Subject Background
Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal (GI) disease. It includes ulcerative colitis (UC) and Crohnrsquo;s disease (CD). UC affects the entire colon while Crohnrsquo;s inflammation involves the gastrointestinal tract. Despite the disease mechanism still undefined, some factors play an important role in IBD, such as genetics, microbiome, environment and immunity.
Currently available therapies for IBD like steroids, antibiotics and immunomodulators aim toward attaining remission from inflammatory episodes. However, these conventional oral formulations are limited for the prolonged use in IBD due to systemic side-effects, which results from their systemic delivery of therapeutics. Oral formulations should be designed to achieve a localized effect within the GI tract. Current therapeutic strategies are based on delayed or controlled release mechanisms. Their design exploits physiological conditions in the colon, including enzymatic degradation, GI transit time and pH. However, these approaches are varied efficacy due to the diverse physiological changes and inter-patient variability.
Recently nanotechnology has been applied to design oral drug delivery systems for colon targeting. Reducing the size of drug delivery carriers to the nanometer scale enhances drug delivery to inflamed intestinal mucosa by eEPR effect and achieves more retention time in inflamed tissues, which allows that drug is more effectively taken up into inflamed tissue and cells. In addition, this reduction in size avoids carrier elimination by diarrhea. Hence, nano-delivery systems have improved therapeutic efficacy for IBD compared with conventional formulations.
The potential of nanoparticle and microparticle taken up into the rectal mucosa of IBD patients was investigated. Microparticles exhibited an obvious accumulation and bioadhesion to the inflamed mucosal well, but no absorption of these particles across the epithelial barrier was detected. Conversely, nanoparticles were detectable only in traces in the mucosa and translocated to the serosal compartment of IBD patients, leading to systemic absorption. Hence, Nanoparticles might not be required for local drug delivery to intestinal lesions.
Although size is an important factor in colon targeting, other colon targeted delivery approaches to achieve maximal retention time are being explored. Modifying the surface charge of nano-delivery systems can influence the electrostatic interaction between the nanocarriers and components in the GI tract. Cationic nano-delivery systems are designed to preferentially adhere to the inflamed mucosal surface via the interaction between the positively charged nanocarrier and the negatively charged intestinal mucosa. Colonic mucins carry a negative charge since their carbohydrates are substituted with numerous sulfate and sialic acid residues. Adhesion to the mucosa can be an advantage for colon targeting as it promotes better contact with the mucosal surface for cellular uptake and drug release. It can also reduce the clearance of nanocarriers.
Anionic nano-delivery systems adhere to inflamed tissue due to electrostatic interaction with the higher concentration of positively charged proteins in inflamed regions. Inflamed intestinal mucosa is accompanied by depletion of the mucus layer and in situ accumulation of positively charged proteins, which results in the buildup of positive charges at the damaged epithelial surface, providing a molecular target for drug carrier with negative surface charge. Furthermore, inflammation is accompanied by up-regulation and release of degradative enzymes. A drug delivery system with negative surface charge and containing an enzyme-labile linker could adhere to inflamed mucosa and release drug in response to enzyme activities, which leads to better bioavailability and improved colonic residence time. Sufeng et al designed an inflammation-targeting hydrogel for drug delivery in IBD. Inflammation-targeting hydrogel microfibers encapsulate hydrophobic drugs and preferentially adhere to the inflamed mucosa due to their negative surface charge. Inflammation-targeting hydrogel has two advantages in comparison to other drug delivery system. On one hand, hydrogel is capable of high drug-loading. On the other hand, drug-loaded hydrogel exhibits long-term stability because water canrsquo;t efficiently penetrate into the hydrophobic fiber core to disassemble the gel and release the drug.
A wide variety of techniques can be used to prepare hydrogel polymer micro-or nanoparticles, including emulsification of polymers, self-assembly and crosslinking of hydrophobically modified or complementary charged polymers. A powerful strategy to prepare hydrophilic polymer nanogels is the controlled radical polymerization of vinyl-type monomers. Controlled radical polymerization techniques have been extensively explored to polymerize hydrophobic monomers under heterogeneous conditions. Direct synthesis of hydrophilic micro-and nanogels in inverse emulsion systems is more recent. N-(2-Hydroxypropyl)methacrylamide (HPMA) is a water soluble vinyl monomer. By incorporation of a disulfide functional crosslinker, biodegradable nanogels could be prepared. Herald et al reported the synthesis of reduction-sensitive PHPMA nanogels via RAFT polymerization in inverse emulsion. Reversible addition-fragmentation chain transfer (RAFT) polymerization is one of several kinds of reversible-deactivation radical polymerization. It makes use of a chain transfer agent to afford control over the generated molecular weight and polydispersity during a free-radical polymerization.
Chloroquine is a commonly used anti-malarial drug. Recently it is prescribed for the treatment of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The pathogenesis of IBD is characterized by enhanced recruitment and retention of macrophages, neutrophils and T cells to release proinflammatory cytokines. An ideal strategy is blocking both innate and adaptive immunity to control inflammatory. Susan et al confirmed that the effect of chloroquin on innate immune response and T cell response. Chloroquine significantly suppresses innate immune response via blocking of TLR1/2 and TLR9 signaling. It also acts on the adaptive immune system by suppressing the T cell cytokine and proliferative responses. Hence, chloroquine could be a therapeutic approach for IBD.
Problem to be solved
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