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.
Adrian V
AV
Fuchs
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute , Brisbane 4102, Australia.
Brian W C
BW
Tse
Amanda K
AK
Pearce
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute , Brisbane 4102, Australia.
Mei-Chun
MC
Yeh
Nicholas L
NL
Fletcher
Department of Nuclear Medicine, Cleveland Clinic , Cleveland, Ohio 44195, United States.
Steve S
SS
Huang
Department of Cancer Biology, Cleveland Clinic , Cleveland, Ohio 44195, United States.
Warren D
WD
Heston
Andrew K
AK
Whittaker
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute , Brisbane 4102, Australia.
Pamela J
PJ
Russell
Kristofer J
KJ
Thurecht
D000954:Antigens, Surface / Q000187:drug effects*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D043425:Glutamate Carboxypeptidase II / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008297:Male; D050997:Nanomedicine; D011108:Polymers / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy
D000954:Antigens, Surface; D008024:Ligands; D011108:Polymers; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II