Characterization of a targeted nanoparticle functionalized with a urea-based inhibitor of prostate-specific membrane antigen (PSMA).
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-beta-ethylene glycol-beta-lactide) and PSMA-inhibitor bound alpha-amino-omega-hydroxy terminated poly (ethylene glycol-beta-epsilon-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 PSMA-producing human prostate tumor xenografts.
Chandran
Sachin S
SS
The Department of Chemical and Biomolecular Engineering, The Johns Hopkins University Whiting School of Engineering, Baltimore, Maryland 21231, USA.
Banerjee
Sangeeta R
SR
Mease
Ron C
RC
Pomper
Martin G
MG
Denmeade
Samuel R
SR
D000951:Antigens, Neoplasm / Q000737:chemistry; D000954:Antigens, Surface; D045744:Cell Line, Tumor; D004705:Endocytosis; D005109:Extracellular Matrix / Q000378:metabolism; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011485:Protein Binding; D014508:Urea / Q000737:chemistry*
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D011108:Polymers; D011092:Polyethylene Glycols; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II