Characterization of a targeted nanoparticle functionalized with a urea-based inhibitor of prostate-specific membrane antigen (PSMA)

Abstract

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.

High expression of prostate-specific membrane antigen in the tumor-associated neo-vasculature is associated with worse prognosis in squamous cell carcinoma of the oral cavity

“…[37][38][39][40][41] Given the strong association of PSMA expression with survival it remains to be shown if a PSMA-specific targeting approach would show a therapeutic benefit in a subset of patients with oral squamous cell carcinoma.…”

Sequential SPECT and Optical Imaging of Experimental Models of Prostate Cancer with a Dual Modality Inhibitor of the Prostate‐Specific Membrane Antigen

“…For large molecular fragments, such as radiometal ( 99m Tc, 68 Ga) chelators, organic fluorescent molecules, and nanoparticles, we have determined that a linking moiety of at least 20Å between the large molecule and the lysine moiety is needed. [16][17][18][19] We hypothesized that conjugation of a dual (radionuclide and optical) modality imaging platform to a PSMA-targeting urea would enable sequential, dual modality imaging of experimental prostate tumors. Such a dual modality PSMA imaging agent could be used to address each of the two items confounding PCa management described above.…”

Metronomic Chemotherapy Regimens Using Microtubule-Targeting Agents: Mechanisms of Action, Preclinical Activity and Future Developments

“…Different approaches have also been successfully used to specifi cally target docetaxel to prostate cancer cells, taking advantage of the selective expression of the prostate-specifi c membrane antigen (PSMA). These include conjugating nanoparticles with RNA aptamers that specifi cally recognise the extracellular domain of PSMA [ 135 ] or with urea-based small-molecule peptidomimetic inhibitor of PSMA [ 136 ]. Finally, one of the most recent developments in drug delivery systems that may have direct application in metronomic chemotherapy is the utilisation of liquid nanocrystals.…”