Therapeutic Effect of Multifunctional Stimuli-Responsive Drug Delivery Carriers for Inflammatory Diseases

Abstract

Chronic inflammatory diseases such as ulcerative colitis (UC) and rheumatoid arthritis (RA) pose significant clinical challenges due to limitations in current therapeutic strategies. These include poor aqueous solubility, low oral absorption, high first-pass metabolism, rapid clearance, low bioavailability, off-target systemic side effects etc., which limit their employability in clinical settings. Nanotechnological advancements have significantly contributed to the amelioration of inflammation and associated disease severity. Therefore, we have focussed on the design and development of innovative enzyme-responsive formulations to enhance drug delivery efficacy for the treatment of UC and RA, addressing key shortcomings of conventional therapies. Firstly, we have developed an enzyme-responsive injectable hydrogel (ER-hydrogel) encapsulated with budesonide for UC treatment. This hydrogel provides prolonged retention at the inflamed colonic site and controlled, enzyme-triggered drug release demonstrated significant therapeutic potential in a dextran sodium sulfate (DSS)-induced UC mouse model, with notable improvements in disease activity, colon length restoration, and the reduction of key inflammatory markers, including IL-1β, TNF-α, and MPO. The ER-hydrogel exhibited excellent mucoadhesive properties and successfully addressed the bioavailability challenges of traditional UC treatments, showing promise for future clinical translation. The effect of this Bud-loaded ER-hydrogel was also evaluated in the collagen-induced arthritis (CIA) model of rheumatoid arthritis. The Bud-loaded hydrogel demonstrated stability and biocompatibility, significantly improving joint health and reducing inflammatory markers including TNF-α and interleukins, showcasing its potential for long-term RA therapy. Next, we developed a gallic acid and glycerol monostearate (GA-GMS) conjugate to develop a novel amphiphilic system that self-assembles into a 3D injectable hydrogel with colon-adhering properties. This GA-GMS hydrogel encapsulated chrysin (CR), a polyphenol with known anti-inflammatory and antioxidant effects, to create a synergistic prodrug system. The CR@GA-GMS hydrogel demonstrated enzyme-mediated disassembly at the inflamed colonic site, targeting hypoxia-associated NLRP3 inflammasome signalling pathways. This system showed superior efficacy in reducing UC symptoms in a DSS-induced colitis model compared to traditional therapeutic enemas, making it a promising approach for localized drug delivery in UC. Lastly, we synthesised a novel PLGA-Gallein conjugate and developed it into nanomicelles for oral delivery in UC. These nanomicelles exhibited prolonged retention at the inflamed colonic site and controlled, enzyme-triggered drug release. In the DSS-induced UC mouse model, this system demonstrated significant therapeutic potential, with notable improvements in physical parameters exhibiting excellent mucoadhesive properties and successfully addressed the bioavailability challenges of traditional UC treatments, showing promise for future clinical translation. Overall, this thesis presents novel drug delivery systems that offer significant advancements in the treatment of UC and RA by enhancing drug retention, targeted release, and therapeutic efficacy. These systems represent a promising step toward the development of more effective, biocompatible therapies for chronic inflammatory diseases.