Development of prostate specific membrane antigen targeted ultrasound microbubbles using bioorthogonal chemistry

Aimen Zlitni, Melissa Yin, Nancy Janzen, Samit Chatterjee, Ala Lisok, Kathleen L. Gabrielson, Sridhar Nimmagadda, Martin G. Pomper, F. Stuart Foster, John F. Valliant

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number0176958
JournalPloS one
Volume12
Issue number5
DOIs
StatePublished - May 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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