| Popis: |
Up to 6.8 million people worldwide suffer from inflammatory bowel diseases. Despite the range of available treatments, patient quality of life is significantly impacted by adverse effects. Oral nanomedicines propose an innovative solution to provide local delivery to the gastrointestinal tract, thereby limiting systemic exposure and enhancing therapeutic efficacy at the site of disease. Preclinical studies have shown that nanoparticles (NPs) preferentially accumulate in inflamed intestinal tissues over healthy tissues, allowing for targeted delivery. NP size is a critical factor affecting the performance of nanomedicines across biological barriers which remains poorly defined in the context of the inflamed intestinal barrier. It was hypothesised that particle size (PS) can be utilised to develop more efficient nanomedicines for targeting the inflamed intestinal barrier.To explore this concept, PLGA-PEG NPs of different particle size (PS) and size distributions were prepared by solvent dispersion and extensively characterised. NPs of average PS of 132 nm, 325 nm and 594 nm were prepared with unimodal (UM), trimodal (TM) and bimodal (BM) size distributions respectively. For multimodal NPs, recovery parameters were optimised using a differential centrifugation strategy to reduce polydispersity and isolate NPs with unimodal size distributions of 292 nm and 596 nm. In vitro models of the healthy and inflamed intestinal epithelial barrier were established using the caco-2 cell line and the interaction, uptake and transport of both UM and multimodal NPs was assessed. NP interaction was significantly enhanced in the inflamed model compared to the healthy. Increased permeability which occurred in the inflamed model also increased transport across the epithelial barrier for NPs up to 300 nm in size. 132 nm UM, 292 nm UM and 594 nm BM NPs were found to possess enhanced cell interaction and transport and were selected to prepare infliximab-loaded NPs using a drug adsorption method. In the inflamed in vitro model, delivery of infliximab by NPs which specifically interact with the epithelial cell barrier (594 nm BM NPs) accelerated recovery of barrier integrity, enhanced anti-inflammatory effects and reduced treatment cytotoxicity in comparison to treatment with free infliximab. The work presented in this thesis provides compelling evidence that PS can be used to differentially target the inflamed intestinal barrier. In the case of infliximab, a novel strategy is presented which directly targets the drug to the epithelial barrier with the aim of accelerating barrier recovery and mucosal healing. |
