title: Anti-prostate-specific membrane antigen liposomes loaded with 225Ac for potential targeted antivascular α-particle therapy of cancer.
abstract: This study evaluates targeted liposomes loaded with the α-particle generator (225)Ac to selectively kill prostate-specific membrane antigen (PSMA)-expressing cells with the aim to assess their potential for targeted antivascular radiotherapy.
  
  
  METHODS
  In this study, PEGylated liposomes were loaded with (225)Ac and labeled with the mouse antihuman PSMA J591 antibody or with the A10 PSMA aptamer. The targeting selectivity, extent of internalization, and killing efficacy of liposomes were evaluated on monolayers of prostate cancer cells intrinsically expressing PSMA (human LNCaP and rat Mat-Lu cells) and on monolayers of HUVEC induced to express PSMA (induced HUVEC).
  
  
  RESULTS
  The loading efficiency of (225)Ac into preformed liposomes ranged from 58.0% ± 4.6% to 85.6% ± 11.7% of introduced radioactivity. The conjugation reactions resulted in approximately 17 ± 2 J591 antibodies and 9 ± 2 A10 aptamers per liposome. The average size of liposomes, 107 ± 2 nm in diameter, was not affected by conjugation or loading. LNCaP cells exhibit 2:1:0.5 relative PSMA expression, compared with MatLu and induced HUVEC, respectively, based on flow cytometry detecting association of the J591 antibody. J591-labeled liposomes display higher levels of total specific binding to all cell lines than A10 aptamer-labeled liposomes. Specific cell association of targeted liposomes increases with incubation time. Cytotoxicity studies demonstrate that radiolabeled J591-labeled liposomes are most cytotoxic, with median lethal dose values, after 24 h of incubation, equal to 1.96 (5.3 × 10(-5)), 2.92 × 10(2) (7.9 × 10(-3)), and 2.33 × 10(1) Bq/mL (6.3 × 10(-4) μCi/mL) for LNCaP, Mat-Lu, and induced HUVEC, respectively, which are comparable to the values for the radiolabeled J591 antibody. For A10 aptamer-labeled liposomes, the corresponding values are 3.70 × 10(1) (1.0 × 10(-3)), 1.85 × 10(3) (5.0 × 10(-2)), and 4.07 × 10(3) Bq/mL (1.1 × 10(-1) μCi/mL), respectively.
  
  
  CONCLUSIONS
  Our studies demonstrate that anti-PSMA-targeted liposomes loaded with (225)Ac selectively bind, become internalized, and kill PSMA-expressing cells including endothelial cells induced to express PSMA. These findings-combined with the unique ability of liposomes to be easily tuned, in terms of size and surface modification, for optimizing biodistributions-suggest the potential of PSMA-targeting liposomes encapsulating α-particle emitters for selective antivascular α radiotherapy.
authors: Departments of Chemical and Biochemical Engineering and Biomedical Engineering, Rutgers University, Piscataway, New Jersey; and.
authors: Amey
authors: A
authors: Bandekar
authors: Charles
authors: C
authors: Zhu
authors: Rohit
authors: R
authors: Jindal
authors: Frank
authors: F
authors: Bruchertseifer
authors: Alfred
authors: A
authors: Morgenstern
authors: Stavroula
authors: S
authors: Sofou
mesh_terms: D000186:Actinium / Q000494:pharmacology*; D000512:Alpha Particles; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry; D000954:Antigens, Surface / Q000737:chemistry*; D045744:Cell Line, Tumor; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008024:Ligands; D008081:Liposomes / Q000737:chemistry; D008297:Male; D008856:Microscopy, Fluorescence; D011092:Polyethylene Glycols / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D011485:Protein Binding; D011868:Radioisotopes / Q000494:pharmacology*; D011877:Radionuclide Imaging; D051381:Rats
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000954:Antigens, Surface; D008024:Ligands; D008081:Liposomes; D011868:Radioisotopes; D011092:Polyethylene Glycols; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D000186:Actinium
keywords: anti-PSMA liposomes; antivascular α-particle radiotherapy; liposomal 225Ac