Smart colon-targeted drug delivery for ibd and colorectal cancer: From pH-responsive to microbiota-triggered platforms

Abstract

IBD (inflammatory bowel disease and colorectal cancer (CRC) are significant health challenges worldwide that are projected to rise substantially in emerging economies such as India, China, Brazil, and Chile. Conventional dosage forms such as oral drugs fail in most cases to offer effective treatment owing to the premature secretion of the drug in the upper gastrointestinal tract (GIT) coupled with high first-pass metabolism, which thus requires high systemic doses that mostly incur adverse effects. The literature reviews the evolution of colon-targeted drug delivery systems, with emphasis on the shift to more advanced dual-trigger oral platforms. On a large scale, although pH-responsive polymers such as Eudragit® are currently being utilized, they tend to have reduced efficacy courtesy of the physiological variation and much lower colonic pH exhibited by IBD patients. To address these limitations, microbiota-responsive systems have developed, and colonic bacterial enzymes and biodegradable polysaccharides have become available, as they are better site-specific. Combining the mechanisms into dual pH-microbiota-responsive platforms provides redundant, independent release triggers suitable for diverse patient populations in the pathology of the one-trigger profile. The review identifies the important formulation strategies, such as composite hydrogels, microparticles, and nanoparticles, and outlines the therapeutic use of model compounds, such as curcumin. These emerging platforms have the potential to improve clinical outcomes and quality-of-life in patients with chronic colonic diseases by addressing regulatory pathways (FDA/EMA), manufacturing scale-up requirements, and long-term biocompatibility considerations. These advances bridge preclinical innovation with clinical reality.

Introduction

IBD, encompassing ulcerative colitis and Crohn’s disease, has transitioned from a Western-centric condition to a rapidly emerging public health concern in developing nations such as India [1], [2], [3]. According to recent epidemiological analyses, India has exhibited one of the highest rates of increase in IBD incidence globally, driven by rapid urbanization, dietary westernization, and environmental changes [1], [4]. In 2019, it was estimated that the prevalence of IBD in India was approximately 20 per 100,000 people, with an annual incidence rate of 2.34 per 100,000—values that are lower than those in Western nations in absolute terms but rising at a faster trajectory than any other region [1]. The burden is notably higher in northern India and urban populations, reflecting changes in microbiota diversity and lifestyle risk factors [1]. Worldwide, over 4.9 million individuals are affected by IBD [1], with the highest prevalence reported in North America and Europe [6], [5]; however, model-based projections suggest that Asia is projected to become the largest contributor to IBD cases by 2035 due to its large population base and rapidly industrializing demographics [7], [8]. Higher prevalence rates of 400–500 per 100,000 [6] are reported in developed countries like the United States and Western Europe, but there is still a massive influx in the prevalence of diseases, which leads to a significant epidemiological shift, called the third wave of IBD, in newly industrialized nations like China, India, and Brazil.

There is observed variation in the expression of disease among sex and age groups. The population studies done on India and Asia-Pacific communities have revealed a sex difference in ulcerative colitis and Crohn’s disease with a preponderance of the male sex in the age group of 15–50 years [4] implying the possible involvement of the sex hormones, occupational exposures, and genetic-environmental interactions (B). It has been observed through analyses conducted in the world that males exhibit a higher rate of being affected by ulcerative colitis past 45 years of age, whereas females show a slightly higher prevalence of Crohn’s disease in the youth population. Additionally, it has been observed to increase within pediatric and geriatric populations, with an added therapeutic complexity since these populations have different disease progression and comorbidities. Although they are classified into the same group, IBD, UC, and CD share different epidemiological distributions. UC has been the most prevalent variant of the disease in most geographic areas and especially in urban populations, but among those men who have the disease, it involves only the colonic mucosa. In contrast, CD presents with a more heterogeneous distribution, showing an increasing occurrence in adolescents and often characterized by a more aggressive disease course consisting of transmural inflammation, strictures, and fistula formation. Mortality from IBD is relatively low; however, the disease is associated with long-term morbidity. Patients suffer from recurring hospitalizations, repeated disease flares, and steroid dependence. All of these, in combination, lead to impaired quality of life and an increased likelihood of colorectal cancer. This emphasizes the need for safer and more effective therapeutic strategies.

Regardless of increasing options for IBD and CRC, conventional oral therapies continue to show limited site-specific drug deposition in the colon. Widely used agents such as mesalamine, corticosteroids, immunomodulators, and phytoconstituent formulations go through premature release and absorption in the upper gastrointestinal tract. This large first-pass hepatic metabolism with a decreased mucosal adaptive localization result in greater systemic amounts of drug needed to attain regional concentrations and, consequently, an increment of the chance of adverse drug effects. Additional patient-to-patient heterogeneity underscores the necessity of new technologies in clinical practices of colon-targeted drug delivery systems. CDDS can precisely and controllably release drugs at the site of inflammation or tumor. This topical delivery reduces systemic exposure and maximizes therapeutic efficacy, which is especially important in chronic therapeutic conditions such as ulcerative colitis and Crohn’s disease, which may require prolonged pharmacological treatment [9]. The etiology of IBD and its development into colorectal cancer is multifactorial and comprises the interaction between hereditary and environmental factors, immune dysregulation, genetic predisposition, and gut microbiota imbalances [10], [11], [12]. The pro-tumorigenic environment produced by chronic inflammation plays a major role, which stimulates the development and further progression of colitis-associated CRC [10].

As part of its treatment approach, there are currently therapeutic options including 5-aminosalicylic acid (5-ASA), corticosteroids, biologics (anti-TNF-alpha medications), immunosuppressants, and new small molecule drugs that regulate the impact of the disease on the various molecular pathways [8], [13]. In the case of CRC, especially in its advanced stages, the treatment is also carried out up to chemotherapy, radiotherapy, and molecularly targeted therapies [14]. However, these traditional methods have major drawbacks. Numerous treatment methods are linked to increased susceptibilities to infections and other negative outcomes [13]. Resistance to the drugs is one of the biggest ones and can create a temporary effect on personalized therapies and disease development [14], [15]. Moreover, not all patients get the best results, which may include anti-drug antibody-mediated inefficiency, withdrawal syndrome, or adverse side effects associated with overriding the immune system [8]. The poor patient tolerability, particularly with the chemotherapy, and the systemic toxicity limit the efficacy of treatment as well [13]. These shortcomings emphasize the necessity of safer and more effective and specifically targeted curative options to avoid progression of IBD and treat CRC [13].

Specifically, colon-targeted drug delivery systems present a promising avenue for mitigating these drawbacks by enabling direct drug release at the disease site, thereby enhancing therapeutic efficacy, reducing systemic exposure, and minimizing adverse effects associated with conventional treatments for inflammatory bowel diseases and colorectal cancer [16], [17].

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Following Eudragit products are mentioned in the article: Eudragit L100, Eudragit FS30D, Eudragit® S100

Harpreet Singh, Bhawna Goel, Smart colon-targeted drug delivery for ibd and colorectal cancer: From pH-responsive to microbiota-triggered platforms, Next Nanotechnology, Volume 10, 2026, 100750, ISSN 2949-8295, https://doi.org/10.1016/j.nxnano.2026.100750.