title: Self-Associating Poly(ethylene oxide)-block-poly(α-carboxyl-ε-caprolactone) Drug Conjugates for the Delivery of STAT3 Inhibitor JSI-124: Potential Application in Cancer Immunotherapy.
abstract: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) in tumor cells and tumor associated dendritic cells (DCs) plays a major role in the progression of cancer. JSI-124 (cucurbitacin I) is a potent inhibitor of STAT3; however, its poor solubility and nonspecificity limit its effectiveness in cancer immunotherapy. In order to achieve a nanocarrier for solubilization and passive targeting of JSI-124 to tumor cells and tumor associated DCs, the drug was chemically conjugated to pendent COOH groups of self-associating poly(ethylene oxide)-block-poly(α-carboxylate-ε-caprolactone) (PEO-b-PCCL). Developed PEO-b-P(CL-JSI-124) conjugates self-assembled to polymeric micelles of 40 nm size range with negligible drug release under physiological mimicking conditions. The conjugation of JSI-124 to PEO-b-PCCL was confirmed by1H NMR, thin layer chromatography (TLC), and HPLC with a conjugation of 8.9% w/w of the polymer. As expected, JSI-124 nanoconjugates showed lower potency in p-STAT3 inhibition and direct anticancer activity in B16-F10 melanoma cells. Interestingly, JSI-124 nanoconjugates were more powerful than free drug in reducing the level of p-STAT3 in tumor exposed bone marrow derived dendritic cells (BMDCs). The JSI-124 nanoconjugates were also significantly more active than free drug in reversing the immunosuppressive effect of B16-F10 tumor and led to significantly better phenotypical and functional stimulation of tumor exposed immature BMDCs in the presence of immune adjuvants like LPS and CpG. Our findings points to great promise for PEO-b-P(CL-JSI-124) micelles for modulation of immunosuppressive microenvironment in melanoma tumors, implicating application of this strategy in cancer immunotherapy.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton, Alberta, Canada.
authors.forename: Shyam M
authors.initials: SM
authors.lastname: Garg
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton, Alberta, Canada.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Vakili
authors.affiliation: Faculty of Pharmacy, Tabriz University of Medical Sciences , Tabriz, Iran.
authors.forename: Ommoleila
authors.initials: O
authors.lastname: Molavi
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton, Alberta, Canada.|Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta , Edmonton, Alberta, Canada.
authors.forename: Afsaneh
authors.identifier: 0000-0001-5108-7124
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects; D005027:Ethylene Oxide / Q000737:chemistry*; D007167:Immunotherapy; D008546:Melanoma, Experimental; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008823:Micelles; D011091:Polyesters; D011108:Polymers; D050796:STAT3 Transcription Factor; D014315:Triterpenes; C000595636:methoxy poly(ethylene oxide)-block-poly(alpha-carboxylate-epsilon-caprolactone); D011092:Polyethylene Glycols; D005027:Ethylene Oxide; C038106:cucurbitacin I
keywords: JSI-124; STAT3 inhibitor; drug conjugates