Submicron-sized hydrogels incorporating cyclic dinucleotides for selective delivery and elevated cytokine release in macrophages

Lee, Eunjoo; Jang, Hyo-Eun; Kang, Yoon Young; Kim, Jihyun; Ahn, Joong‐Hoon; Mok, Hyejung

doi:10.1016/j.actbio.2015.10.025

Cited by 44 publications

(61 citation statements)

References 51 publications

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“…FITC‐labeled OVA (FITC‐OVA) was prepared as previously described . Briefly, OVA (100 mg) dissolved in 1 m sodium carbonate‐bicarbonate buffer (pH 9.0; 1 mL) was reacted with FITC (1.5 mg) in anhydrous dimethyl sulfoxide (DMSO) (150 μL) at 4 °C overnight with stirring.…”

Section: Methodsmentioning

confidence: 99%

Polydopamine-Coated Porous Microspheres Conjugated with Immune Stimulators for Enhanced Cytokine Induction in Macrophages

Jang

Mok

2016

Macromol. Biosci.

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Polydopamine-coated porous microsphere (PPM) is investigated as a simple and versatile immobilization strategy for immune-stimulating biomolecules to enhance delivery efficiency and immune-stimulating effects such as cytokine induction in macrophages. The PPMs, with diameters of about 2 μm, exhibit simultaneous and efficient incorporation of biomolecules (nucleotides and proteins), which is comparable to that achieved using microspheres carrying biomolecules internally by virtue of their porous structure. Ovalbumin-conjugated PPMs are internalized into macrophages efficiently and selectively via the phagocytic pathway, without any noticeable toxicity. Internalized CpG oligodeoxynucleotide (ODN)-conjugated PPMs (PPM-CpG) greatly enhance the induction of selected cytokines (TNF-α and IL-6) in RAW 264.7 cells compared to that by the soluble CpG ODN and ionic complexes. Therefore, PPMs generated in this study may serve as effective carriers of immune-stimulating biomolecules such as diverse toll-like receptor agonists.

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Section: Methodsmentioning

confidence: 99%

Polydopamine-Coated Porous Microspheres Conjugated with Immune Stimulators for Enhanced Cytokine Induction in Macrophages

Jang

Mok

2016

Macromol. Biosci.

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“…As an alternative approach, a nanoparticle-based delivery system developed by Lee and colleagues also enables in vitro delivery of cyclic dinucleotides to target STING pathways for anti-tumour effects [221] (Figure 6). This method employs polyethyleneimine / hyaluronic acid (LH) -based hydrogels to enclose dinucleotide drugs into micron size spheres, which are selectively taken up by phagocytic cells such as RAW 264.7 macrophages, L929 fibroblasts and bone marrow-derived macrophages (BMDMs), but not by non-phagocytic fibroblasts.…”

Section: Therapeutic Targeting Of the Sting Pathwaymentioning

confidence: 99%

“…Thus, the micron-sized particles appear to target phagocytosis specifically to gain entry into the cytoplasm. Furthermore, Lee et al showed that LH-cGAMP hydrogel can induce IFN-I spikes in RAW264.7 macrophages, which were more than twice the magnitude of that induced by lipofectamine-delivered cGAMP at the same dose [221]. Administration of ovalbumin-containing LH-cGAMP particles in mice activates both the type I interferon response and humoral production of IgG to protect against ovalbumin challenge.…”

Section: Therapeutic Targeting Of the Sting Pathwaymentioning

confidence: 99%

Regulating STING in health and disease

Li¹,

Wilson

Kiss-Tóth³

2017

J Inflamm

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The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named “STimulator of INterferon Genes (STING)”. STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases. This review will summarise the recent structural and functional findings of STING, and discuss how STING research has promoted the development of novel therapeutic approaches and experimental tools to improve treatment of tumour and autoimmune diseases.

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“…Advantages of DDS include their ability to profoundly alter and improve drug pharmacokinetics, provide targeted drug delivery, and therefore alleviate TRAEs whilst enhancing therapeutic outcomes [ 125 , 126 , 127 , 128 ]. The three main DDS discussed here are liposomes, polymers and hydrogels ( Table 3 ) [ 14 , 123 , 124 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ]. Liposomes are cationic lipid structures with an aqueous core, making them great candidates for encapsulating negatively charged, hydrophilic CDN compounds [ 138 , 139 , 140 ].…”

Section: Future Directionsmentioning

confidence: 99%

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Aval

Pease

Sharma

et al. 2020

JCM

154

130

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Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

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Submicron-sized hydrogels incorporating cyclic dinucleotides for selective delivery and elevated cytokine release in macrophages

Cited by 44 publications

References 51 publications

Polydopamine-Coated Porous Microspheres Conjugated with Immune Stimulators for Enhanced Cytokine Induction in Macrophages

Polydopamine-Coated Porous Microspheres Conjugated with Immune Stimulators for Enhanced Cytokine Induction in Macrophages

Regulating STING in health and disease

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

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