Development of an automated production process of [64Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications

Cyclotron-produced copper-64 radioisotope tracers offer the possibility to perform both diagnostic investigation by positron emission tomography (PET) and radiotherapy by a theranostic approach with bifunctional chelators. The versatile chemical properties of copper add to the importance of this isotope in medicinal investigation. [⁶⁴Cu][Cu (ATSM)] has shown to be a viable candidate for imaging of tumor hypoxia; a critical tumor microenvironment characteristic that typically signifies tumor progression and resistance to chemo-radiotherapy. Various production and radiosynthesis methods of [⁶⁴Cu][Cu (ATSM)] exist in labs, but usually involved non-standardized equipment with varying production qualities and may not be easily implemented in wider hospital settings. [⁶⁴Cu][Cu (ATSM)] was synthesized on a modified GE TRACERlab FXN automated synthesis module. End-of-synthesis (EOS) molar activity of [⁶⁴Cu][Cu (ATSM)] was 2.2–5.5 Ci/μmol (HPLC), 2.2–2.6 Ci/μmol (ATSM-titration), and 3.0–4.4 Ci/μmol (ICP-MS). Radiochemical purity was determined to be >99% based on radio-HPLC. The final product maintained radiochemical purity after 20 h. We demonstrated a simple and feasible process development and quality control protocols for automated cyclotron production and synthesis of [⁶⁴Cu][Cu (ATSM)] based on commercially distributed standardized synthesis modules suitable for PET imaging and theranostic studies.     

Synthesis of [18F] 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide (IDO5L): a novel potential PET probe for imaging of IDO1 expression

To synthesize ¹⁸F‐labeled positron emission tomography (PET) ligands, reliable labeling techniques inserting ¹⁸F into a target molecule are necessary. The ¹⁸F‐fluorobenzene moiety has been widely utilized in the synthesis of ¹⁸F‐labeled compounds. The present study utilized [¹⁸F]‐labeled aniline as intermediate in [¹⁸F]‐radiolabeling chemistry for the facile radiosynthesis of 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide ([¹⁸F]IDO5L) as indoleamine 2,3‐dioxygenase 1 (IDO1) targeted tracer. IDO5L is a highly potent inhibitor of IDO1 with low nanomolar IC₅₀. [¹⁸F]IDO5L was synthesized via coupling [¹⁸F]3‐chloro‐4‐fluoroaniline with carboximidamidoyl chloride as a potential PET probe for imaging IDO1 expression. Under the optimized labeling conditions, chemically and radiochemically pure (>98%) [¹⁸F]IDO5L was obtained with specific radioactivity ranging from 11 to 15 GBq/µmol at the end of synthesis within ~90 min, and the decay‐corrected radiochemical yield was 18.2 ± 2.1% (n = 4).     

Suitability of liposomal carriers for systemic delivery of risedronate using the pulmonary route

Abstract

Objective: This study aims at testing the hypothesis that reversed phase evaporation liposomes (REVs) are suitable for systemic delivery of an anti-osteporotic drug (risedronate sodium (RS)) via pulmonary nebulization.

Materials and methods: RS REVs were prepared using phospholipids and cholesterol with or without stearylamine, and were characterized for morphology, entrapment efficiency (EE%), in vitro release, particle size and aerosolization behavior from an actively vibrating mesh nebulizer. RS accumulation in rat bones following intra-tracheal administration of the selected formulation was assessed using a radiolabelling-based technique, and histological examination of rat lung tissue was performed to assess its safety.

Results: The EE% of RS REVs ranged from 8.8% to 58.96% depending on cholesterol molar ratio, phospholipid type and presence of stearylamine. RS REVs’ particle size ranged from 2.15 to 3.61?µm and were spherical and moderately polydisperse. Nebulization of the selected formulation showed an aerosol output of 85%, a fine particle fraction of 70.75% and a predicted alveolar deposition of 30.39%. The amount of radiolabelled RS deposited in rat bones after pulmonary administration was 20%, while being considerably safe on lung tissues.

Conclusion: Cationic REVs is a promising carrier for systemic delivery of RS for treatment of bone resorptive diseases.     

Synthesis and Biological Evaluation of New Quinoxaline Derivatives of ICF01012 as Melanoma-Targeting Probes

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Development and characterization of a 99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

The aim of this work was to develop and evaluate a ^99mTc‐labeled neuropeptide Y derivative with affinity toward Y1‐receptor. The selected amino acid sequence included nine amino acids derived from the C‐terminal portion of the NPY complemented with the addition of one cysteine‐mercaptoacetic acid moiety to bind the radiometal. Labeling was achieved through the preparation of a 3 + 1 nitrido complex. Physicochemical evaluation, cell uptake, internalization and externalization studies, and competitive assays were performed. Biodistribution experiments were carried out in normal and tumor‐bearing mice. A single product with radiochemical purity >90% and high stability was obtained. In vitro analysis showed specific cellular uptake, IC₅₀ of 73.2 nM, and a high internalization rate (80%). Biodistribution studies showed low blood and renal uptake and combined hepatobiliary and urinary elimination. Preliminary studies in mice bearing induced breast tumors rendered promising uptake values.     

Exchange radioiodination produces inversion at C‐4 of 1‐(4‐deoxy‐4‐iodo‐β‐D‐xylopyranosyl)‐2‐nitroimidazole

The title compound, 3a , when exchange labeled with ¹²⁵I results in three new labeled products. The major labeled product (84.1%) is 1‐(4‐deoxy‐4‐iodo‐β‐L‐arabinopyranosyl)‐2‐nitroimidazole, 3b , that could result from inversion of configuration at C‐4. Exchange labeling carried out under conditions of kinetic control yielded dramatically different product ratios than thermodynamic equilibrium reactions. Confirmation of these results was established by extensive ¹HNMR spectral analyses. A possible mechanism is presented. Copyright © 2002 John Wiley & Sons, Ltd.     

A novel versatile precursor suitable for 18F‐radiolabeling via “click chemistry”

As an effort to improve ¹⁸F‐radiolabeling of biomolecules in method robustness and versatility, we report the synthesis and radiolabeling of a new azido precursor potentially useful for the so‐called “click reaction,” in particular the ligand‐free version of the copper(I)‐catalyzed alkyne‐azide cycloaddition. The new azido precursor may help to overcome problems sometimes exhibited by most of the currently used analogues, as it is safe to handle and it displays long‐term chemical stability, thus facilitating the development of new radiolabeling procedures. Moreover, the formed ¹⁸F‐labeled 1,2,3‐triazole is potentially metabolically stable and could enhance the in vivo circulation time. The above azido precursor was successfully radiolabeled with ¹⁸F, with 51% radiochemical yield (nondecay‐corrected). As a proof of concept, the ¹⁸F‐labeled azide was then tested with a suitable alkyne functionalized aminoacid (l ‐propargylglycine), showing 94% of conversion, and a final radiochemical yield of 27% (>99% radiochemical purity), nondecay‐corrected, with a total preparation time of 104 minutes.     

DNA探针的高效标记和哺乳动物细胞转化子的检测

本实验采用随机引物法标记探针DNA.探针DNA加热变性成单链,以单链DNA为模板,六聚脱氧核苷酸为引物,在DNA多聚酶I大片段的作用下进行放射性标记.标记探针的比放射性达10~8cpm/μg DNA以上.放射性底物的掺入率为60%.用该方法标记的人高度重复顺序探针,可以检出微微克水平的阳性分子.与人HeLa S_3细胞DNA转化的小鼠LTK~+细胞DNA打点杂交呈阳性,与未经转化的小鼠LTK~-细胞DNA杂交为阴性,证明小鼠转化细胞中存在HeLa细胞DNA,DNA转化是成功的.     

In-labeled KCCYSL peptide as an imaging probe for ErbB-2-expressing ovarian carcinomas

Aberrant expression of ErbB-2, a member of the epidermal growth factor family of receptors, has been implicated in the formation of various malignancies including ovarian cancer. The objective of this study was to determine if the bacteriophage (phage) display-selected ErbB-2 targeting peptide, KCCYSL, once radiolabeled with (111)In would serve as a tumor targeting and Single Photon Emission Computed Tomography (SPECT/CT) imaging agent in a mouse model of human ovarian carcinoma expressing ErbB-2. The KCCYSL peptide was synthesized with a chelator 1,4,7,10-tetra-azacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), and a Gly-Ser-Gly (GSG) spacer between DOTA and amino terminus of the peptide and radiolabeled with (111)InC1(3). In vitro cell binding studies indicated that (111)In-DOTA-GSG-KCCYSL bound to cultured ovcar-3 carcinoma cells. Biodistribution studies in scid mice bearing human ovcar-3 tumor xenografts revealed a tumor uptake of 0.50 ± 0.05 percent injected dose per gram (%ID/g) at 1 h, and 0.39 ± 0.1 %ID/g at 2 h. Blocking studies with non-radiolabeled counterpart indicated a partial inhibition (41%) (P = 0.04) in tumor uptake of (111)In-DOTA-GSG-KCCYSL. In vivo tumor uptake of (111)In-DOTA-GSG-KCCYSL was clearly evident through SPECT/CT images after 2 h post injection. These studies suggest the potential of this peptide as a radiopharmaceutical for imaging of ErbB-2-expressing ovarian tumors.     

Curcumin-docetaxel co-loaded nanosuspension for enhanced anti-breast cancer activity

ABSTRACT

Purpose: A curcumin-docetaxel co-loaded nanosuspension with increased anti-breast cancer activity was developed. Curcumin is a potential anticancer agent with p-glycoprotein (p-gp) inhibiting activity may be co-administered with docetaxel as a nanosuspension to enhance its anticancer effect by increasing the oral bioavailability and decreasing drug efflux.

Methods: Nanosuspensions of curcumin and docetaxel were prepared by precipitation-homozenisation technique and evaluated for particle size, polydispersity, zeta potential and drug release. The in vitro MTT assay was conducted using MCF-7 for anti-breast cancer activity. The in vivo biodistribution by radiolabeling and tumor inhibition study was conducted in mice.

Results: Homogenous nanosuspensions of 80 ± 20 nm were obtained with increased solubility. The drugs as nanosuspensions showed higher cytotoxicity on MCF-7 cell line compared to their suspensions due to the increased in vitro cellular uptake. Due to this increased solubility, sensitization of tumor cells and inhibition of p-gp the in-vivo results showed greater tumor inhibition rate of up to 70% in MCF-7 treated mice. Histopathological results showed higher apoptotic activity and reduced level of angiogenesis.

Conclusions: The in vitro and in vivo study of the nanosuspensions has shown that Co-administration of Curcumin as a p-gp inhibitor with docetaxel may have the potential to increase the anti-breast cancer efficacy of both drugs.