Combination Therapy for Ulcerative Colitis: Orally Targeted Nanoparticles Prevent Mucosal Damage and Relieve Inflammation

Abstract

Combination therapy is an emerging strategy that is under intensive preclinical investigation for the treatment of various diseases. CD98 is highly overexpressed on the surfaces of epithelial cells and macrophages in the colon tissue with ulcerative colitis (UC), which is usually associated with mucosal damage and inflammation. We previously proved that CD98 siRNA (siCD98)-induced down-regulation of CD98 in colitis tissue decreased the severity of UC to a certain extent. In an effort to further improve the therapeutic efficacy, we aim to simultaneously deliver siCD98 in combination with a potent anti-inflammatory agent, curcumin (CUR), using hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant spherical HA-siCD98/CUR-NPs are featured by a desirable particle size (∼246 nm) and slightly negative zeta potential (∼-14 mV). The NPs functionalized with HA are able to guide the co-delivery of drugs to the targeted cells related to UC therapy (colonic epithelial cells and macrophages). Compared to either siCD98- or CUR-based monotherapy, co-delivery of siCD98 and CUR by HA-functionalized NPs can exert combinational effects against UC by protecting the mucosal layer and alleviating inflammation both in vitro and in vivo. This study shows the promising capability of the co-delivered siCD98 and CUR for boosting the conventional monotherapy via this novel nanotherapeutic agent, which offers a structurally simple platform for orally administered delivery of drugs to target cells in UC therapy.

Therapeutic effects of Crocin in autoimmune diseases: A review

“…UC is a chronic inflammatory disorder and its incidence is increasing worldwide. 52 UC results in mucosal inflammation starting from the rectum and extending to proximal segments of the colon. 53 UC is characterized by interchanging periods of intense inflammation and long periods of remission in the colon.…”

Oral non-viral gene delivery for applications in DNA vaccination and gene therapy

“…Delivery of genetic materials, such as plasmid DNA or siRNA [5–9], as well as combination therapies that deliver both genetic and pharmacological treatments [10], via the oral route, have been explored for the treatment of several diseases. Oral gene delivery has the potential to treat GI tract-specific diseases, such as ulcerative colitis (UC) and cancer, as well as promote systemic therapeutic effects outside of the GI tract, e.g.…”

“…Expanding on dual material particulate systems, Xiao and colleagues designed an oral delivery system that combined both siRNA and a pharmacological agent encapsulated in hyaluronic acid (HA)-functionalized, CS-coated poly(lactic-co-glycolic acid) (PLGA) dual material NPs to alleviate inflammation associated with UC [10]. HA functionalization of PLGA was used to target the NP delivery system to colonic epithelial cells and macrophages of UC tissues that over-express the surface glycoprotein CD44.…”

“…For this study, siRNA against CD98, a cell surface marker overexpressed on epithelial cells and macrophages in UC patients, in combination with the anti-inflammatory drug, curcumin was encapsulated in PLGA/CS NPs. Oral delivery of the PLGA/CS/siRNA system was shown to promote an anti-inflammatory environment within the gut and protect the mucosal layer in a mouse model of UC [10]. Mice receiving these particles were protected against weight loss and had lower levels of CD98 and TNF-α compared to mice that received particles containing curcumin alone, highlight to potential for gene delivery to enhance pharmacological treatment of UC.…”

Oral delivery of curcumin via porous polymeric nanoparticles for effective ulcerative colitis therapy

“…3, 22 Based on these successive actions, drug-loaded NPs would be able to penetrate into colitis tissues, resulting in the increasing local drug concentration, the enhanced drug efficacy and the reduced side effect. 13 In addition, the preference of oral drug administration also provides convenience of self-medication while avoiding pain and contamination via parenteral drug administration. 23 …”