Glutamate carboxypeptidase II (GCPII) in the central nervous system is referred to as the prostate-specific membrane antigen (PSMA) in the periphery. PSMA serves as a target for imaging and treatment of prostate cancer and because of its expression in solid tumor neovasculature has the potential to be used in this regard for other malignancies as well. An overview of GCPII/PSMA in cancer, as well as a discussion of imaging and therapy of prostate cancer using a wide variety of PSMA-targeting agents is provided.

Polymeric nanoparticles represent a form of targeted therapy due to their ability to passively accumulate within the tumor interstitium via the enhanced permeability and retention (EPR) effect. We used a combined approach to decorate the surface of a nanoparticle with a urea-based small-molecule peptidomimetic inhibitor of prostate specific membrane antigen (PSMA). PSMA is expressed by normal and malignant prostate epithelial cells and by the neovasculature of almost all solid tumors. This strategy takes advantage of both the avidity of the functionalized nanoparticle for binding to PSMA and the ability of the nanoparticle to be retained for longer periods of time in the tumor due to enhanced leakage via EPR into the tumor interstitium. As an initial step to introducing the targeting moiety, the amino terminus of the small-molecule PSMA inhibitor was conjugated to PEG (M n 3400) bearing an activated carboxyl group to obtain a PEGylated inhibitor. Studies undertaken using a radiolabeled PSMA-substrate based assay established that the PEGylated inhibitor had an IC 50 value similar to the uncomplexed inhibitor. Subsequently, nanoparticles loaded with docetaxel were formulated using a mixture of poly(lactide-β-ethylene glycol-β-lactide) and PSMA-inhibitor bound α-amino-ω-hydroxy terminated poly (ethylene glycol-β-ε-caprolactone). In vitro studies using these nanoparticles demonstrated selective cytotoxicity against PSMA-producing cells. Binding of fluorescently labeled PSMA-targeted particles to PSMA-producing cells has also been directly observed using fluorescence microscopy and observed in secondary fashion using a PSMA substrate based enzyme inhibition assay. Ongoing in vivo studies address the localization, activity and toxicity of these targeted nanoparticles against PSMAproducing human prostate tumor xenografts.

The ability of a potential human anti-cancer therapeutic agent to inhibit the growth of xenografted tumors in nude mice has been an established and accepted testing method for several decades. The current report shows that a single, low-level intravenous dose of [32P]ATP significantly inhibits the growth of established xenografted tumors in nude mice. This inhibitory effect becomes appreciable very rapidly, within only five days post-injection and the low dose demonstrates little or no toxicity in the mice. Surprisingly, a narrow dose window of optimum effectiveness is seen, whereby either decreasing or increasing the [32P]ATP dose results in far less growth inhibition. Thus, the intravenous systemic injection of [32P]ATP may represent a simple, potent method to target and inhibit primary human tumors and malignant lesions.

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