title: Discovery of PSMA-specific peptide ligands for targeted drug delivery.
abstract: Prostate-specific membrane antigen (PSMA) has been widely used as a biomarker and targeting receptor for prostate cancer therapy because of its overexpression in most prostate cancer cells. In this study, a novel combinatorial phage biopanning procedure was developed to discover PSMA-specific peptides that can be potentially used as ligands for targeted drug delivery to prostate cancer cells. Five rounds of biopanning against recombinant human PSMA extracellular domain (ECD), PSMA-positive LNCaP cells, and LNCaP xenografts in nude mice were conducted. Various affinity assays were conducted to identify high-affinity peptides for PSMA ECD and PSMA-positive prostate cancer cells. Among them, the GTI peptide shows the highest affinity as well as specificity to PSMA in prostate cancer cells. The apparent Kdvalues of the GTI peptide to PSMA-positive LNCaP and C4-2 cells are 8.22μM and 8.91μM, respectively. The GTI peptide can specifically deliver the proapoptotic peptideD(KLAKLAK)2to LNCaP cells to induce cell death. In the biodistribution study, the GTI peptide shows the highest uptake in C4-2 xenografts, while its uptake in other major organs, such as the liver and spleen, are either low or negligible. Compared to its scrambled control (random permutation of the GTI peptide), the GTI peptide exhibits higher and more specific uptake in C4-2 xenografts. All the results suggest that the GTI peptide is a potentially promising ligand for PSMA-targeted drug delivery for prostate cancer therapy.
authors: Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, United States.
authors: Wei
authors: W
authors: Jin
authors: Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, United States.
authors: Bin
authors: B
authors: Qin
authors: Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, United States.
authors: Zhijin
authors: Z
authors: Chen
authors: Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, United States.
authors: Hao
authors: H
authors: Liu
authors: Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, United States.
authors: Ashutosh
authors: A
authors: Barve
authors: Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, United States. Electronic address: chengkun@umkc.edu.
authors: Kun
authors: K
authors: Cheng
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018994:Myosin Light Chains; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011506:Proteins / Q000008:administration & dosage* / Q000378:metabolism; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D008024:Ligands; C000599129:MYL4 protein, human; D018994:Myosin Light Chains; D010455:Peptides; D011506:Proteins; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: Combinatorial biopanning; PSMA; Peptide ligand; Phage display; Prostate cancer