期刊
BIOCONJUGATE CHEMISTRY
卷 21, 期 3, 页码 436-444出版社
AMER CHEMICAL SOC
DOI: 10.1021/bc9003102
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资金
- NCI NIH HHS [5R25 CA118681, K01 CA104706, K01 CA104706-05, P50 CA114747, K01 CA104706-02, K01 CA104706-04, K01 CA104706-03, 5K01 CA104706, R25 CA118681, K01 CA104706-01] Funding Source: Medline
Previously, we used directed evolution to engineer Mutants of the Ecballium elaterium trypsin inhibitor (EETI-II) knottin that bind to alpha(v)beta(3) and alpha(v)beta(5) integrin receptors with low nanomolar affinity, and showed that Cy5.5- or Cu-64-DOTA-labeled knottin peptides could be used to image integrin expression in mouse tumor models using near-infrared fluorescence (NIRF) imaging or positron emission tomography (PET). Here, we report the development of a dual-labeled knottin peptide conjugated to both NIRF and PET imaging agents for multimodality imaging in living Subjects. We created all orthogonally protected peptide-based linker for stoichiometric Coupling Of Cu-64-DOTA and Cy5.5 onto (he knottin N-terminus and confirmed that conjugation did not affect binding to alpha(v)beta(3) and alpha(v)beta(5) integrins. NIRF and PET imaging studies in tumor xenograft models showed that Cy5.5 conjugation significantly increased kidney uptake and retention compared to the knottin peptide labeled With Cu-64-DOTA alone. In the turner, the dual-labeled Cu-64-DOTA/Cy5.5 knottin peptide showed decreased wash-out leading to significantly better retention (p < 0.05) compared to the Cu-64-DOTA-labeled knottin peptide. Tumor uptake was significantly reduced (p < 0.05) when the dual-labeled knottin peptide was coinjected with an excess of unlabeled competitor and when tested ill a tumor model with lower levels of integrin expression. Finally, Plots of tumor-to-background tissue ratios for Cy5.5 versus Cu-64 uptake were well-correlated over several time points post injection, demonstrating pharmacokinetic cross validation of imaging labels. This dual-modality NIRF/PET imaging agent is promising for further development in clinical applications where high sensitivity and high resolution arc desired, Such as detection of tumors located deep within file body and image-guided Surgical resection.
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