期刊
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
卷 105, 期 11, 页码 2977-2985出版社
WILEY
DOI: 10.1002/jbm.a.36151
关键词
vaccine and immunotherapy; liposome and nanoparticle; metabolism; drug delivery and controlled release; tolerance and autoimmunity
资金
- NSF CAREER Award [1351688]
- National Multiple Sclerosis Society [RG-1501-02968]
- Damon Runyon Foundation [DRR3415]
- Young Investigator of the Alliance for Cancer Gene Therapy [15051543]
- Melanoma Research Alliance [348963]
- NSF CAREER Award [1351688]
- National Multiple Sclerosis Society [RG-1501-02968]
- Damon Runyon Foundation [DRR3415]
- Young Investigator of the Alliance for Cancer Gene Therapy [15051543]
- Melanoma Research Alliance [348963]
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1351688] Funding Source: National Science Foundation
Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation. The therapeutic potential of PHCCC, however, is hindered by dose-limiting toxicity, poor solubility, and the need for frequent dosing. We hypothesized liposomal delivery of PHCCC might enable safe, effective delivery of this hydrophobic drug to exploit metabolism as a means of controlling inflammation in self-reactive immune cells. PHCCC was readily encapsulated in liposomes modified with polyethylene glycol. Under sink conditions, controlled release resulted in 58% of drug released into media over 18 hours. Culture of primary DCs with PHCCC liposomes reduced pro-inflammatory cytokine secretion while reducing toxicity four-fold compared with soluble PHCCC. During co-culture of DCs with myelin-reactive T cells from transgenic mice, PHCCC liposomes reduced T cell proliferation and interferon gamma secretion. These results support the potential of using liposomes to promote tolerance through biocompatible delivery of metabolic modulators. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2977-2985, 2017.
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