title: Development of a poly(d,l-lactic-co-glycolic acid) nanoparticle formulation of STAT3 inhibitor JSI-124: implication for cancer immunotherapy.
abstract: Constitutively activated signal transducer and activator of transcription-3 (STAT3) in tumor and dendritic cells (DCs) plays a critical role in tumor-induced immunosuppression. This is considered a major challenge in effective immunotherapy of cancer. Herein we describe the development of a polymeric nanocarrier for the delivery of JSI-124 (a small molecule inhibitor of STAT3) to tumor and immunosuppressed DCs using poly(d,l-lactic-co-glycolic acid) nanoparticles (PLGA NPs). For this purpose, JSI-124 was chemically conjugated to PLGA and the PLGA-JSI-124 conjugate was formulated into nanoparticles using the emulsification solvent evaporation method. The attachment of JSI-124 to PLGA was confirmed by a combination of thin layer chromatography and (1)H NMR. The level of JSI-124 in NPs, determined by liquid chromatography-mass spectrometry, was found to be 1.7 +/- 0.3 microg per mg of PLGA. The PLGA-JSI-124 NPs demonstrated a controlled drug release profile over a 1-month period and exhibited potent anticancer and STAT3 inhibitory activity comparable to the soluble JSI-124 after 24 h incubation with B16 melanoma cells, in vitro. Moreover, PLGA-JSI-124 NPs efficiently suppressed the level of p-STAT3 in p-STAT3(high) DCs, generated from mouse bone marrow cells in the presence of conditioned media of B16 cells (B16CM-DCs), and improved their function as assessed by mixed lymphocyte reaction (MLR). Specifically cotreatment of B16CM-DCs with PLGA-JSI-124 NPs and PLGA NPs containing the DC adjuvant CpG resulted in higher levels of T cell proliferation in the MLR assay compared with B16CM-DCs untreated or treated with either CpG NPs or JSI-124 NPs alone. Our results indicate that PLGA NPs containing conjugated JSI-124 can potentially provide a useful platform for sustained JSI-124 release in tumor and its targeted delivery to DCs leading to the modulation of anticancer response by JSI-124 in tumor cells and immunosuppressed DCs, in vitro.
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, T6G 2N8, Canada.
authors.forename: Ommoleila
authors.initials: O
authors.lastname: Molavi
authors.forename: Abdullah
authors.initials: A
authors.lastname: Mahmud
authors.forename: Samar
authors.initials: S
authors.lastname: Hamdy
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Hung
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: John
authors.initials: J
authors.lastname: Samuel
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D019344:Lactic Acid / Q000737:chemistry*; D007959:Lymphocyte Culture Test, Mixed; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014315:Triterpenes / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D050796:STAT3 Transcription Factor; D014315:Triterpenes; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C038106:cucurbitacin I