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Dual-Nuclide Radiopharmaceuticals for Positron Emission Tomography Based Dosimetry in Radiotherapy.

ABSTRACT: Improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual-nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, which are based on common and widely available metal radionuclides. Dual-chelator conjugates, featuring interlinked cyclen- and triazacyclononane-based polyphosphinates DOTPI and TRAP, allow for strictly regioselective complexation of therapeutic (e.g., ¹⁷⁷ Lu, ⁹⁰ Y, or ²¹³ Bi) and PET (e.g., ⁶⁸ Ga) radiometals in the same molecular framework by exploiting the orthogonal metal ion selectivity of these chelators (DOTPI: large cations, such as lanthanide(III) ions; TRAP: small trivalent ions, such as Ga^III ). Such DOTPI-TRAP conjugates were decorated with 3?Gly-urea-Lys (KuE) motifs for targeting prostate-specific membrane antigen (PSMA), employing Cu-catalyzed (CuAAC) as well as strain-promoted (SPAAC) click chemistry. These were labeled with ¹⁷⁷ Lu or ²¹³ Bi and ⁶⁸ Ga and used for in vivo imaging of LNCaP (human prostate carcinoma) tumor xenografts in SCID mice by PET, thus proving practical applicability of the concept.

SUBMITTER: Wurzer A

PROVIDER: S-EPMC5813229 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Dual-Nuclide Radiopharmaceuticals for Positron Emission Tomography Based Dosimetry in Radiotherapy.

Wurzer Alexander A Seidl Christof C Morgenstern Alfred A Bruchertseifer Frank F Schwaiger Markus M Wester Hans-Jürgen HJ Notni Johannes J

Chemistry (Weinheim an der Bergstrasse, Germany) 20170914 3

Improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual-nuclide ...[more]

PMID: 28833667

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Dataset Information

Dual-Nuclide Radiopharmaceuticals for Positron Emission Tomography Based Dosimetry in Radiotherapy.

Publications

Dual-Nuclide Radiopharmaceuticals for Positron Emission Tomography Based Dosimetry in Radiotherapy.

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