Clinical Translation of an Albumin-Binding PET Radiotracer <sup>68</sup>Ga-NEB

Zhang, Jingjing; Lang, Lixin; Zhu, Zhaohui; Li, Fang; Niu, Gang; Chen, Xiaoyuan

doi:10.2967/jnumed.115.159640

Cited by 46 publications

(68 citation statements)

References 33 publications

(32 reference statements)

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“…Dosimetry was calculated according to the European Association of Nuclear Medicine dosimetry guidance (37) and a previously reported procedure (38). Non–decay-corrected time–activity curves based on SUVs were generated for each organ.…”

Section: Methodsmentioning

confidence: 99%

⁶⁸Ga-NOTA-Aca-BBN(7–14) PET/CT in Healthy Volunteers and Glioma Patients

Zhang¹,

Lang

et al. 2015

J Nucl Med

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This work was designed to study the safety, biodistribution, and radiation dosimetry of a gastrin-releasing peptide receptor (GRPR)– targeting, 68Ga-labeled bombesin (BBN) peptide derivative PET tracer, NOTA-Aca-BBN(7–14) (denoted as 68Ga-BBN) in healthy volunteers and to assess the level of receptor expression in glioma patients. Methods Four healthy volunteers (2 male and 2 female) underwent whole-body PET/CT at multiple time points after a bolus injection of 68Ga-BBN (111 ± 148 MBq). Regions of interest were drawn manually over major organs, and time–activity curves were obtained. Dosimetry was calculated using the OLINDA/EXM software. Twelve patients with glioma diagnosed by contrast-enhanced MRI underwent PET/CT at 30–45 min after 68Ga-BBN injection. Within 1 wk afterward, the tumor was surgically removed and immunohistochemical staining of tumor samples against GRPR was performed and correlated with the PET/CT results. Results 68Ga-BBN was well tolerated in all healthy volunteers, with no adverse symptoms being noticed or reported. 68Ga-BBN cleared rapidly from the circulation and was excreted mainly through the kidneys and urinary tract. The total effective dose equivalent and effective dose were 0.0335 ± 0.0079 and 0.0276 ± 0.0066 mSv/MBq, respectively. In glioma patients, all MRI-identified lesions showed high signal intensity on 68Ga-BBN PET/CT. SUVmax and SUVmean were 2.08 ± 0.58 and 1.32 ± 0.37, respectively. With normal brain tissue as background, tumor-to-background ratios were 24.0 ± 8.85 and 13.4 ± 4.54 based on SUVmax and SUVmean, respectively. The immunohistochemical staining confirmed a positive correlation between SUV and GRPR expression level (r2 = 0.71, P < 0.001). Conclusion 68Ga-BBN is a PET tracer with favorable pharmacokinetics and a favorable dosimetry profile. It has the potential to evaluate GRPR expression in glioma patients and guide GRPR-targeted therapy of glioma.

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Section: Methodsmentioning

confidence: 99%

⁶⁸Ga-NOTA-Aca-BBN(7–14) PET/CT in Healthy Volunteers and Glioma Patients

Zhang¹,

Lang

et al. 2015

J Nucl Med

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Section: Figmentioning

confidence: 99%

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

2016

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Albumin is the most abundant circulating protein in plasma and has recently emerged as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide or protein based drugs. Three drug delivery technologies related to albumin have been developed, which include the coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugating bioactive proteins by albumin fusion technology (AFT), and encapsulation of drugs into albumin nanoparticles. This review article starts with a brief introduction of human serum albumin (HSA), and then summarizes the mainstream chemical strategies of developing HSA binding molecules for coupling with drug molecules. Moreover, we also concisely condense the recent progress of the most important clinical applications of HSA-binding platforms, and specify the current challenges that need to be met for a bright future of HSA-binding.

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“…1; Supplemental Fig. 1) (supplemental materials are available at http://jnm.snmjournals.org): 64 Cu-NMEB-RGD, which has a high affinity for integrin a v b 3 and contains an albuminbinding moiety; 64 Cu-NMEB-RAD, a control peptide with no affinity for the integrin a v b 3 receptor (11) but retaining the albuminbinding moiety; 64 Cu-NOTA-RGD, which has a high affinity for the integrin a v b 3 receptor but lacks the albumin-binding moiety; and 64 Cu-NEB, which is the albumin-binding moiety (4,12).…”

Section: Preparation Of Radiolabeled Compoundsmentioning

confidence: 99%

Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents

et al. 2016

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One of the major design considerations for a drug is its pharmacokinetics in the blood. A drug with a short half-life in the blood is less available at a target organ. Such a limitation dictates treatment with either high doses or more frequent doses, both of which may increase the likelihood of undesirable side effects. To address the need for additional methods to improve the blood half-life of drugs and molecular imaging agents, we developed an "add-on" molecule that contains 3 groups: a truncated Evans blue dye molecule that binds to albumin with a low micromolar affinity and provides a prolonged half-life in the blood; a metal chelate that allows radiolabeling for imaging and radiotherapy; and maleimide for easy conjugation to drug molecules. Methods: The truncated Evans blue molecule was conjugated with the chelator NOTA or DOTA, and the resulting conjugate was denoted as NMEB or DMEB, respectively. As a proof of concept, we coupled NMEB and DMEB to c(RGDfK), which is a small cyclic arginine-glycine-aspartic acid (RGD) peptide, for targeting integrin a v b 3 . NMEB and DMEB were radiolabeled with 64 Cu and 90 Y, respectively, and tested in xenograft models. Results: The resulting radiolabeled conjugates showed a prolonged circulation half-life and enhanced tumor accumulation in integrin a v b 3 -expressing tumors. Tumor uptake was markedly improved over that with NOTA-or DOTA-conjugated c(RGDfK). Tumor radiotherapy experiments in mice with 90 Y-DMEB-RGD showed promising results; existing tumors were eliminated. Conclusion: Conjugation of our novel add-on molecule, NMEB or DMEB, to potential tracers or therapeutic agents improved blood half-life and tumor uptake and could transform such agents into theranostic entities. Thegoalofdr ug development is to achieve high activity and specificity for a desired biologic target. However, many potential pharmaceuticals that meet these criteria fail as therapeutics because of unfavorable pharmacokinetics, in particular, rapid blood clearance, which prevents the achievement of therapeutic concentrations. For some drugs, the administration of large or frequently repeated doses is required to achieve and maintain therapeutic levels (1) but can, in turn, increase the probability of undesired side effects. One chemical modification that delays the rate of drug clearance and has been effective for some drugs is the addition of polyethylene glycol (PEG) (2). However, recent studies showed that PEGylation of drugs has disadvantages, including immunogenicity caused by the development of anti-PEG antibodies, heterogeneity of the PEGylated drugs, and decreased biologic activity and bioavailability of the drugs (1,3).To address the need for additional methods to improve the blood half-life of drugs and molecular imaging agents, we made use of molecules with a high affinity for albumin. We previously developed a radiolabeled truncated derivative of Evans blue (EB) that allowed imaging of the blood volume because of the affinity of EB for albumin (4). This result encouraged us to e...

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Clinical Translation of an Albumin-Binding PET Radiotracer ⁶⁸Ga-NEB

Cited by 46 publications

References 33 publications

⁶⁸Ga-NOTA-Aca-BBN(7–14) PET/CT in Healthy Volunteers and Glioma Patients

⁶⁸Ga-NOTA-Aca-BBN(7–14) PET/CT in Healthy Volunteers and Glioma Patients

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents

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Clinical Translation of an Albumin-Binding PET Radiotracer 68Ga-NEB

Cited by 46 publications

References 33 publications

68Ga-NOTA-Aca-BBN(7–14) PET/CT in Healthy Volunteers and Glioma Patients

68Ga-NOTA-Aca-BBN(7–14) PET/CT in Healthy Volunteers and Glioma Patients

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

Novel “Add-On” Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents

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Clinical Translation of an Albumin-Binding PET Radiotracer ⁶⁸Ga-NEB

⁶⁸Ga-NOTA-Aca-BBN(7–14) PET/CT in Healthy Volunteers and Glioma Patients

⁶⁸Ga-NOTA-Aca-BBN(7–14) PET/CT in Healthy Volunteers and Glioma Patients