title: Micellar nano-carriers for the delivery of STAT3 dimerization inhibitors to melanoma.
abstract: The objective of this research was to develop polymeric micellar formulations of inhibitors of signal transducer and activator of transcription 3 (STAT3) dimerization, i.e., S3I-1757 and S3I-201, and evaluate the activity of successful formulations in B16-F10 melanoma, a STAT3 hyperactive cancer model, in vitro and in vivo. STAT3 inhibitory agents were encapsulated in methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO114-b-PCL22) and methoxy poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (PEO114-b-PBCL20) micelles using co-solvent evaporation. Polymeric micelles of S3I-1757 showed high encapsulation efficiency (>88%), slow release profile (<32% release in 24 h) under physiological conditions, and a desirable average diameter for tumor targeting (33-54 nm). The same formulations showed low encapsulation efficiencies and rapid drug release for S3I-201. Further studies evidenced the delivery of functional S3I-1757 by polymeric micelles to B16-F10 melanoma cells, leading to a dose-dependent inhibition of cell growth and vascular endothelial growth factor (VEGF) production comparable with that of free drug. Encapsulation of S3I-1757 in polymeric micelles significantly reduced its cytotoxicity in normal bone marrow-derived dendritic cells (DCs). Micelles of S3I-1757 were able to significantly improve the function of B16-F10 tumor-exposed immunosuppressed DCs in the production of IL-12, an indication for functionality in the induction of cell-mediated immune response. In a B16-F10 melanoma mouse model, S3I-1757 micelles inhibited tumor growth and enhanced the survival of tumor-bearing mice more than free S3I-1757. Our findings show that both PCL- and PBCL-based polymeric micelles have potential for the solubilization and delivery of S3I-1757, a potent STAT3 inhibitory agent.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Amir H
authors.initials: AH
authors.lastname: Soleimani
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Shyam M
authors.initials: SM
authors.lastname: Garg
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Igor M
authors.initials: IM
authors.lastname: Paiva
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Vakili
authors.affiliation: Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Abdulraheem
authors.initials: A
authors.lastname: Alshareef
authors.affiliation: Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Yung-Hsing
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.|Faculty of Pharmacy, Tabriz University of Medical Science, Tabriz, Iran.
authors.forename: Ommoleila
authors.initials: O
authors.lastname: Molavi
authors.affiliation: Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. afsaneh@ualberta.ca.|Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 2142F Katz Group Rexall Center for Pharmacy and Health Research, 11361-87 Ave NW, Edmonton, AB, T6G 2E1, Canada. afsaneh@ualberta.ca.
authors.forename: Afsaneh
authors.identifier: http://orcid.org/0000-0001-5108-7124
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D000636:Aminosalicylic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D019281:Dimerization; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D065546:Drug Liberation; D005260:Female; D007783:Lactones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D008810:Mice, Inbred C57BL; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011091:Polyesters / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000636:Aminosalicylic Acids; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D004337:Drug Carriers; D007783:Lactones; D008823:Micelles; C520337:NSC 74859; D011091:Polyesters; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C547053:poly(ethylene oxide)-b-poly(alpha-benzyl carboxylate epsilon-caprolactone); C473831:poly(ethylene oxide)-b-poly(caprolactone); C467480:vascular endothelial growth factor A, mouse; D011092:Polyethylene Glycols
keywords: B16-F10; Polymeric micelles; S3I-1757; STAT3 inhibition