title: GRP78-targeted nanotherapy against castrate-resistant prostate cancer cells expressing membrane GRP78.
abstract: Glucose-regulated protein 78, GRP78, is a chaperone protein mainly located in the endoplasmic reticulum (ER) of normal cells. In stress conditions, GRP78 is overexpressed and in different cancer cell types, it is expressed at the cell surface, whereas it stays intracellular in non-cancerous cells. Therefore, it appears as a strategic target to recognize malignant cells. Prostate cancer is one of the most diagnosed cancers in men. The development of castrate resistant tumors and the resistance to chemotherapy frequently occur. The carboxy-terminal ER retention domain is defined by the KDEL amino acid sequence. We developed anti-KDEL functionalized polymeric nanoparticles (NPs) loaded with paclitaxel (Tx) to specifically target prostate cancer cells expressing GRP78. The sensitivity to Tx in different formulations was compared in three prostate cell lines: PNT1B, a normal cell line, PC3, a cancer cell line faintly expressing GRP78 at its surface, and DU145, a cancer cell line expressing GRP78 at its cell surface. Our results show that the targeted formulation significantly increases Tx sensitivity of cell line expressing GRP78 at its surface compared to other treatments suggesting the added value of GRP78 targeted therapy for castrate resistant tumor which expresses GRP78 at its cell surface.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, Quai Ernest Ansermet 30, 1211, Geneva 4, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Delie
authors.forename: Patrick
authors.initials: P
authors.lastname: Petignat
authors.forename: Marie
authors.initials: M
authors.lastname: Cohen
mesh_terms: D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D053758:Nanoparticles / Q000008:administration & dosage*; D009842:Oligopeptides / Q000276:immunology; D017239:Paclitaxel / Q000008:administration & dosage*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021382:Protein Sorting Signals; D015398:Signal Transduction
chemical_list: D000906:Antibodies; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D009842:Oligopeptides; D021382:Protein Sorting Signals; C073762:lysyl-aspartyl-glutamyl-leucine; D017239:Paclitaxel