Pathophysiology of IBD as a Key Strategy for Polymeric Nanoparticle Development

Abstract

Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal (GI) tract with an uncertain etiology. Currently, IBD therapy relies on the induction of clinical remission followed by maintenance therapy using anti-inflammatory drugs and immunosuppressants; however, a definite cure of the disease is still out of scope. Established approaches are characterized by adverse drug-related side effects that can even be potentially life-threatening. In contrast, increased interest and remarkable scientific progress in targeted drug delivery systems offer a promising approach to reduce systemic adverse events, delivering the therapeutic substances only to inflamed tissue. All alteration in gastrointestinal barrier integrity, especially a disturbed epithelial barrier, a unique pattern of the receptors on cell surface and/or an oxidative stress milieu in inflamed areas can be used as effective approaches for targeted and controlled drug delivery. Hence, this review focuses on the pathophysiology of the inflamed GI tract as a potential strategy for targeted polymeric nanoparticles for IBD treatment. Interdisciplinary efforts between the polymeric chemistry and gastroenterology/immunology promise to create novel synergies that improve the development of effective nanoparticle systems with significant clinical impact. In this regard, the current challenges in the clinical translation of promising nanomedicine are also discussed.

Introduction

1.1 Established Strategies in IBD Treatment

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders that dramatically change the lives of millions of patients.[1, 2] CD is characterized by a transmural inflammation from the mouth to the anus, while UC is a chronic inflammation of the colorectal mucosa.[3, 4] While the etiology of IBD is still unknown, genetic predispositions, microbiome–host interactions, or the environment play an important role in its multifunctional pathogenesis.[5, 6] There are a number of treatment strategies currently available for IBD patients. These depend on several factors, including the severity of CD or UC, associated diseases, previous treatment, age, and treatment aim.[3] The focus of IBD treatment is to inhibit the immune-inflammatory cascade and to induce and maintain clinical remission. Management of IBD treatment includes aminosalicylates (mesalamine, balsalazide, sulfalazine), orally or parenterally applied corticosteroids, immunosuppressants (azathioprine, mercaptopurine, methotrexate, and/or calcineurine inhibitors), intravenous biologic drugs (antibodies against TNF-α, α4β7 integrins, IL-12/23 and/or IL-23), and small molecules (JAK inhibitors and/or sphingosine-1-phosphate receptor modulators).[3, 7-10] While there is a huge list of possible treatment regimes, nowadays there is no cure for the disease, which can control the clinical remission and improve the life conditions of IBD patients.

1.2 Limitations of Conventional Drug Delivery System in IBD Treatment

Conventional drug delivery systems, such as suppositories, foams, enemas, tablets and injectables, have several limitations. They often lack specificity, have high toxicity and require high drug dosages. Additionally, while biologics demonstrated very promising clinical results, 30–50% of patients do not respond to biologics or may develop neutralizing antibodies that lead to a secondary loss of response.[7, 11] Moreover, patients with IBD face an extensive list of mild to moderate drug related side effects, including cancer, infections including opportunistic infections, glaucoma, cataracts, tremor, osteoporosis, osteonecrosis, hepatic fibrosis, hypersensitivity pneumonitis or hepatitis, myopathy, gingival hyperplasia, seizures, hypertension, hyperglycemia, emotional disturbances, weight gain, etc.[7, 11-13] This extensive list of adverse reactions, together with repeated surgery, highlights the urgent need for novel treatment approaches and therapeutic options, as well as new drug delivery systems.[4, 14, 15] In contrast to conventional drug delivery systems, nanoparticles can be fabricated for high specific gastrointestinal targeting and controlled drug release. In principle, nanoparticles could potentially cover the drawbacks of conventional therapeutic options.

Here, in this review we focused on polymeric nanoparticles as drug delivery systems in the context of the pathophysiology of IBD. Polymeric nanoparticles offer several advantages as they can be fine-tuned and tailored in their design, shape, and size, or adapted by sophisticated modification.[16] At the same time, alterations in the GI tract during IBD can provide the opportunity for such nanoparticles to target the inflamed areas of the intestine, releasing the encapsulated drug selectively at the targeted cells. Since the immune-inflammatory cascade alters the structural and functional characteristics of the GI tract, it is critical to consider these changes during the fabrication and modification of nanoparticles. Ligand-modified nanoparticles can actively target cells with increased expression of specific surface receptors. In addition, stimuli-responsive nanoparticles can be exploited due to oxidative stress and the abnormal release of reactive oxygen species (ROS) in the inflamed intestine. Thus, a thorough understanding of the pathophysiology of IBD is essential for the development of highly effective polymeric nanoparticles for drug delivery (Figure 1).

It is noteworthy that there are currently no approved medications for patients with IBD that incorporate nanoparticles. However, numerous smart delivery systems have demonstrated promising results in vivo experiments. The aim of this review is to provide a summary of the current progress in the field of nanomedicine for potential IBD therapy, with a particular focus on polymeric nanoparticles and the pathophysiological changes observed in patients.

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Excipients mentioned in the study: Eudragit S 100, Eudragit RS 100, Kolliphor F 127

Elena Gardey, Johannes C. Brendel, and Andreas Stallmach, Pathophysiology of IBD as a Key Strategy for PolymericNanoparticle Development, dvanced Therapeutics, DOI: 10.1002/adtp.202400439, Adv. Therap. 2025, 2400439 2400439 (1 of 17) © 2025 The Author(s). Advanced Therapeutics published by Wiley-VCH GmbH