Abstract
BackgroundThere is a need to develop new and more potent radiofluorinated peptide and their hybrid conjugates for multiple-receptors targeting properties that overexpress on many cancers.MethodsWe have synthesized MUC1-[18F] SFB and MUC1-FA-[18F] SFB hybrid conjugates using a convenient and one-step nucleophilic displacement reaction. In vitro cell binding and in vivo evaluation in animals were performed to determine the potential of these radiolabeled compounds.ResultsRadiochemical yields for MUC1-[18F] SFB and MUC1-FA-[18F] SFB conjugates were greater than 70% in less than 30 min synthesis time. Radiochemical purities were greater than 97% without HPLC purification, which makes these approaches amenable to automation. In vitro studies on MCF7 breast cancer cells showed that the significant amounts of the radiofluorinated conjugates were associated with cell fractions and held good affinity and specificity for MCF7 cells. In vivo characterization in Balb/c mice revealed rapid blood clearance with excretion predominantly by urinary as well as hepatobiliary systems for MUC1-[18F] SFB and MUC1-FA-[18F] SFB, respectively.Biodistribution in SCID mice bearing MCF7 xenografts, demonstrated excellent tumor uptake (12% ID/g) and favorable kinetics for MUC1-FA-[18F] SFB over MUC1-[18F]SFB. The tumor uptake was blocked by the excess co-injection of cold peptides suggesting the receptor-mediated process.ConclusionInitial PET/CT imaging of SCID mice with MCF7 xenografts, confirmed these observations. These results demonstrate that MUC1-FA-[18F] SFB may be a useful PET imaging probe for breast cancer detection and monitoring tumor response to the treatment.
Highlights
Many tumor-associated antigens (TAAs) have been discovered and identified in the last decade and have provided new hope for the treatment of patients with malignant disease (Knutson et al, 2001; Brossart et al, 2000)
The human epithelial mucin encoded by the gene MUC1 is an example of a tumor-specific antigen that is highly restricted on normal tissues but it is overexpressed on almost all human cancers and in particular, by primary and metastatic breast cancers (Kufe, 2009; Lakshminarayanan et al, 2012; Singh & Bandyopadhyay, 2007), making MUC1 a promising tumor-antigen with diagnostic as well as therapeutic potential in the management and treatment of cancer (Moore et al, 2004; Muller & Hanisch, 2002)
Organic chemistry The MUC1 peptide investigated was successfully prepared in good yields (30%) by solid-phase synthesis according to standard Fmoc/HBTU methodology
Summary
We have developed a one-step and rapid synthetic approach for the radiofluorination of the receptor-targeting peptide and their hybrids via carbon atom nucleophilic displacement reactions. In vitro binding studies on MCF7 breast cancer cell line showed superior affinity of MUC1FA-[18F] SFB hybrid peptide over only MUC1-[18F] SFB peptide conjugate. In SCID mice model bearing human breast cancer cell line xenografts, MUC1-FA-[18F] SFB hybrid peptide demonstrated excellent tumor uptake and favorable pharmacokinetics over MUC1-. These observations were confirmed by initial Nano PET/CT imaging with a high accumulation of radioactivity in the tumor. These results demonstrate that MUC1-FA-[18F] SFB hybrid peptide conjugate may be useful as a dual receptortargeting PET imaging probe for breast cancer detection and monitoring tumor response to the treatment, further evaluation is warranted
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