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.

An in silico analysis of nanoparticle/cell diffusive transfer: Application to nano-artificial antigen-presenting cell:T-cell interaction

“…Similar observations have been reported through out the literature with different cell types in proximal contact with micro-and nano-sized particles releasing drug 31–33 inhibitory factors 34, 35 or stimulatory factors 7, 24. …”

Tailoring Biomaterials for Cancer Immunotherapy: Emerging Trends and Future Outlook

“…Cancer cells can alter the TME into an immunosuppressive environment that promotes tumor growth and metastasis. [99][100][101] The latter is a hydrophobic small molecule for inhibition of STAT3 signaling pathway that suppresses T helper 1 cell and dendritic-cell function but promotes proliferation of regulatory T cells. [90][91][92][93][94][95][96][97][98] For example, Liao et al [92] developed tumor-targeting liposome nanoparticles loaded with a signal transducer and an activator of transcription 3 (STAT3) inhibition.…”

Engineering Nano‐ and Microparticles to Tune Immunity

“…Thus, therapies aimed to silence STAT3 expression in either tumor or stromal cells may provide beneficial immune responses in the tumor microenvironment. NPs composed of PLGA directly conjugated with JSI‐124, a small molecule inhibitor of STAT3, exhibited sustained drug release over one month, and suppressed activation of STAT3 in DCs, while promoting T cell proliferation in a mixed lymphocyte assay in vitro 164. In addition to small‐molecule drugs, siRNA, which has recently emerged as a powerful therapeutic modality for specific and effective downregulation of protein expression, can be delivered via NPs in a targeted manner and mediate profound immunomodulation in the tumor microenvironment.…”