title: Nanoconjugation of PSMA-Targeting Ligands Enhances Perinuclear Localization and Improves Efficacy of Delivered Alpha-Particle Emitters against Tumor Endothelial Analogues.
abstract: This study aims to evaluate the effect on killing efficacy of the intracellular trafficking patterns of α-particle emitters by using different radionuclide carriers in the setting of targeted antivascular α-radiotherapy. Nanocarriers (lipid vesicles) targeted to the prostate-specific membrane antigen (PSMA), which is unique to human neovasculature for a variety of solid tumors, were loaded with the α-particle generator actinium-225 and were compared with a PSMA-targeted radiolabeled antibody. Actinium-225 emits a total of four α-particles per decay, providing highly lethal and localized irradiation of targeted cells with minimal exposure to surrounding healthy tissues. Lipid vesicles were derivatized with two types of PSMA-targeting ligands: a fully human PSMA antibody (mAb) and a urea-based, low-molecular-weight agent. Target selectivity and extent of internalization were evaluated on monolayers of human endothelial cells (HUVEC) induced to express PSMA in static incubation conditions and in a flow field. Both types of radiolabeled PSMA-targeted vesicles exhibit similar killing efficacy, which is greater than the efficacy of the radiolabeled control mAb when compared on the basis of delivered radioactivity per cell. Fluorescence confocal microscopy demonstrates that targeted vesicles localize closer to the nucleus, unlike antibodies which localize near the plasma membrane. In addition, targeted vesicles cause larger numbers of dsDNAs per nucleus of treated cells compared with the radiolabeled mAb. These findings demonstrate that radionuclide carriers, such as PSMA-targeted lipid-nanocarriers, which localize close to the nucleus, increase the probability of α-particle trajectories crossing the nuclei, and, therefore, enhance the killing efficacy of α-particle emitters.
authors.affiliation: Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854.
authors.forename: Charles
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Chemical and Biochemical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854.
authors.forename: Amey
authors.initials: A
authors.lastname: Bandekar
authors.affiliation: Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sempkowski
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School, Baltimore, MD 21287.
authors.forename: Sangeeta Ray
authors.initials: SR
authors.lastname: Banerjee
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School, Baltimore, MD 21287.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements, P.O. Box 2340, D-76125 Karlsruhe, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements, P.O. Box 2340, D-76125 Karlsruhe, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854.|Department of Chemical and Biochemical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Sofou
mesh_terms: D000186:Actinium; D000512:Alpha Particles; D000954:Antigens, Surface / Q000378:metabolism*; D001692:Biological Transport; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space; D008024:Ligands; D008055:Lipids; D008297:Male; D008856:Microscopy, Fluorescence; D058726:Nanoconjugates; D019275:Radiopharmaceuticals / Q000008:administration & dosage*
chemical_list: D000954:Antigens, Surface; C468783:H2AX protein, human; D006657:Histones; D008024:Ligands; D008055:Lipids; D058726:Nanoconjugates; D019275:Radiopharmaceuticals; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D000186:Actinium