vivo.

Cisplatin (CDDP) is an important drug for chemotherapy in patients with head and neck squamous cell carcinoma. Nephrotoxicity and lack of an effect on bone invasion are limitations of CDDP. To increase its antitumor effect on bone invasion and reduce toxicity problems, anionic Pt complex (3Pt) has been developed. The present study aimed to characterize the basis of the cytotoxicity of the novel platinum complex 3Pt in comparison with that of CDDP for oral squamous cell carcinoma. The ionic platinum complex was prepared to increase solubility and avoid platinum nephrotoxicity. Furthermore, 3Pt was designed to target bone hydroxyapatite and has germinal bisphosphonate moieties for drug delivery. In vitro antitumor activity was assayed in two oral squamous cell carcinoma cell lines. To investigate the antitumor and nephrotoxic effects of 3Pt, nude mice with OSC‐19 were given 3Pt and CDDP. The in vitro growth‐inhibitory effect of 3Pt was significantly less than that of CDDP. However, both 3Pt and CDDP showed equivalent antitumor effects in vivo. Mice injected with CDDP developed renal cell apoptosis; however, those injected with 3Pt were almost free of renal cell injury. In addition to similar in vivo antitumor effects, 3Pt decreased the volume of bone resorption compared to that with CDDP in a bone invasion model using OSC‐19. In conclusion, considering the potential advantages in terms of noticeable antitumor activity on bone invasion and reduced nephrotoxicity, 3Pt represents a significant improvement in the development of bone‐targeting platinum drugs.

Phosphorus, occurring mainly in the form of phosphate, is an essential element for the proper functioning of living systems. Phosphate and polyphosphate groups occur as inorganic phosphate (free phosphate anion in solution) and are present in biomolecules such as phosphorylated amino acids, nucleotides, and phytic acid. In solution, phosphates can exist in four different forms depending on pH, and they are involved in non-covalent interactions with positively charged species. This review summarizes the participation of phosphates of nucleotides, phosphorylated amino acids, and phytic acid in weak interactions with biogenic amines and in complexes with biometal ions not only in solution but also in solid state. The study of these processes can enable to understand many of the most important aspects of a cell’s life, thus explaining why, for example, abnormal phosphorylation leads to the development of diseases, and highlighting the role of phosphates in chemical interactions. In addition, the formation of one-, two-, and three-dimensional polynuclear metal-phosphonate assemblies by phosph(on)ate ligands has been described.

Pt(II) coordination, like of cis -(NH 3 ) 2 Pt(II), affects the acid-base properties of guanosine derivatives. The acidity constants of such complexes are calculated by curve-fitting procedures using published 1 H NMR shift data measured in aqueous solution (D 2 O) in dependence on pH (pD). Comparison of the p K a values of the ligands with those of the Pt(II) complexes reveals the expected behavior for (N7)-platination, i.e., (N1)H sites are acidified due to charge repulsion. These effects of Pt(II) are compared with those of Ni 2+ and Cd 2+ , allowing predictions for the acidification of Zn 2+ . Studied are the cis -(NH 3 ) 2 Pt(II) complexes of inosylyl(3′ → 5′)inosine, guanylyl(3′ → 5′)guanine (GpG) − , its 2′-deoxy relative d(GpG) − , and its phosphorylated derivative d(pGpG) 3− . The Pt(II) effect is mostly rather symmetrical, like with d(CpGpG) 2− , but it can also be quite asymmetrical, like with d(CpCpGpG) 3− or in the cyclohexylamine-substituted Cisplatin complex of d(GpG) − . Potential consequences for base pairing between the platinated guanine and the complementary cytosine are discussed. It is proposed that partial deprotonation of dG under the influence of Pt(II) at physiological pH leads in water to a marked reduction in pairs with intact Watson–Crick hydrogen bonds, thereby adding to the well established thermal destabilization of double-stranded DNA by G,G intrastrand cross-links of Cisplatin.

A detailed kinetic study of the reactions of phenylboronic acid (PhB(OH)2), 2-methylphenylboronic acid (2-MePhB(OH)2), 2-isopropylphenylboronic acid (2-iPrPhB(OH)2), and 1-hydroxy-3H-2,1-benzoxaborole (BxB(OH)) with D-fructose was carried out to clarify the nature of the reactive boron species in D-fructose sensing and investigate the corresponding reaction mechanism. Both the boronic acids (RB(OH)2) and boronate ions (RB(OH)3−) were reactive toward D-fructose, while out of the five D-fructose anomers only α-D-fructofuranose was reactive toward boron species. The reactions of all substrates proceeded consecutively in two steps (steps 1 and 2). We concluded that the first intermolecular step (step 1) corresponds to the parallel reactions (two parallel reactions for 2-iPrPhB(OH)2 and three for the other systems) of the boronic acid and the boronate ion with α-D-fructofuranose to form bicoordinate complexes (mixture of exo- and endo-isomers), and the second intramolecular step (step 2) corresponds to the formation of a tricoordinate α-D-fructofuranose complex from the bicoordinate complexes. It was found that both the boronic acid and the boronate ion were kinetically reactive toward D-fructose, with the latter being more reactive.

The reaction of d -fructose with diphenylborinic acid (Ph2B(OH)), to which d -fructose cannot coordinate tridentately, was kinetically investigated in order to solve the reaction mechanism, and to find a clue to resolve the two-step reaction mechanism of boronic acid (RB(OH)2) with d -fructose. The title reaction was a single-step reaction under the pseudo first-order conditions with large excess d -fructose over Ph2B(OH), which suggests that the reaction of RB(OH)2 with d -fructose consists of the fast formation of a two-coordinate complex followed by the slow formation of a three-coordinate complex. The kinetic reactivity of Ph2B(OH) was considerably higher than that of its conjugate base, diphenylborinate ion (Ph2B(OH)2−). It was shown that Ph2B(OH)2− interacted with CHES buffer to form an outer-sphere complex, whereas no interaction was observed between Ph2B(OH) and CHES buffer. Both the free borinate ion and the restrained borinate ion into the outer-sphere complex react with d -fructose to form the chelate complex via stable binary and ternary outer-sphere complexes, respectively.

Herein we report the syntheses, characterization, photophysical and photochemical properties, and in vitro biological efficacy of Zn(II) and In(III) porphyrins coordinated with Pt(II) groups. In-Pt porphyrin showed excellent therapeutic potential in BALB/c mice having Colon26 tumors. These results imply that the mixed-metal complex In-4cisPtTPyP could be a promising anticancer agent for photodynamic therapy.

Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol ( 5 ) (K i = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5 . The radioiodine labeled probe [ 125 I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([ 125 I] 10 ) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both in vitro and in vivo . Co-injection of [ 125 I] 10 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo , indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes.

Although it has been traditionally surmised that phosphatidylserine (PS) externalization is a hallmark of apoptosis, most other non-apoptotic modes of cell death, such as necrosis, are also associated with PS externalization. Bis(zinc-dipicolylamine) (ZnDPA) complexes have been reported to exhibit affinity for PS. The present study aimed to develop novel radiolabeled ZnDPA derivatives for cell death imaging in tumor after treatment with anticancer drugs.[The radiochemical purities of [[

Somatostatin receptors are highly expressed in neuroendocrine tumors, and many radiolabeled somatostatin analogs for diagnosis and treatment have been developed. To simultaneously detect not only primary cancer but also bone metastases, this study aimed to develop a positron emission tomography probe using generator-produced nuclide Gallium-68 (T1/2 = 68 min), in which a carrier for primary cancer, a carrier for bone metastases lesions, and a stable gallium complex are introduced into the one molecule. Based on this strategy, the somatostatin receptor-targeted peptide, [Tyr3]-octreotate (TATE), aspartic acid peptide (Dn) with high binding affinity for hydroxyapatite, and Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a stable gallium complex were selected. The novel complexes, Ga-DOTA-Dn-TATE (n = 0, 2, 5, 8, or 11), were designed, synthesized, and evaluated. The radiogallium complexes were prepared using the easy-to-handle radioisotope 67Ga due to relatively long half-life. The radiogallium complex precursor DOTA-Dn-TATE was synthesized by the Fmoc-based solid-phase method and by the air oxidation method to form the disulfide bond. [67Ga]Ga-DOTA-Dn-TATE was synthesized by reacting DOTA-Dn-TATE and 67Ga. Hydroxyapatite binding assays, in vitro cellular uptake experiments in AR42J tumor cells, in biodistribution experiments in AR42J tumor-bearing mice, were performed using [67Ga]Ga-DOTA-Dn-TATE. The radiochemical purities of [67Ga]Ga-DOTA-Dn-TATE were > 96.0%. In in vitro and in vivo experiments, [67Ga]Ga-DOTA-D11-TATE had a high affinity for hydroxyapatite and highly accumulated in bone. However, the uptake of [67Ga]Ga-DOTA-D11-TATE into somatostatin receptor-positive AR42J cells was lower than that of [67Ga]Ga-DOTA-TATE, and the accumulation of [67Ga]Ga-DOTA-D11-TATE in tumor was significantly low. Ga-DOTA-D11-TATE may not be recognized by somatostatin receptor by the introduction of D11, and the charge adjustment may be important for somatostatin receptor-positive cell uptake.

金沢大学疾患モデル総合研究センター, Radiolabeled cyclic peptides containing the (Arg-Gly-Asp) RGD sequence for use in positron emission tomography (PET) imaging, single-photon emission computed tomography (SPECT) imaging, and targeted radionuclide therapy of cancer have been reported. In this study, RGD was used as a model carrier peptide for diagnosis and therapy of cancer. To evaluate the characteristics of radiohalogen-labeled peptides, several kinds of labeled RGD peptides [125I-c(RGDyK), 77Br-c(RGDyK), [125I]SIB-c(RGDfK), [77Br]SBrB-c(RGDfK), [125I]SIB-EG2-c(RGDfK), and [77Br]SBrB-EG2-c(RGDfK)] were designed, prepared, and evaluated. In these initial studies, 77Br (t1/2=57.0h) and 125I (t1/2=59.4d) were used because of their longer half-lives. Precursor peptides were synthesized using a standard 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase methodology. Radiolabeled peptides were prepared by chloramine-T method or conjugation of RGD peptides with [125I]N-succinimidyl 3-iodobenzoate ([125I]SIB) or [77Br]N-succinimidyl 3-bromobenzoate ([77Br]SBrB). Measurement of the partition coefficients, integrin binding assay, and biodistribution experiments in tumor-bearing mice were performed. 125I and 77Br labeling were successfully performed using similar methods, and in vitro characteristics and biodistributions were similar between the 125I-labeled and corresponding 77Br-labeled peptides. [125I]SIB- and [77Br]SBrB-conjugated RGD peptides showed higher partition coefficients, lower tumor uptakes, and higher intestinal uptake than 125I-c(RGDyK) and 77Br-c(RGDyK). [125I]SIB-EG2-c(RGDfK) and [77Br]SBrB-EG2-c(RGDfK), which possess an ethylene glycol linker, decreased lipophilicity and uptake in intestine compared with [125I]SIB-c(RGDfK) and [77Br]SBrB-c(RGDfK), which possess no linker. However, the improvement in biodistribution of [125I]SIB-EG2-c(RGDfK) and [77Br]SBrB-EG2-c(RGDfK)] was insufficient. In conclusion, directly radiohalogenated c(RGDyK) peptides are potentially more useful for tumor imaging and therapy than indirectly radiohalogenated ones. © 2018 The Pharmaceutical Society of Japan.

The determination of equilibrium constants is an important process for many branches of chemistry. In this review we provide the readers with a discussion on computer methods which have been applied for elaboration of potentiometric experimental data generated during complexes formation in solution. The review describes both: general basis of modeling tools and examples of the use of calculated stability constants.

Platinum compounds represent one of the great success stories of metals in medicine. Following the unexpected discovery of the anticancer activity of cisplatin (Fig. 1) in 1965 by Prof. Rosenberg [1], a large number of its variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. Although cisplatin has been in use for over four decades, new and more effective platinum-based therapeutics are finally on the horizon. A wide introduction to anticancer studies is given by the authors of the previous chapter. This chapter aims at providing the readers with a comprehensive and in-depth understanding of recent developments of platinum anticancer drugs and to review the state of the art. The chapter is divided into two parts. In the first part we present a historical aspect of platinum and its complexes, while in the second part we give an overview of developments in the field of platinum anticancer agents.

C13H12Cl4N2PtO, monoclinic, C2/m (no. 12), a = 17.497(4) Å, b = 6.8214(15) Å, c = 14.183(3) Å, β = 93.441(7)°, Z = 4, V = 1689.7(6) Å3, R gt(F) = 0.0309, wR ref(F 2) = 0.0696, T = 93 K.

Introduction Sigma-1 receptor is a target for tumor imaging. In a previous study, we synthesized a vesamicol analog, (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol [(+)-pBrV], with a high affinity for sigma-1 receptor, and synthesized radiobrominated (+)-pBrV. This radiobrominated (+)-pBrV showed high tumor uptake in tumor-bearing mice; however, radioactivity accumulation in normal tissues, such as the liver, was high. We assumed that the accumulation of (+)-pBrV in the non-target tissues was partially derived from its high lipophilicity; therefore, we synthesized and evaluated (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-bromophenol [(+)-BrV-OH], which is a more hydrophilic compound. Although we aimed to develop a PET tracer using 76Br, in these initial studies, we used 77Br because of its longer half-life. Methods (+)-[77Br]BrV-OH was synthesized using the chloramine-T method with a radiochemical purity of 95%. Lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were determined, and biodistribution experiments were performed. We also performed an in vivo blocking study by co-injecting excess amounts of the sigma-1 receptor ligand, SA4503, into mice. Results The lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were lower than those of (+)-[77Br]pBrV. (+)-[77Br]BrV-OH also showed high tumor uptake in biodistribution experiments in DU-145 tumor-bearing mice,. Although (+)-[77Br]pBrV was retained in most tissues, (+)-[77Br]BrV-OH was cleared from these tissues. In blocking studies, the co-injection of SA4503 significantly decreased the tumor uptake of (+)-[77Br]BrV-OH. Conclusion These results indicate that (+)-[76Br]BrV-OH has potential as a PET probe for sigma-1 receptor imaging.

Introduction Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated 131 I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[ 131 I] p IV], which has a high affinity for sigma receptors. Therefore, (+)-[ 131 I] p IV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[ 211 At] p AtV, an 211 At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy. Methods The radiolabeled sigma receptor ligand (+)-[ 211 At] p AtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[ 211 At] p AtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[ 211 At] p AtV and (+)-[ 125 I] p IV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. Results The lipophilicity of (+)-[ 211 At] p AtV was similar to that of (+)-[ 125 I] p IV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+)-[ 211 At] p AtV and (+)-[ 125 I] p IV. Namely, (+)-[ 211 At] p AtV demonstrated high uptake and retention in tumor via binding to sigma receptors. Conclusion These results indicate that (+)-[ 211 At] p AtV could function as an new agent for alpha-radionuclide receptor therapy.

(68)Ga (T(1/2) = 68 min, a generator-produced nuclide) is an interesting radionuclide for clinical positron emission tomography (PET). Recently, it was reported that radiogallium-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated (Asp)n peptide [Ga-DOTA-(Asp)n] has great potential for bone metastases imaging. In the current study, a compound containing an aspartic acid peptide linker (D11) as a carrier to bone metastases, an RGD peptide [c(RGDfK) peptide] as a carrier to the primary cancer, and Ga-DOTA as a stable radiometal complex for imaging in one molecule, Ga-DOTA-D11-c(RGDfK), was designed, prepared, and evaluated to detect both the primary cancer and bone metastases simultaneously using (67)Ga, which is easy to handle. After DOTA-D11-c(RGDfK) was synthesized using Fmoc-based solid-phase methodology, (67)Ga-DOTA-D11-c(RGDfK) was prepared by complexing DOTA-D11-c(RGDfK) with (67)Ga. Hydroxyapatite binding assays, integrin binding assays, biodistribution experiments, and single photon emission tomography (SPECT) imaging using tumor-bearing mice were performed using (67)Ga-DOTA-D11-c(RGDfK). (67)Ga-DOTA-D11-c(RGDfK) was prepared with a radiochemical purity of97%. In vitro, (67)Ga-DOTA-D11-c(RGDfK) had a high affinity for hydroxyapatite and αvβ3 integrin. In vivo, (67)Ga-DOTA-D11-c(RGDfK) exhibited high uptake in bone and tumor. The accumulation of (67)Ga-DOTA-D11-c(RGDfK) in tumor decreased when it was co-injected with c(RGDfK) peptide. (68)Ga-DOTA-D11-c(RGDfK) has great potential as a PET tracer for the diagnosis of both the primary cancer and bone metastases simultaneously.

Aim: This study aimed to characterize the cellular basis of the platinum cytotoxicity of two novel platinum complexes, 3Pt and 1Pt, in comparison with that of cisplatin. 3Pt comprises anionic phosphate moieties, while 1Pt comprises neutral aromatic ligands. Methods: We compared the cytotoxic potency of 3Pt and 1Pt with that of cisplatin in osteosarcoma cell lines and an orthotopic mouse model. Results: The cytotoxic potency of 3Pt was markedly higher than that of cisplatin in all cell lines. Both novel platinum complexes showed a complete lack of cross resistance in cisplatin-resistant cells. Caffeine enhanced the cytotoxic potency of these novel platinum complexes, as observed for cisplatin. Apoptosis after drug administration was observed by DNA ladder formation and an annexin V/PI assay. DNA double-strand breaks were confirmed by phosphorylation of histone H2AX. In vivo, the antitumor activity of 3Pt and 1Pt was superior and similar, respectively, to that of cisplatin. Both novel platinum complexes exerted strong antitumor effects on osteosarcoma in vitro and in vivo. Conclusions: 3Pt may be an effective drug for the treatment of bone cancer because the PO3 moiety has a high affinity to bone, as exhibited by bisphosphonates, and is expected to decrease the incidence of side effects at extraskeletal sites and overcome drug resistance. Cationic 1Pt may also be an effective antitumor drug because of its unique chemical structure and properties. Further investigations to detail the antitumor effects of these ionic Pt complexes on osteosarcoma are warranted. © 2015 Bentham Science Publishers.

// Kentaro Igarashi 1, 2, 3 , Kei Kawaguchi 1, 2 , Takashi Murakami 1, 2 , Tasuku Kiyuna 1, 2 , Kentaro Miyake 1, 2 , Norio Yamamoto 3 , Katsuhiro Hayashi 3 , Hiroaki Kimura 3 , Scott D. Nelson 4 , Sarah M. Dry 4 , Yunfeng Li 4 , Arun S. Singh 5 , Shinji Miwa 3 , Akira Odani 6 , Fritz C. Eilber 7 , Hiroyuki Tsuchiya 3 and Robert M. Hoffman 1, 2 1 AntiCancer, Inc., San Diego, California, USA 2 Department of Surgery, University of California, San Diego, California, USA 3 Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan 4 Department of Pathology, University of California, Los Angeles, California, USA 5 Division of Hematology-Oncology, University of California, Los Angeles, California, USA 6 Division of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan 7 Division of Surgical Oncology, University of California, Los Angeles, California, USA Correspondence to: Robert M. Hoffman, email: all@anticancer.com Fritz C. Eilber, email: fceilber@mednet.ucla.edu Hiroyuki Tsuchiya, email: tsuchi@med.kanazawa-u.ac.jp Keywords: platinum complex, 3Pt, undifferentiated pleomorphic sarcoma, PDOX, efficacy Received: April 25, 2017 Accepted: May 12, 2017 Published: June 28, 2017 ABSTRACT A patient high-grade undifferentiated pleomorphic soft-tissue sarcoma (UPS) from a striated muscle was previously orthotopically implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) nude-mouse model. In the present study, two weeks after orthotopic transplantation of the UPS, mice were treated intraperitoneally with cisplatinum (CDDP), doxorubicin (DOX) or a novel anionic-phosphate-platinum compound 3Pt. Treatments were repeated weekly for a total of 3 times. Six weeks after transplantation, all mice were sacrificed and evaluated. After two weeks treatment, tumor sizes were as follows: control (G1): 2208.3 mm 3 ; CDDP (G2): 841.8±3 mm 3 , p=0.0001; DOX (G3): 693.1±3 mm 3 , p=6.56E-7; 3Pt (G4): 333.7±1 mm 3 , p=4.8E-8. 3Pt showed significantly more efficacy compared to other therapy drugs tested: CDDP (p=0.0002), DOX (p=0.001). There were no animal deaths in any of the four groups. The present results suggest 3Pt is a promising new candidate for UPS since it was demonstrated to be effective in a PDOX model.

67Ga-DOTA-(L-Asp)11 and 67Ga-DOTA-(L-Asp)14, which have been developed as bone imaging agents, showed a high accumulation in bone and a rapid blood clearance in mice. However, peptides composed of D-amino acids are more stable in vivo than those composed of their L-equivalents. In this study, 67Ga-DOTA-(D-Asp)n (n = 2, 5, 8, 11, or 14) were synthesized using the Fmoc-based solid-phase methodology and evaluated. In hydroxyapatite binding assay, binding of 67Ga-DOTA-(D-Asp)n tended to increase with increasing length of the amino acid chain. 67Ga-DOTA-(D-Asp)11 and 67Ga-DOTA-(D-Asp)14 caused a high accumulation of radioactivity in the bones of the mice. However, the results for 67Ga-DOTA-(D-Asp)n and 67Ga-DOTA-(L-Asp)n were comparable. In urine analyses, the proportion of intact complex after injection of 67Ga-DOTA-(D-Asp)14 was significantly higher than that of 67Ga-DOTA-(L-Asp)14. Although 67Ga-DOTA-(D-Asp)14 was more stable than 67Ga-DOTA-(L-Asp)14, the properties of 67Ga-DOTA-(D-Asp)n and 67Ga-DOTA-(L-Asp)n as bone imaging agents may be comparable.

Radioactive nuclides leak into the surrounding environment after nuclear power plant disasters, such as the Chernobyl accident and the Fukushima Daiichi Nuclear Power Plant disaster. Cesium-137 (

Radiolabeled monoclonal antibodies (mAbs) are very useful molecular probes for nuclear imaging technique due to their high-target specificity and high-stability in the bloodstream. MAbs are generally labeled by indirect method using the combination of relatively long-lived metallic radionuclides (including (64)Cu, (89)Zr, and (111)In) and bifunctional chelating agents which are capable of binding both antibodies and radio metals. The indirect radiolabeling method has some advantages such as high labeling efficiency and long-term retention ability within their target cells. However, this conventional labeling method can potentially lead to low-target affinity of the mAb probes, because of the non-site-specific introduction of the bifunctional chelators into the active site of the mAbs. To overcome the shortcoming, we proposed a new direct labeling method utilizing fusion proteins comprising mAbs linked to metal binding peptides at the N- or C-terminus. In this study, we synthesized new peptide derivatives possessing an N-terminal tripeptide sequence (Xaa-Yaa-His) called the amino terminal Cu(2+)- and Ni(2+)-binding (ATCUN) motif as (64)Cu binding peptides for the proposed labeling method. Moreover, we studied the stability constants of Cu(2+)-ATCUN peptide complexes by pH titration. From these studies, we found that a low basicity of the N-terminal amine in the peptide resulted in a high stability constant of the complex. This finding may provide valuable guidelines in designing the ATCUN peptide with high-binding affinity toward (64)Cu.

The following reaction systems, with and without proton ambiguity, were set up for direct measurements of the rate constants of borate and boronate ions: boric acid [B(OH)3] and 4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt (Tiron); 3-nitrophenylboronic acid [3-NO2PhB(OH)2] and Tiron; phenylboronic acid [PhB(OH)2] and 4-nitrocatechol; boric acid and 4-nitrocatechol. Each rate constant for boric or boronic acid is larger than that for the conjugate borate or boronate ion for the reaction systems without proton ambiguity. These results explicitly indicate that the widespread belief that the rate constants of boronate ions are several orders of magnitude larger than those of the conjugate boronic acids is erroneous. The relative kinetic reactivities of RB(OH)2 and RB(OH)3– were investigated in relation to the linear free energy relationships between the rate constants and acidities of the boronic acids and diols.

Introduction Sigma receptors are appropriate targets for tumor imaging because they are highly expressed in a variety of human tumors. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)- p IV), with high affinity for sigma receptors, and prepared radioiodinated (+)- p IV. In this study, to develop a radiobromine-labeled vesamicol analog as a sigma receptor imaging agent for PET, nonradioactive and radiobromine-labeled (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol ((+)- p BrV) was prepared and evaluated in vitro and in vivo . In these initial studies, 77 Br was used because of its longer half-life. Methods (+)-[ 77 Br] p BrV was prepared by a bromodestannylation reaction with radiochemical purity of 98.8% after HPLC purification. The partition coefficient of (+)-[ 77 Br] p BrV was measured. In vitro binding characteristics of (+)- p BrV to sigma receptors were assayed. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[ 77 Br] p BrV and (+)-[ 125 I] p IV into DU-145 tumor-bearing mice. Results The lipophilicity of (+)-[ 77 Br] p BrV was lower than that of (+)-[ 125 I] p IV. As a result of in vitro binding assay to sigma receptors, the affinities of (+)- p BrV to sigma receptors were competitive to those of (+)- p IV. In biodistribution experiments, (+)-[ 77 Br] p BrV and (+)-[ 125 I] p IV showed high uptake in tumor via sigma receptors. The biodistributions of both radiotracers showed similar patterns. However, the accumulation of radioactivity in liver after injection of (+)-[ 77 Br] p BrV was significantly lower compared to that of (+)-[ 125 I] p IV. Conclusion These results indicate that radiobromine-labeled p BrV possesses great potential as a sigma receptor imaging agent for PET.

To develop a water-soluble and tumor-targeted photosensitizer for photodynamic therapy (PDT), a porphyrin framework containing the metal ion gallium(III) was combined with platinum(II)-based groups to produce two new pentacationic metalloporphyrinates, Ga-4cisPtTPyP (5,10,15,20-tetrakis{cis-diammine-chloro-platinum(II)}(4-pyridyl)-porphyrinato gallium(III) hydroxide tetranitrate) and Ga-4transPtTPyP (5,10,15,20-tetrakis{trans-diammine-chloro-platinum(II)} (4-pyridyl)-porphyrinato gallium(III) hydroxide tetranitrate). Both complexes exhibited high singlet oxygen quantum yields (Φ∆) and remarkable photocytotoxicity with appreciable phototoxic indexes (PIs). In particular, Ga-4cisPtTPyP showed a low IC50 value (Colon 26: 0.12 μM; Sarcoma 180: 0.08 μM) under illumination and its PI up to 1000. With outstanding tumor accumulation (tumor/muscle ratio > 9), Ga-4cisPtTPyP almost completely inhibited tumor growth over two weeks in an in vivo PDT assay. These results imply that Ga-4cisPtTPyP could be a promising anticancer agent for use in PDT.

金沢大学新学術創成研究機構, Background Release of radionuclides, such as 137Cs and 90Sr, into the atmosphere and the ocean presents an important problem because internal exposure to 137Cs and 90Sr could be very harmful to humans. Chlorella has been reported to be effective in enhancing the excretion of heavy metals; thus, we hypothesized that Chlorella could also enhance the elimination of 137Cs or 90Sr from the body. We evaluated the potential of Chlorella as a decorporation agent in vitro and in vivo, using 85Sr instead of 90Sr. Methods In vitro experiments of adsorption of 137Cs and 85Sr to Chlorella were performed under wide pH conditions. The maximum sorption capacity of Chlorella to strontium was estimated using the Langmuir model. A 85Sr solution was orally administrated to mice pretreated with Chlorella. At 48 h after 85Sr administration, the biodistribution of radioactivity was determined. Results In the in vitro experiments, although 85Sr barely adsorbed to Chlorella at low pH, the 85Sr adsorption ratio to Chlorella increased with increasing pH. The maximum sorption capacity of Chlorella to strontium was 9.06 mg / g. 137Cs barely adsorbed to Chlorella under any pH conditions. In the biodistribution experiments, bone accumulation of radioactivity after 85Sr administration was significantly decreased in the Chlorella pretreatment group compared with the non-treatment control group. Conclusions In conclusion, these results indicated that Chlorella could inhibit the absorption of 90Sr into the blood and enhance the elimination of 90Sr from the body through adsorption in intestine. Further studies are required to elucidate the mechanism and the components of Chlorella needed for adsorption to strontium and could promote the development of more effective decorporation agents. © 2016 Ogawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The compound beta-citryl-L-glutamate (beta-CG) was initially isolated from developing brains, while it has also been found in high concentrations in testes and eyes. However, its functional roles are unclear. To evaluate its coordination with metal ions, we performed pH titration experiments. The stability constant, logbeta(pqr) for M(p)(beta-CG)(q)H(r) was calculated from pH titration data, which showed that beta-CG forms relatively strong complexes with Fe(III), Cu(II), Fe(II) and Zn(II). beta-CG was also found able to solubilize Fe more effectively from Fe(OH)(2) than from Fe(OH)(3). Therefore, we examined the effects of beta-CG on Fe-dependent reactive oxygen species (ROS)-generating systems, as well as the potential ROS-scavenging activities of beta-CG and metal ion-(beta-CG) complexes. beta-CG inhibited the Fe-dependent degradation of deoxyribose and Fe-dependent damage to DNA or plasmid DNA in a dose-dependent manner, whereas it had no effect on Cu-mediated DNA damage. In addition, thermodynamic data showed that beta-CG in a physiological pH solution is an Fe(II) chelator rather than an Fe(III) chelator. Taken together, these findings suggest that beta-CG is an endogenous low molecular weight Fe chelator.