Exosomes are membrane vesicles composed of lipid bilayer with diameter of approximately 100 nm and are released from various types of cells. Exosomes work as endogenous intercellular delivery vehicles. Intercellular delivery by exosomes has been demonstrated to be related to the development, progression and metastasis of gastrointestinal cancer. On the other hand, exosomes, endogenous delivery carriers, can be effective DDS targeting gastrointestinal cancer. Here, we describe problems in the development of exosome-based DDS and solutions for the problems and introduce reported examples of exosome-based DDS targeting gastrointestinal cancer.

Oral administration is preferred route for pharmacotherapy, but there are many drugs that are not effective orally due to insufficient stability and low permeability of gastrointestinal membrane. Transcellular permeation are mediated by specific transporters and endocytosis as well as nonspecific lipophilicity-dependent simple diffusion. In this article, transporters that may affect permeability of drugs and could be used as the target of intestinal delivery of drugs are described, including both absorptive influx and excretory efflux transporters. Many reports demonstrated that several drugs are absorbed as the substrates of influx transporters. In addition, there are challenge of a chemical modification of active drug molecule as prodrug to be substrate of influx transporters. Known influx drug transporters are peptide transporter PEPT1, nucleoside transporters CNTs and ENTs, organic anion/cation transporters OATP2B1 and OCTs, and bile acid transporter ASBT/IBAT. When efflux transporters suppress intestinal drug absorption, certain excipients used for formulation of drugs have a potential to inhibit P-glycoprotein. Usually substrates of transporters are small molecules with molecular weight less than about 1,000. Endocytosis could be applied for the absorption enhancement of biological large molecule drugs. Since transporters are membrane proteins and could be surface receptor to recognize their substrates as ligands, utilization of nanoparticles labeled with transporter substrates (ligands) could be targeted to the transporters, resulting in delivery of the cargo in the particles. Accordingly, transporters are promising targets to design DDS to improve absorption of both of small and large molecular drugs by variable approaches. In this review, we focus on current approaches and future possibilities of oral DDS targeting intestinal transporters.

For therapy of digestive diseases, generally drug treatment has been employed. There have been problems due to even drug distribution in the target and non-target organ. Since it is difficult to attain local drug activity after conventional administration such as intravenous and oral routes, we have tried to develop a new administration system utilizing drug absorption from the organ surface such as liver in the peritoneal cavity. As a non-invasive procedure, endoscopic surgery would enable us to achieve drug targeting to the diseased region in the peritoneal cavity. Although direct drug application to the organ surface could yield local drug availability, drug absorption characteristics from the organ surface such as liver surface had not been reported in the literature. Therefore, we first analyzed the efficiency of absorption of several organic anions and dextrans of various molecular weights, as marker compounds, following application to the rat liver surface in vivo employing a cylindrical diffusion cell. Each compound was absorbed from the rat liver surface with the different rates depending on the physicochemical properties. The absorption process from the liver surface might not obey an active transport system because of no detectable effect by dose and transport inhibitors. In addition, molecular weight and lipophilicity were found to be one of determinant factors of absorption through the liver surface. The ability of targeting to the desired region in the liver was enhanced significantly by application to the liver surface, compared to intravenous administration. Viscous additives, absorption enhancer, and vasomodulaters were proved to be effective to improve the drug availability in the target region. We also have obtained several expecting results from the application of this new drug delivery system for anticancer drugs. On the other hand, I have clarified the characteristics of drug absorption from the surfaces of the kidney, stomach, cecum and small intestine, and expect to apply the physiological findings to other fields. Furthermore, it is possible to apply the organ surface administration to genetic medicine. We successfully enhanced transgene expression onto the organ surface based on various strategies.

Mesalazine, also known as mesalamine or 5-aminosalicylic acid (5-ASA), is an aminosalicylate anti-inflammatory drug used as a primary agent to treat inflammatory bowel disease, including ulcerative colitis and to maintain remission in Crohn's disease. The efficacy of 5-ASA is determined by the degree of drug delivery to the site of inflammation, but it depends on the formulation. In recent years, 5-ASA preparations using drug-delivery system (DDS) technology as a therapeutic agent for ulcerative colitis have been developed one after another, contributing to improvement of therapeutic effect. In this article, we focus on the pharmacokinetic characteristics of each 5-ASA preparation, and introduce the features and clinical usefulness of the preparation.

Current advances in the treatment of inflammatory bowel disease (IBD) are mainly due to improvement in selectivity or specificity of therapeutic target molecules and mechanisms of action. However, it is not necessarily sufficient from the viewpoint of selective target to gastrointestinal tracts. Development of drug delivery system targeted to the gastrointestinal tract using biodegradable microspheres, which could carry and sustained release various materials such as corticosteroids, anti-inflammatory cytokines and growth factors would be expected to contribute to future therapeutic strategy for inflammatory bowel disease.

Inflammatory bowel disease (IBD) commonly occurs in young people, and the number of IBD patients is still increasing in Japan. Regarding the treatment of IBD, glucocorticosteroids (CSs), immunosuppressants, and biologics are used for the purpose of controlling excessive immune response. Although the therapeutic effect of CSs has been established, physicians always concern about adverse events related to long-term use of CSs. Additionally, treatment with anti-inflammatory cytokines has been expected, however, the efficacy of their systemic administration is not necessarily expected because of their short half-life. Drug delivery system (DDS) can in principle provide enhanced efficacy and/ or reduced toxicity of drugs. Until now, there have been various reports of therapeutic effects of DDS with genetically modified intestinal bacteria, that can produce anti-inflammatory substances, on IBD models. Previously, DDS with genetically modified intestinal bacteria producing interleukin-10 had been focused. Recently, reports on DDS with genetically modified intestinal bacteria producing proteins and other cytokines except IL-10 are increasing. On the other hand, further studies will be required to elucidate how kinds of intestinal bacteria and anti-inflammatory substances affect therapeutic efficacy in ameliorating intestinal inflammation. Additionally, to assess the safety of treatment with these DDS and the risk influencing environment will be necessary before clinical application.