Abstract
The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but ...usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu
2+
-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu
2+
into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing
64
Cu
2+
, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an “ideal” PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.
We studied the simple separation of radiosilvers from proton- or deuteron-irradiated natural palladium (
Pd) targets, and successfully separated radiorhodium, radiosilver and radiopalladium using an ...anion-exchange resin. The yields of radiosilvers were
Ag: 1.0 ± 0.32 MBq/μAh;
Ag: 2.0 ± 0.64 MBq/μAh;
Ag: 0.019 ± 0.0063 MBq/μAh (
= 4) at the end of bombardment with a total recovery rate of 98 % under the following irradiation conditions (deuteron beam energy: 20 MeV; beam current: 10 μA; irradiation time: 2.25 ± 0.50 h). We also evaluated the recycling of the palladium target.
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Thiocarbonyl-11Cdisulfiram (11CDSF) was synthesized via iodine oxidation of 11Cdiethylcarbamodithioic acid (11CDETC), which was prepared from 11Ccarbon disulfide and diethylamine. The ...decay-corrected isolated radiochemical yield (RCY) of 11CDSF was greatly affected by the addition of unlabeled carbon disulfide. In the presence of carbon disulfide, the RCY was increased up to 22% with low molar activity (Am, 0.27 GBq/μmol). On the other hand, 11CDSF was obtained in 0.4% RCY with a high Am value (95 GBq/μmol) in the absence of carbon disulfide. The radiochemical purity of 11CDSF was always >98%. The first PET study on 11CDSF was performed in mice. A high uptake of radioactivity was observed in the liver, kidneys, and gallbladder. The uptake level and distribution pattern in mice were not significantly affected by the Am value of the 11CDSF sample used. In vivo metabolite analysis showed the rapid decomposition of 11CDSF in mouse plasma.
Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. ...This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of 64CuDPA and investigated the tumor engagement of 64Cu/68GaDPA in mouse models. Our results revealed that intact 64Cu/68GaDPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of 64CuDPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.
The in vivo fate and target engagement of a PD-L1 binding D-peptide, DPA, were comprehensively tracked by PET imaging, revealing that DPA is a superior targeting vehicle for radiotheranostic agents. Display omitted
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DAA1106 (N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for the translocator protein (18 kDa, TSPO) in brain mitochondrial fractions ...of rats and monkey (Ki = 0.043 and 0.188 nM, respectively). In this study, to translate 18FDAA1106 for clinical studies, we performed automated syntheses of 18FDAA1106 using the spirocyclic iodonium ylide (1) as a radiolabelling precursor and conducted preclinical studies including positron emission tomography (PET) imaging of TSPO in ischemic rat brains. Radiofluorination of the ylide precursor 1 with 18FF−, followed by HPLC separation and formulation, produced the 18FDAA1106 solution for injection in 6% average (n = 10) radiochemical yield (based on 18FF−) with >98% radiochemical purity and molar activity of 60–100 GBq/μmol at the end of synthesis. The synthesis time was 87 min from the end of bombardment. The automated synthesis achieved 18FDAA1106 with sufficient radioactivity available for preclinical and clinical use. Biodistribution study of 18FDAA1106 showed a low uptake of radioactivity in the mouse bones. Metabolite analysis showed that >96% of total radioactivity in the mouse brain at 60 min after the radiotracer injection was unmetabolized 18FDAA1106. PET study of ischemic rat brains visualized ischemic areas with a high uptake ratio (1.9 ± 0.3) compared with the contralateral side. We have provided evidence that 18FDAA1106 could be routinely produced for clinical studies.
Background
18
FFluoromisonidazole (
18
FFMISO) and 1-
18
Ffluoro-3-((2-((1
E
,3
E
)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzodthiazol-6-yl)oxy)propan-2-ol (
18
FPM-PBB3 or
18
...FAPN-1607) are clinically used radiotracers for imaging hypoxia and tau pathology, respectively. Both radiotracers were produced by direct
18
F-fluorination using the corresponding tosylate precursors 1 or 2 and
18
FF
−
, followed by the removal of protecting groups. In this study, we synthesized
18
FFMISO and
18
FPM-PBB3 by
18
F-fluoroalkylation using
18
Fepifluorohydrin (
18
F5) for clinical applications.
Results
First,
18
F5 was synthesized by the reaction of 1,2-epoxypropyl tosylate (8) with
18
FF
−
and was purified by distillation. Subsequently,
18
F5 was reacted with 2-nitroimidazole (6) or PBB3 (7) as a precursor for
18
F-labeling, and each reaction mixture was purified by preparative high-performance liquid chromatography and formulated to obtain the
18
FFMISO or
18
FPM-PBB3 injection. All synthetic sequences were performed using an automated
18
F-labeling synthesizer. The obtained
18
FFMISO showed sufficient radioactivity (0.83 ± 0.20 GBq at the end of synthesis (EOS);
n
= 8) with appropriate radiochemical yield based on
18
FF
−
(26 ± 7.5 % at EOS, decay-corrected;
n
= 8). The obtained
18
FPM-PBB3 also showed sufficient radioactivity (0.79 ± 0.10 GBq at EOS;
n
= 11) with appropriate radiochemical yield based on
18
FF
−
(16 ± 3.2 % at EOS, decay-corrected;
n
= 11).
Conclusions
Both
18
FFMISO and
18
FPM-PBB3 injections were successfully synthesized with sufficient radioactivity by
18
F-fluoroalkylation using
18
F
5
.
Targeted radionuclide therapy (TRT) provides new and safe opportunities for cancer treatment and management with high precision and efficiency. Here we have designed a novel semiconducting polymer ...nanoparticle (SPN)-based radiopharmaceutical (211At-MeATE-SPN-GIP) for TRT against glucose-dependent insulinotropic polypeptide receptor (GIPR)-positive cancers to further explore the applications of nanoengineered TRT. 211At-MeATE-SPN-GIP was engineered via nanoprecipitation, followed by its functionalization with a glucose-dependent insulinotropic polypeptide (GIP) to target GIPR and deliver 211At for α therapy. The therapeutic effect and biological safety of 211At-MeATE-SPN-GIP were investigated using GIPR-overexpressing human pancreatic cancer CFPAC-1 cells and CFPAC-1-bearing mice. In this work, 211At-MeATE-SPN-GIP was produced with a radiochemical yield of 43% and radiochemical purity of 98%, which exhibited a specifically high uptake in CFPAC-1 cells, inducing cell cycle arrest at the G2/M phase and extensive DNA damage. In the CFPAC-1-bearing tumor model, 211At-MeATE-SPN-GIP exhibited high therapeutic efficiency, with no obvious side effects. The GIPR-specific binding of 211At-MeATE-SPN-GIP combined with effective inhibition of tumor growth and fewer side effects compared to control suggests that 211At-MeATE-SPN-GIP TRT holds great potential as a novel nanoengineered TRT strategy for patients with GIPR-positive cancer.
We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-1,2,4triazolo4,3-apyrazine-5-
Ccarbonitrile (
CMTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. ...For the fully automated production of
CMTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of
CMTP38 using
Chydrogen cyanide (
CHCN) as a PET radiopharmaceutical. Radiosynthesis of
CMTP38 was performed using an automated
C-labeling synthesizer developed in-house within 40 min after the end of irradiation.
CMTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on
CCO
at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the
CMTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of
CMTP38 for clinical applications using an
C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical
CMTP38 suitable for clinical applications.
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