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Development of Dual Receptor Enhanced Pre-Targeting Strategy-A Novel Promising Technology for Immuno-Positron Emission Tomography Imaging.

ABSTRACT: PET imaging has become an important diagnostic tool in the era of precise medicine. Various pre-targeting systems have been reported to address limitations associated with traditional immuno-PET. However, the application of these mono-receptor based pre-targeting (MRPT) strategies is limited to non-internalizable antibodies, and the tumor uptake is usually much lower than that in the corresponding immuno-PET. To circumvent these limitations, we develop the first Dual-Receptor Pre-Targeting (DRPT) system through entrapping the tumor-receptor-specific radioligand by the pre-administered antibody. Besides the similar ligation pathway happens in MRPT, incorporation of a tumor-receptor-specific peptide into the radioligand in DRPT enhances both concentration and retention of the radioligand on tumor, promoting its ligation with pre-administered mAb on cell-surface and/or internalized into tumor-cells. In this study, ⁶⁴Cu based DRPT shows superior performance over corresponding MRPT and immuno-PET using internalizable antibodies. Besides, the compatibility of DRPT with short-lived and generator-produced ⁶⁸Ga is demonstrated, leveraging its advantage in reducing radio-dose exposure. Furthermore, the feasibility of reducing the amount of the pre-administered antibody is confirmed, indicating the cost saving potential of DRPT. In summary, synergizing advantages of dual-receptor targeting and pre-targeting, we expect that this DRPT strategy can become a breakthrough technology in the field of antibody-based molecular imaging.

SUBMITTER: Sun L

PROVIDER: S-EPMC8932640 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Development of Dual Receptor Enhanced Pre-Targeting Strategy-A Novel Promising Technology for Immuno-Positron Emission Tomography Imaging.

Sun Lingyi L Gai Yongkang Y Li Zhonghan Z Zhang Xiaohui X Li Jianchun J Ma Yongyong Y Li Huiqiang H Barajas Ramon J RJ Zeng Dexing D

Advanced therapeutics 20210821 10

PET imaging has become an important diagnostic tool in the era of precise medicine. Various pre-targeting systems have been reported to address limitations associated with traditional immuno-PET. However, the application of these mono-receptor based pre-targeting (MRPT) strategies is limited to non-internalizable antibodies, and the tumor uptake is usually much lower than that in the corresponding immuno-PET. To circumvent these limitations, we develop the first Dual-Receptor Pre-Targeting (DRPT ...[more]

PMID: 35309962

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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

Development of Dual Receptor Enhanced Pre-Targeting Strategy-A Novel Promising Technology for Immuno-Positron Emission Tomography Imaging.

Publications

Development of Dual Receptor Enhanced Pre-Targeting Strategy-A Novel Promising Technology for Immuno-Positron Emission Tomography Imaging.

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