Mei-Chun Yeh

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

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.

Regulation of neutrophil-mediated killing of Staphylococcus aureus and chemotaxis by c-jun NH2 terminal kinase.

The role of JNK in neutrophil chemotaxis and killing of microbial pathogens remains unclear. Using a recently described cell‐permeable peptide inhibitor of the JNK pathway, based on the JBD of JIP‐1, coupled to the protein transduction domain of HIV‐TAT (TAT‐JIP), in association with control peptides, we demonstrate that the JNK pathway plays a major role in regulating human neutrophil chemotaxis and killing of microbial pathogens. Serum‐opsonized Staphylococcus aureus elicited JNK activation and c‐jun phosphorylation. The activation of the JNK pathway and bactericidal activity were inhibited by the TAT‐JIP peptide. The stimulation of oxygen radical generation by S. aureus was dependent on the JNK signaling pathway, as was the phagocytosis of serum‐opsonized bacteria. Chemotaxis to activated serum complement but not random migration was inhibited by the TAT‐JIP peptide. The findings demonstrate a major role for the JNK signaling pathway in neutrophil‐mediated defense against microbial pathogens.

Using prostate specific membrane antigen (PSMA) expression in clear cell renal cell carcinoma for imaging advanced disease

Prostate specific membrane antigen (PSMA) is a 750 amino acid, type II transmembrane glycoprotein that has been shown to be over-expressed in both prostate cancer cells and the vasculature of solid tumours.1 Also known as folate dehydrolase, glutamate carboxypeptidase II or N-acetyl-L-aspartyl-L-glutamate peptidase I,2 PSMA has numerous metabolic roles and high levels of expression have been associated with tumour aggressiveness and malignant potential of prostate cancer cells...