Mannose-modified Nanomedicines For The Therapy Of Macrophage-related Inflammatory Diseases

Macrophage-related inflammatory diseases such as rheumatoid arthritis(RA,an autoimmune diseases)and Chagas(a parasitic disease)have become a serious global public health problem.Currently,the drugs used in the clinics for both diseases have the disadvantages of low bioavailability,serious side-effects,poor efficacy and drug resistance.Therefore,development of cure or drugs for these macrophage-related inflammatory diseases with high efficacy and low toxicity is highly desired.Chapter 1 reviews the clinical treatments of RA and Chagas,the present problems and the current anti-inflammatory drugs-based nanomedicines,followed by the design of this thesis:mannose-modified nanomedicines for macrophage-targeted therapy of inflammatory diseases.To deal with RA,in Chapter 2 mannose(Man)-modified,disulfide-crosslinked polymersomes based on PEG-P(TMC-DTC)for loading hydroxychloroquine(Man-PS-HCQ)were constructed for macrophage-targeted therapy of RA mice with high efficacy and low toxicity.Man-PS-HCQ with average sizes of 46-49 nm showed macrophage targeting ability to M1 phenotype macrophages(M1M)that overexpress mannose receptor(CD206)and inhibited maturation of bone marrow-derived dendritic cells(BMDC).Moreover,Man-PS-HCQ could repolarize pro-inflammatory M1M to anti-inflammatory M2 phenotype macrophages(M2M).Therefore,the secretion of pro-inflammatory cytokines was significantly inhibited,and the production of anti-inflammatory cytokines was promoted.Furthermore,Man-PS-HCQ exhibited excellent ROS scavenging ability in macrophages.Upon intravenous injection into the zymosan-induced rheumatoid arthritis(ZIA)mouse,Man-PS-HCQ acquired higher accumulation and longer retention in inflamed joint than PS-HCQ.To treat ZIA mouse model,Man-PS-HCQ as compared to the free HCQ significantly decreased the pro-inflammatory cytokines,meanwhile markedly increased the anti-inflammatory cytokines,and resulted in ameliorated symptoms of the RA joints.Remarkably,Man-PS-HCQ as compared to the free HCQ indued more greatly increased in the proportion of macrophages especially infiltrating M2M in the joints and decreased in the proportion of mature DCs(CD11c~+CD80~+CD86~+)and CD3~+CD4~+T cells in the diseased joints.Therefore,Man-PS-HCQ having facile preparation process,high drug loading,good stability and reduction responsiveness,could effectively modulate the immune microenvironment in the diseased joints and relieve the inflammation,thus providing an alternative for targeted therapy of RA and other macrophages-related inflammatory diseases.To cope with the protozoans sequestered inside macrophages in chronic stage of chagas,in Chapter 3tyrocidine(Trc)loaded mannose functionalized micellar nanomedicine(Man-MS-Trc)based on PEG-P(CL-DTC)were designed.For Trc with strong hydrophobicity,Man-MS-Trc had exceptional loading contents over 50 wt.%.Man-MS-Trc effectively increased the hemolytic concentration as compared to free Trc thus having reduced the toxicity to normal cells.Man-MS-Trc displayed clear targetability to M1M.The parameters for preparing freeze-dried powder were optimized,and satisfactory freeze-dried powder of Man-MS-Trc was obtained,which lays the foundation for further treatment of macrophage-related parasitic diseases.Finally,Chapter 4 summarizes the whole thesis and gives perspective for future work.