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 by H 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.

Multifunctional nanoparticles for cancer immunotherapy: A groundbreaking approach for reprogramming malfunctioned tumor environment

“…All these tumorigenic immune responsive factors create the immunosuppressive tumor environment through the secretion of chemokines, metabolic mediators, and cytokines as well as through cell signaling mechanisms. Thus, understanding the role of tumor-associated immune cells and inhibiting their contribution to tumor progression has become the central focus of cancer research [6, 73–76]. Inhibitors of immune-suppressing molecules have been widely used in the clinic for treating various types of solid and hematological cancers.…”

“…Thus, once HA-PEI micelle internalized into the cell, it sheds off the HA layer, revealing the cationic complex in the cytosol of the cell that leads to selective production of cytokines like monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNF-α) further inhibiting cell growth [72]. Another study, self-assembled block copolymer composed of poly(ethylene oxide)-block-poly(α-carboxylate-ε-caprolactone) was conjugated with a STAT3 inhibitor able to reverse the immunosuppressive effect in a class of tumor cells, and the effect was enhanced in the presence of adjuvants [73]. Although the literature on polymeric micelles in cancer immunotherapy is not well explored, current trends showing more research outcome in polymeric micelles for tumor immune modulation.…”

Chemical modulation of transcription factors

“…Furthermore this conjugation led to increased inhibitory activity in immune suppressed BMDCs. 55 Although this approach proved valuable in terms of bioavailability, the compound is in dire need of optimization. This task will prove quite challenging, given the fact that no mode of action or binding site for the tetracyclic triterpene 9 was described.…”

Development of Polyelectrolyte Complex Nanoparticles-PECNs Loaded with Ampicillin by Means of Polyelectrolyte Complexation and Ultra-High Pressure Homogenization (UHPH)

“…However, the development of polymeric NPs is not exclusive to biopolymeric systems, since they can also be obtained with biocompatible synthetic materials, which are mainly homopolymers and copolymers of polylactide (PLA) [34,35], polycaprolactone (PCL) [36], polyglycolic acid (PGA) [37,38] and acrylate-based polymers [39][40][41][42][43]. Likewise, the polymeric NPs are subclassified according to their architecture, where the most usual correspond to nanospheres [44][45][46][47][48], nanocapsules [8,[49][50][51][52], polymer nanoconjugates [53][54][55][56][57], and polyelectrolyte complexes (PECNs) [58][59][60][61][62]. Regarding PECNs, these can be obtained by several methodologies, being the traditional process of polyelectrolytic complexation (bottom-up method) one of the most used [63][64][65][66][67].…”