silicon and Inflammatory-Bowel-Diseases

Osteoporosis is one of the most common extraintestinal complications among patients suffering from inflammatory bowel diseases. The role of vitamin D and calcium in the prevention of a decreased bone mineral density is well known, although other nutrients, including micronutrients, are also of extreme importance. Despite the fact that zinc, copper, selenium, iron, cadmium, silicon and fluorine have not been frequently discussed with regard to the prevention of osteoporosis, it is possible that a deficiency or excess of the abovementioned elements may affect bone mineralization. Additionally, the risk of malnutrition, which is common in patients with ulcerative colitis or Crohn's disease, as well as the composition of gut microbiota, may be associated with micronutrients status.

Topics: Bone Density; Cadmium; Calcium; Colitis, Ulcerative; Copper; Crohn Disease; Female; Fluorine; Gastrointestinal Microbiome; Humans; Inflammatory Bowel Diseases; Iron Deficiencies; Iron Overload; Male; Malnutrition; Micronutrients; Osteoporosis; Risk Factors; Selenium; Silicon; Vitamin D; Zinc

Inflammatory bowel disease (IBD) affects a confined area of the intestine and, therefore, administration of drugs via oral route is preferable. However, obstacles such as changes in the pH along gastrointestinal tract (GIT), enzymatic activity, and intraluminal pressure may cause low drug availability in the target tissue when delivered orally. Previous studies have pointed out the benefits of using micron-sized particles for targeting inflamed intestinal mucosa and nanoparticles for delivery of anti-inflammatory agents to the affected epithelial cells. We hypothesized that by combining the benefits of micro- and nano- particles, we could create a more efficient delivery system for budesonide, a glucocorticosteroid commonly used for anti-inflammatory IBD therapy. The aim of this study was to develop a novel multistage system for oral delivery designed to increase concentrations budesonidein the inflamed intestinal tissue. The multistage system consists of Stage 1 mesoporous silicon microparticles (S1MP) loaded with stage 2 poly-lactic-glycolic acid (PLGA) budesonide-encapsulating nanoparticles (BNP). BNP were efficiently loaded into S1MP (loading efficiency of 45.9 ± 14.8%) due to the large pore volume and high surface area of S1MP and exhibited controlled release profiles with enhanced drug dissolution rate in biologically relevant pHs. Due to the robustness in acidic pH and their geometry, S1MP protected the loaded budesonide in the acidic (gastric) pH with only 20% release. This allowed for the prolonged release of the BNP in the higher pH conditions (intestinal pH). The sustained release of BNP could facilitate accumulation in the inflamed tissue, enabling BNP to penetrate inflamed mucosa and release active budesonide to the target site. The multistage systems of S1MP and BNP were further evaluated in three-dimensional (3D) in vitro model of IBD and were found to (1) increase accumulation of BNP in the inflamed areas, (2) restore the barrier function of Caco-2 inflamed monolayer, and (3) significantly reduce pro-inflammatory cytokine release almost to the level of the healthy control.

Topics: Anti-Inflammatory Agents; Budesonide; Caco-2 Cells; Cell Line, Tumor; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Hydrogen-Ion Concentration; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Nanoparticles; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Silicon; Solubility

Orally administrable drug delivery vehicles are developed to manage incurable inflammatory bowel disease (IBD), however, their therapeutic outcomes are compromised by the side effects of systemic drug exposure. Herein, we use hyaluronic acid functionalized porous silicon nanoparticle to bridge enzyme-responsive hydrogel and pH-responsive polymer, generating a hierarchical structured (nano-in-nano-in-micro) vehicle with programmed properties to fully and sequentially overcome the multiple obstacles for efficiently delivering drugs locally to inflamed sites of intestine. After oral administration, the pH-responsive matrix protects the embedded hybrid nanoparticles containing drug loaded hydrogels against the spatially variable physiological environments of the gastrointestinal tract until they reach the inflamed sites of intestine, preventing premature drug release. The negatively charged hybrid nanoparticles selectively target the inflamed sites of intestine, and gradually release drug in response to the microenvironment of inflamed intestine. Overall, the developed hierarchical structured and programmed vehicles load, protect, transport and release drugs locally to inflamed sites of intestine, contributing to superior therapeutic outcomes. Such strategy could also inspire the development of numerous hierarchical structured vehicles by other porous nanoparticles and stimuli-responsive materials for the local delivery of various drugs to treat plenty of inflammatory gastrointestinal diseases, including IBD, gastrointestinal cancers and viral infections.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Budesonide; Cell Line; Delayed-Action Preparations; Drug Delivery Systems; Humans; Hyaluronic Acid; Hydrogen-Ion Concentration; Inflammatory Bowel Diseases; Intestines; Male; Mice, Inbred C57BL; Nanoparticles; Polymers; Porosity; Silicon