Delivery of Antibodies and Small Interfering RNA Using Nano-carriers for the Modulation of Immune Response

Author:Liu An

Supervisor:wang jun

Database:Doctor

Degree Year:2019

Download:87

Pages:96

Size:7312K

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The immune system is a crucial "guard" to maintain a stable and healthy environment inside the body.However,in some cases,due to the changes in the microenvironment of the lesion and the instability of the immune system,the immune system can not properly perform its functions of immune surveillance and immune clearance,such as immune escape of tumors and autoimmune diseases.How to make immune cells function properly is one of the most crucial steps in the treatment process.With the development of drugs,more and more antibody and siRNA are used to target immune cells and restore the normal function of immune cells.However,due to the efficiency of drug delivery,its therapeutic effect in clinical application is significantly affected.How to deliver these drugs to the lesion area or immune cells more accurately and efficiently to improve the efficacy and reduce the side effects has becomes a concern of drug researchers.In this dissertation,we found two immunotherapy regimens and used two different delivery systems to deliver antibody and siRNA,respectively.It can inhibit tumor growth or control autoimmune diseases by flexibly using drug functions,enhancing or weakening immune cell functions more efficiently.This topic is mainly divided into the following two parts:(1)Based on a Nano-Adapter delivery system for delivering antibody,build an antibodies delivery system(ACNA)which carrying aKLRGl antibody and aPDL1 antibody to target NK cells and tumor cells,inhibit signal transduction of inhibitory receptor on the surface of NK cells,promote NK cell activation,enhance the combination of NK cells on tumor cell efficiency and reaction efficiency,achieve the effect of inhibiting tumor growth.We further found that ACNA can target both NK cells and tumor cells,enhance the immune response of NK cells,promote the release of cytokines,and enhance their killing effect on tumor cells in vitro.Moreover,the effectiveness of ACNA in killing tumor cells and inhibiting tumor growth through NK cells has been demonstrated in subcutaneous tumor models and lung metastasis models of melanoma cell line B16-F10 and breast cancer cell line 4T1.(2)Bruton’s tyrosine kinase(BTK)in B cells and macrophages is an effective treatment for potential targets on rheumatoid arthritis(RA),we employed a cationic lipid-assisted PEG-b-PLGA nanoparticle delivering small interfering RNA(siRNA)for silencing Bruton’s tyrosine kinase gene expression in B cells and macrophages’ s winding glycine kinase expression,to reduce symptoms of autoimmune diseases of inflammation and other purposes.We further found that B cells and macrophages were able to efficiently ingest CLAN both in vitro and in vivo.Thereafter,we encapsulated siRNA targeting BTK(siBTK)into CLAN(CLANsiBTK),and demonstrated that CLANsiBTK significantly inhibited BTK expression in B cells and macrophages.In a collagen-induced mouse arthritis model,CLANsiBTK treatment dramatically reduced joint inflammation and other RA symptoms but caused no toxicity,proving that CLANsiBTK is a promising approach for RA therapy.