Multifunctional peptide carrier-modified polymer micelle accelerates oral siRNA-delivery to the colon and improves gene silencing-mediated therapeutic effects in ulcerative colitis

Abstract

In the treatment of inflammatory bowel diseases such as ulcerative colitis (UC), siRNAs are expected to enable fundamental suppression of the expression of pathogenic genes. Oral administration is considered the most desirable route of drug-administration as it can act directly on the affected area and improve the patient's quality of life. However, when orally administered, naked siRNA is easily degraded in the gastrointestinal tract; therefore, it is necessary to use a carrier to protect the siRNA from degradation. We have previously shown that systemic administration of the multifunctional peptide carrier (CH2R4H2C)-modified methoxy polyethylene glycol-polycaprolactone polymer micelles (MPEG-PCL-CH2R4H2C)/siRNA has high therapeutic efficacy against inflammatory diseases. In the present study, we aimed to apply MPEG-PCL-CH2R4H2C nano-micelles to apply MPEG-PCL-CH2R4H2C nano-micelles for oral delivery of siRNA to treat dextran sodium sulfate-induced UC model mice. Agarose gel electrophoresis and cell viability and cytotoxicity assays were performed. The therapeutic effects of siRelA in UC mice were assessed. MPEG-PCL-CH2R4H2C/siRNA complexes with an N/P ratio of more than 50 were not degraded at the gastrointestinal pH environment of 1.2 and 6.8, and showed high cellular uptake ability without showing cytotoxicity in macrophages. In addition, oral administration of the MPEG-PCL-CH2R4H2C/siRNA to mice showed improved delivery to the colon compared to naked siRNA. Finally, RelA-targeted siRNA suppressed the RelA mRNA expression and deterioration of clinical symptoms, such as bloody stool, diarrhea, weight loss, and colonic shortening, by complexation with MPEG-PCL-CH2R4H2C micelles. These results suggest that MPEG-PCL-CH2R4H2C micelles are useful as novel siRNA carriers for oral administration.