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: Ommoleila Molavi, Abdullah Mahmud, Samar Hamdy, Ryan W Hung, Raymond Lai, John Samuel, Afsaneh Lavasanifar
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 7 Issue 2 Pg. 364-74 (Apr 05 2010) ISSN: 1543-8392 [Electronic] United States
• PMID: 20030320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• STAT3 Transcription Factor
• Triterpenes
• Polylactic Acid-Polyglycolic Acid Copolymer
• Polyglycolic Acid
• Lactic Acid
• cucurbitacin I

Topics

• Animals
• Cell Line, Tumor
• Cells, Cultured
• Dendritic Cells (drug effects, immunology)
• Flow Cytometry
• Immunotherapy (methods)
• Lactic Acid (chemistry)
• Lymphocyte Culture Test, Mixed
• Melanoma, Experimental (immunology, therapy)
• Mice
• Models, Biological
• Nanoparticles (chemistry)
• Neoplasms (immunology, therapy)
• Polyglycolic Acid (chemistry)
• Polylactic Acid-Polyglycolic Acid Copolymer
• STAT3 Transcription Factor (antagonists & inhibitors)
• Triterpenes (chemistry, therapeutic use)