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Prostate specific membrane antigen PSMA targeted microbubbles MBs were developed using bioorthogonal chemistry. Streptavidin-labeled MBs were treated with a biotinylated tetrazine MBTz and targeted to PSMA expressing cells using trans-cyclooctene TCO-functionalized anti-PSMA antibodies TCO-anti-PSMA. The extent of MB binding to PSMA positive cells for two different targeting strategies was determined using an in vitro flow chamber. The initial approach involved pretargeting, where TCO-anti-PSMA was first incubated with PSMA expressing cells and followed by MBTz, which subsequently showed a 2.8 fold increase in the number of bound MBs compared to experiments performed in the absence of TCO-anti-PSMA. Using direct targeting, where TCO-anti-PSMA was linked to MBTz prior to initiation of the assay, a 5-fold increase in binding compared to controls was observed. The direct targeting approach was subsequently evaluated in vivo using a human xenograft tumor model and two different PSMA-targeting antibodies. The US signal enhancements observed were 1.6- and 5.9-fold greater than that for non-targeted MBs. The lead construct was also evaluated in a head-to-head study using mice bearing both PSMA positive or negative tumors in separate limbs. The human PSMA expressing tumors exhibited a 2-fold higher US signal compared to those tumors deficient in human PSMA. The results demonstrate both the feasibility of preparing PSMA-targeted MBs and the benefits of using bioorthogonal chemistry to create targeted US probes.



Autor: Aimen Zlitni, Melissa Yin, Nancy Janzen, Samit Chatterjee, Ala Lisok, Kathleen L. Gabrielson, Sridhar Nimmagadda, Martin G. Pompe

Fuente: http://plos.srce.hr/



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