Oral infliximab nanomedicines for targeted treatment of inflammatory bowel diseases.

BACKGROUND AND AIMS: Anti-TNF biological therapies such as infliximab (INF) have revolutionised the treatment of inflammatory bowel diseases (IBD). However, serious adverse effects due to systemic administration can significantly impact patient quality of life, limiting their success. Oral nanomedicines propose an innovative solution to provide local delivery to inflamed gastrointestinal tissues, thereby limiting systemic exposure and enhancing therapeutic efficacy. This study aimed to examine the potential of INF nanomedicines for IBD treatment with a focus on nanoparticle (NP) size to modulate the targeting of INF to the epithelial barrier. METHODS: Healthy and inflamed in vitro models of the intestinal epithelial barrier were established to examine the cell interaction of PLGA-PEGNPs of varying particle sizes and polydispersities. INF-loaded NPs were prepared by electrostatic interaction of INF with NPs and examined for their therapeutic efficacy in the inflamed epithelial cell barrier model. RESULTS: NP interaction was significantly enhanced in the inflamed cell barrier model, with increased transport observed for 130 - 300 nm NPs and accumulation of larger NPs (∼600 nm) at the barrier. Delivery of INF directly to the inflamed barrier by ∼600 nm NPs accelerated recovery of barrier integrity and reduced inflammatory cytokine secretion and cytotoxicity in comparison to treatment with INF alone. CONCLUSIONS: Results from this study show that NP particle size can be used to differentially target and treat the inflamed intestinal barrier. Oral INF nanomedicines of modulated size present a novel strategy for the local, targeted treatment of IBD.

Optimising PLGA-PEG Nanoparticle Size and Distribution for Enhanced Drug Targeting to the Inflamed Intestinal Barrier.

Oral nanomedicines are being investigated as an innovative strategy for targeted drug delivery to treat inflammatory bowel diseases. Preclinical studies have shown that nanoparticles (NPs) can preferentially penetrate inflamed intestinal tissues, allowing for targeted drug delivery. NP size is a critical factor affecting their interaction with the inflamed intestinal barrier and this remains poorly defined. In this study we aimed to assess the impact of NP particle size (PS) and polydispersity (PDI) on cell interaction and uptake in an inflamed epithelial cell model. Using 10, 55 and 100 mg/mL poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG), NPs of 131, 312 and 630 nm PS, respectively, were formulated by solvent dispersion. NP recovery was optimised by differential centrifugation to yield NPs of decreased and unimodal size distribution. NP-cell interaction was assessed in healthy and inflamed caco-2 cell monolayers. Results show that NP interaction with caco-2 cells increased with increasing PS and PDI and was significantly enhanced in inflamed cells. Trypan blue quenching revealed that a significant proportion of multimodal NPs were primarily membrane bound, while monomodal NPs were internalized within cells. These results are interesting as the PS and PDI of NPs can be optimised to allow targeting of therapeutic agents to the epithelial membrane and/or intracellular targets in the inflamed intestinal epithelium.

The future of nanomedicine in optimising the treatment of inflammatory bowel disease.

There have been major advancements in the treatment of inflammatory bowel disease (IBD) over the past three decades. However despite significant progress, the best available treatments continue to demonstrate variable efficacy in patients and are associated with adverse effects. Therefore there remains an unmet clinical need for ongoing therapeutic advances for IBD. In recent years nanomedicines have emerged as promising diagnostic and therapeutic tools. Nanoparticles in particular show promise to facilitate targeted oral drug delivery in IBD. Here we discuss the pitfalls of current therapies and explore the potential for nanoparticles to improve the treatment of IBD. This review examines the range of conventional and novel therapies which have benefited from nanoparticle-mediated delivery and highlights the proven therapeutic efficacy of this approach in preclinical models. These strategies under development represent a novel and innovative treatment for IBD.