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Polysaccharide mycophenolate-based nanoparticles for enhanced immunosuppression and treatment of immune-mediated inflammatory diseases.

ABSTRACT: Immune-mediated inflammatory diseases (IMIDs) are characterized by immune dysregulation and severe inflammation caused by the aberrant and overactive host immunological response. Mycophenolic acid (MPA)-based immunosuppressive drugs are potential treatments for IMIDs because of their mild side-effect profile; however, their therapeutic effects are limited by the high albumin binding rate, unsatisfactory pharmacokinetics, and undefined cellular uptake selectivity. Methods: Polysaccharide mycophenolate was synthesized by conjugating MPA molecules to dextran (a typical polysaccharide widely used in drug delivery) and encapsulated extra free MPA molecules to fabricate MPA@Dex-MPA nanoparticles (NPs). The efficacy of these NPs for mediating immunosuppression and treatment of IMIDs was evaluated in imiquimod-induced psoriasis-like skin inflammation in Balb/c mice, a representative IMID model. Results: The MPA@Dex-MPA NPs exhibited high MPA loading efficiency, low albumin binding rates, and sustained MPA release, resulting in improved pharmacokinetics in vivo. Compared to free MPA, MPA@Dex-MPA NPs induced more robust therapeutic effects on IMIDs. Mechanistic studies indicated that MPA@Dex-MPA NPs were primarily distributed in dendritic cells (DCs) and significantly suppressed the overactivated DCs in vivo and in vitro. Furthermore, the recovered DCs rehabilitated the IL-23/Th17 axis function and significantly ameliorated imiquimod-induced psoriasis-like skin inflammation. Importantly, MPA@Dex-MPA NPs showed favorable safety and biocompatibility in vivo. Conclusion: Our results indicated the polysaccharide mycophenolate-based NPs to be highly promising for IMID treatment.

SUBMITTER: Li Y

PROVIDER: S-EPMC7914372 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Polysaccharide mycophenolate-based nanoparticles for enhanced immunosuppression and treatment of immune-mediated inflammatory diseases.

Li Yuce Y Lou Yuchen Y Chen Yu Y Yang Jing J Li Danqi D Jiang Biling B Lan Jiajia J Wen Jingjing J Fu Yangxue Y Zhang Yamin Y Tao Juan J Zhu Jintao J

Theranostics 20210126 8

Immune-mediated inflammatory diseases (IMIDs) are characterized by immune dysregulation and severe inflammation caused by the aberrant and overactive host immunological response. Mycophenolic acid (MPA)-based immunosuppressive drugs are potential treatments for IMIDs because of their mild side-effect profile; however, their therapeutic effects are limited by the high albumin binding rate, unsatisfactory pharmacokinetics, and undefined cellular uptake selectivity. <b>Methods:</b> Polysaccharide m ...[more]

PMID: 33664856

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Project description:IntroductionMedication adherence is critical in chronic immune-mediated inflammatory diseases (IMIDs) and could be affected by patients' treatment-related beliefs. The objective of this study was to determine beliefs about systemic medications in patients with IMIDs and to explore the association of those beliefs and other factors with adherence.MethodsThis was a multi-country, cross-sectional, self-administered survey study. Included were adults diagnosed with one of six IMIDs receiving conventional systemic medications and/or tumor necrosis factor inhibitors (TNFi). Patients' necessity beliefs/concerns towards and adherence to treatments were assessed by the Beliefs about Medicines Questionnaire and four-item Morisky Medication Adherence Scale. Correlation of patients' beliefs about treatment and other factors with adherence were evaluated by multivariable regression analyses.ResultsAmong studied patients (N = 7197), 32.0% received TNFi monotherapy, 27.7% received TNFi-conventional combination therapy, and 40.3% received conventional medications. Across IMIDs, high adherence to systemic treatment was more prevalent in TNFi groups (61.3-80.7%) versus corresponding conventional treatment groups (28.4-64.7%). In at least four IMIDs, greater perception of the illness continuing forever (P < 0.001), of the treatment helping (P < 0.001), and more concerns about the illness (P < 0.01), but not clinical parameters, were associated with higher treatment necessity beliefs. Higher treatment necessity beliefs, older age, Caucasian race, and TNFi therapy were associated with high medication adherence in at least four IMIDs.ConclusionsTreatment necessity beliefs were higher than concerns about current medication in patients with IMID. Illness perceptions had a greater impact on treatment necessity beliefs than clinical parameters. Older age, greater treatment necessity beliefs, and TNFi therapy were associated with high self-reported medication adherence in at least four IMIDs.Trial registrationACTRN12612000977875.FundingAbbVie.

Project description:Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151-as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/STING-driven inflammatory conditions.

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Polysaccharide mycophenolate-based nanoparticles for enhanced immunosuppression and treatment of immune-mediated inflammatory diseases.

Publications

Polysaccharide mycophenolate-based nanoparticles for enhanced immunosuppression and treatment of immune-mediated inflammatory diseases.

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