Evaluation of Polymeric Nanomedicines Targeted to PSMA: Effect of Ligand on Targeting Efficiency

Abstract

Targeted nanomedicines offer a strategy for greatly enhancing accumulation of a therapeutic within a specific tissue in animals. In this study, we report on the comparative targeting efficiency toward prostate-specific membrane antigen (PSMA) of a number of different ligands that are covalently attached by the same chemistry to a polymeric nanocarrier. The targeting ligands included a small molecule (glutamate urea), a peptide ligand, and a monoclonal antibody (J591). A hyperbranched polymer (HBP) was utilized as the nanocarrier and contained a fluorophore for tracking/analysis, whereas the pendant functional chain-ends provided a handle for ligand conjugation. Targeting efficiency of each ligand was assessed in vitro using flow cytometry and confocal microscopy to compare degree of binding and internalization of the HBPs by human prostate cancer (PCa) cell lines with different PSMA expression status (PC3-PIP (PSMA+) and PC3-FLU (PSMA-). The peptide ligand was further investigated in vivo, in which BALB/c nude mice bearing subcutaneous PC3-PIP and PC3-FLU PCa tumors were injected intravenously with the HBP-peptide conjugate and assessed by fluorescence imaging. Enhanced accumulation in the tumor tissue of PC3-PIP compared to PC3-FLU highlighted the applicability of this system as a future imaging and therapeutic delivery vehicle.

Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand

“…The high 18 F-PSMA-11 uptake in LNCaP and low uptake in PC3 tumors is explained by the high and low PSMA expression of the corresponding tumors [3, 34]. Both xenografts demonstrated 18 F-FDG avidity, confirming viable tumor tissue and further supporting the target selectivity of 18 F-PSMA-11.…”

Development and Application of a Novel Model System to Study “Active” and “Passive” Tumor Targeting

“…Once tumors were established, the three different J591-conjugates were intravenously injected and NIR-fluorescent imaging was applied to quantify the PSMA-specific ‘active’ targeting and PSMA-negative ‘passive’ targeting, respectively, over a five day period. This bilateral tumor imaging approach is commonly applied to study receptor-specific targeting in vivo (29-31). To our knowledge, this is the first application of such a system to evaluate ‘active’ and ‘passive’ tumor targeting simultaneously.…”

Oral Delivery of Multicompartment Nanomedicines for Colorectal Cancer Therapeutics: Combining Loco‐Regional Delivery with Cell‐Target Specificity

“…Methyl methacrylate (MMA: Sigma‐Aldrich, 99%) and poly(ethylene glycol) monomethyl ether methacrylate (PEGMA: M n = 500 g mol −1 , Sigma‐Aldrich) were freed from inhibitor by passing through a column of basic alumina and subsequently stored at −20 °C prior to use. Synthesis of pentafluorophenol‐activated methacrylic acid (PFP‐MA) was performed according to Fuchs et al., and 4‐cyano‐4‐(((phenethylthio) carbonothioyl) thio) pentanoic acid (BCPA) chain transfer agent (CTA) was synthesized according to Semsarilar et al . Milli‐Q water (18.2 mΩ cm −1 ) was used for all dialysis and self‐assembly procedures.…”