The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of 64 Cu-DOTA-trastuzumab in humans. Methods: PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe 64 Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of 64 Cu-DOTA-trastuzumab and during the 1-wk follow-up period. Results: According to our results, the best timing for the assessment of 64 Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during 64 Cu-DOTA-trastuzumab PET was equivalent to that during conventional 18 F-FDG PET. The radioactivity in the blood was high, but uptake of 64 Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, 64 Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, 64 Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. Conclusion: The findings of this study indicated that 64 Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

BackgroundThe purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with 64Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab.MethodsPET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe 64Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of 64Cu-DOTA-trastuzumab.ResultsMetastatic brain lesions could be visualized by 64Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of 64Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS.ConclusionsCu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer.Trial registrationUMIN000004170

No abstract

Body image: Self‐activating Huisgen 1,3‐dipolar cycloaddition and 6π azaelectrocyclization of lysine‐based dendrimers (see picture) enable the in vivo dynamics and organ‐specific accumulation of N‐glycans to be visualized. The sugar structure and glycosyl bond linkages of N‐glycans control the whole‐body trafficking of the clusters in nude mice and a cancer model.

Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure.