Zwitterionic Modification of PSMA Ligands Reduces Off-Target Binding and Tissue Retention

TL;DR

This paper shows that adding zwitterionic groups to PSMA-targeted drugs improves their performance by reducing unwanted tissue retention.

Contribution

The study introduces zwitterionic modification as a novel strategy to enhance PSMA-targeted drug specificity and reduce off-target effects.

Findings

Adding two zwitterionic groups to PSMA ligands significantly reduced off-target tissue retention.

Compound 10 showed high PSMA-binding affinity and good tumor uptake in mice.

The modification can be easily applied using standard synthesis methods.

Abstract

Off-target tissue retention is a serious limitation for
prostate-specific
membrane antigen (PSMA)-targeted drugs. This study addresses key questions
regarding the role of zwitterionic modifications in PSMA-ligand design
for tissue distribution. A series of fluorescent PSMA-ligands was
synthesized and evaluated with respect to PSMA-binding, tumor uptake,
and biodistribution in cell experiments and in mice. The data revealed
that the introduction of two zwitterionic groups into the linker domain
of the PSMA-specific conjugates was particularly advantageous. The
resulting compound 10 combined high and specific PSMA-binding
affinity (IC50 = 4.39 ± 1.69 nM) and good uptake in
tumor cells and tumor xenografts with extremely low off-target tissue
retention. A major practical advantage of this strategy is its simple
synthetic realization using solid-phase peptide synthesis with commercial
building blocks and their modification using click-chemistry. Zwitterionization
is therefore easily transferable to other targeting vectors and alternative
effector molecules, for example in radiopharmaceuticals.

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