ORAL ADMINISTRATION OF NANOLIPOSOMES LOADED M13 MAY TREAT ULCERATIVE COLITIS AND COLITIS-ASSOCIATED CANCER WITHOUT CAUSING ANY SIDE EFFECTS

Abstract

Intestinal inflammation, especially chronic (such as inflammatory bowel disease [IBD]), is an indispensable participant in the colonic neoplastic process, fostering the proliferation, survival, and migration of colonic tumor cells. Molecularly targeted therapeutics (e.g. anti-TNF-α agents) that exploit the targets involved in the pathophysiology of inflammatory responses in IBD are the most potent drugs currently available to treat IBD, which may also present anti-colon cancer effects. Unfortunately, most of these drugs were administered systemically in a high dose, and their use is limited by severe side effects. There is an unmet need for a targeted carrier system capable of delivering drugs specifically and effectively to inflamed colonic regions over a prolonged period. Such a system could significantly reduce drug dosage and side effects that limit existing treatments. The goal of the present study is to engineer natural “nanoliposomes” from the lipids of ginger-derived-nanoparticles and load with an anti-inflammatory drug candidate (M13), test its anticancer activity, and evaluate its safety. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay demonstrated that M13, a stable metabolite from 6-Shogaol as demonstrated by the incubation with intestinal microsomes, was more cytotoxic against cancerous intestinal cells (e.g. HCT-116, Caco-2/BBe, and human colon cancer stem cell) than normal intestinal cells (e.g. HIEC-6, FHC, and human colon stem cell). The results suggested that M13 has more a better ability to specifically target cancerous intestinal cells over normal intestinal cells. Protein point hybridization data showed that nanoliposomes-loaded M13 decreased the expression levels of proteins involved in colon cancer progressions such as Survivin, EGFR, and BCL-x in colon cancer cells. Further, orally administered nanoliposomes-loaded M13 presented potent wound-healing/anti-inflammatory effects in the DSS-induced mouse model of colitis and anti-cancer effects in the AOM/DSS-induced colon cancer model. We also demonstrated that nanoliposomes-loaded M13 treatment did not affect blood. In addition, we examined the anti-inflammatory activity of M13 on active ulcerative mucosal biopsies (Reprocell tissue protocol TPS-008) from a patient (42-year-old white male) undergoing therapeutic resection for ulcerative colitis. The results of the RT2 Profiler PCR Array demonstrated that M13 had very potent anti-inflammatory activity and reduced the expression levels of the pro-inflammatory cytokines involved in IBD, including TNF-α, IL-1β, IL-6, and IL-23A, in the M13-treated human ulcerative biopsies compared to the untreated controls. Our proposed targeted therapy using nanoliposomes that deliver M13 to the colon might be used to treat ulcerative colitis and colitis-associated cancer without causing any side effects.