The efficiency of cytosolic drug delivery using pH-responsive endosomolytic polymers does not correlate with activation of the NLRP3 inflammasome

Baljon, Jessalyn J.; Dandy, Aamina; Wang-Bishop, Lihong; Wehbe, Mohamed; Jacobson, Max E.; Wilson, John T.

doi:10.1039/c8bm01643g

Cited by 21 publications

(38 citation statements)

References 53 publications

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“…Macrophages are the main source of IL-1β and IL-18 produced in the body, and their accumulation in vascular lesions is the main cause of local inflammatory response and plaque formation (9,10). According to previous studies, ligands bind to NLRP3 to promote the formation of inflammatory corpuscles and activate Casp-1, ultimately resulting in maturation and secretion of pro-IL-1β and pro-IL-18 (14). In this investigation, the levels of serum NLRP3, IL-1β and IL-18 in mice were detected.…”

Section: Discussionmentioning

confidence: 99%

“…Nod-like receptor protein 3 (NLRP3), an inflammatory corpuscle most closely related to chronic inflammatory response, is a kind of pattern recognition receptor in innate immune cells that has been studied widely, which plays a decisive role in innate immunity (13). After the ligand binds to NLRP3, the formation of inflammatory corpuscles is promoted, and Casp-1 is activated, ultimately promoting the maturation and secretion of pro-IL-1β and pro-IL-18, so that the pro-inflammatory factors IL-1β and IL-18 are produced (14).…”

Section: Introductionmentioning

confidence: 99%

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Tacrolimus reduces atherosclerotic plaque formation in ApoE-/- mice by inhibiting NLRP3 inflammatory corpuscles

Xiao¹,

Shang²,

Sun³

2019

Exp Ther Med

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Effect of tacrolimus on atherosclerotic plaques and its influence on Nod-like receptor protein 3 (NLRP3) inflammatory pathway were studied by establishing the mouse model of atherosclerosis. The mice were divided into 3 groups: C57BL/6 mouse group (WT group), ApoE-/mouse group (ApoE-/group) and ApoE-/mouse + tacrolimus intervention group (ApoE-/-+ Tac group). The area of atherosclerotic plaques and the pathological morphologic changes were observed. The NLRP3, interleukin-1β (IL-1β), IL-18, NLRP3 inflammatory corpuscles, pro-inflammatory factors IL-1β and IL-18 in the aorta were analyzed. The area of atherosclerotic plaques in ApoE-/mice was increased significantly, and it was significantly reduced after tacrolimus intervention. After tacrolimus intervention, the arterial intima became obviously thinner and no obvious cholesterol crystals were observed. The macrophage infiltration in atherosclerotic plaques was significantly increased, and the content of smooth muscle cells was also increased. The levels of serum IL-1β, IL-18 and NLRP3 in ApoE-/mice were significantly increased, and they remarkably declined after tacrolimus intervention. ROS content in atherosclerotic plaques was increased in ApoE-/mice, and it remarkably declined after tacrolimus intervention. The protein content of NLRP3, ASC, Casp-1, IL-1β and IL-18 in the aorta in ApoE-/mice was remarkably increased, and they were inhibited to some extent after tacrolimus intervention. In conclusion, it is speculated that tacrolimus may reduce the formation of AS through inhibiting ROS in macrophages and activation of NLRP3 inflammatory corpuscles and reducing the release of IL-1β and IL-18.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tacrolimus reduces atherosclerotic plaque formation in ApoE-/- mice by inhibiting NLRP3 inflammatory corpuscles

Xiao¹,

Shang²,

Sun³

2019

Exp Ther Med

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“…While no statistical differences were observed between the two active carriers, only the polymer containing 20 wt% PEG with 300 Da PEGMA (3‐w20‐DB30k) resulted in a significant increase in STING activation relative to controls, validating this as the lead carrier. While both carriers have similar in vitro activity, this difference may be attributed to the slightly larger particle size generated using the 3‐w20‐DB30k polymer (600 versus 400 nm) that could have prolonged intratumoral nanoparticle retention or perhaps be a consequence of increased stability of a multi‐compartment morphology [ 14 ] that appears to form when polymers are synthesized with 20 wt% PEG with 300 Da PEGMA, a possibility that merits future investigation.…”

Section: Resultsmentioning

confidence: 99%

Amphiphilic Polyelectrolyte Graft Copolymers Enhance the Activity of Cyclic Dinucleotide STING Agonists

Nguyen

Shae

Pagendarm

et al. 2020

Adv Healthcare Materials

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Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) hold great therapeutic potential, but their activity is hindered by poor drug‐like properties that restrict cytosolic bioavailability. Here, this challenge is addressed through the synthesis and evaluation of a novel series of PEGMA‐co‐DEAEMA‐co‐BMA copolymers with pH‐responsive, membrane‐destabilizing activity to enhance intracellular delivery of the CDN, cGAMP. Copolymers are synthesized with PEGMA of two different molecular weights (300 and 950 Da) and over a range of PEG mass fraction and polymer molecular weight, and relationships between copolymer structure, self‐assembly, endosomal escape, and cGAMP activity are elucidated. A subset of polymers that self‐assembled into 50–800 nm nanoparticles is identified, which can be loaded with cGAMP via a simple mixing strategy, resulting in significantly enhanced immunostimulatory activity. Increased cGAMP activity is found to be highly correlated with the capacity of carriers to enhance intracellular CDN uptake and to promote endosomal destabilization, findings that establish efficient cytosolic delivery as a criterion for CDN carriers. Additionally, it is demonstrated that a lead CDN carrier formulation can enhance STING activation in vivo in a model of intratumoral immunotherapy. Collectively, these investigations demonstrate the utility of PEGMA‐co‐DEAEMA‐co‐BMA copolymers as carriers for CDNs and potentially other cytosolically‐acting drug cargo.

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“…Thiolation, surface charge, surface carboxylation, hydrophobicity, and ability to activate the inflammasome may all contribute to materials‐based adjuvancy and bear further investigation in the context of tissue‐resident memory. [ 65,131 ]…”

Section: Perspectives On the Future Of Trm Vaccine Designmentioning

confidence: 99%

Engineering Vaccines for Tissue‐Resident Memory T Cells

Knight

Wilson

2021

Advanced Therapeutics

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In recent years, tissue‐resident memory T cells (TRM) have attracted significant attention in the field of vaccine development. Distinct from central and effector memory T cells, TRM cells take up residence in home tissues such as the lung or urogenital tract and are ideally positioned to respond quickly to pathogen encounter. TRM are found to play a role in the immune response against many globally important infectious diseases for which new or improved vaccines are needed, including influenza and tuberculosis. It is also increasingly clear that TRM play a pivotal role in cancer immunity. Thus, vaccines that can generate this memory T cell population are highly desirable. The field of immunoengineering—that is, the application of engineering principles to study the immune system and design new and improved therapies that harness or modulate immune responses—is ideally poised to provide solutions to this need for next‐generation TRM vaccines. This review covers recent developments in vaccine technologies for generating TRM and protecting against infection and cancer, including viral vectors, virus‐like particles, and synthetic and natural biomaterials. In addition, it offers critical insights on the future of engineering vaccines for tissue‐resident memory T cells.

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The efficiency of cytosolic drug delivery using pH-responsive endosomolytic polymers does not correlate with activation of the NLRP3 inflammasome

Abstract: Polymers that are unable to escape the early endosome, and instead cause lysosomal rupture, activate the NLRP3 inflammasome.

Cited by 21 publications

References 53 publications

Tacrolimus reduces atherosclerotic plaque formation in ApoE-/- mice by inhibiting NLRP3 inflammatory corpuscles

Tacrolimus reduces atherosclerotic plaque formation in ApoE-/- mice by inhibiting NLRP3 inflammatory corpuscles

Amphiphilic Polyelectrolyte Graft Copolymers Enhance the Activity of Cyclic Dinucleotide STING Agonists

Engineering Vaccines for Tissue‐Resident Memory T Cells

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