title: Attuning hydroxypropyl methylcellulose phthalate to oral delivery vehicle for effective and selective delivery of protein vaccine in ileum.
abstract: Orally delivered proteins or antigens are taken up by epithelial microfold cells (M cells) in Peyer's patches, especially abundant in the ileum of small intestine. However, several barriers including gastric pH, enzymatic degradation, rapid transit and lack of specificity of proteins towards M cells, has made the goal of oral delivery of proteins very challenging. To overcome the problems, we developed an ileum targeted protein delivery system using hydroxypropyl methylcellulose phthalate (HPMCP). Initially, we attuned pH-sensitive property of HPMCP for controlled dissolution at ileum pH (≥7.4) by thiolation. Thiolation also improved mucoadhesive property of HPMCP to prolong the particles transit time through the gastrointestinal tract. Typically, thiolated HPMCP (T-HPMCP) prevented protein release in acidic pH in stomach and duodenum but released the proteins at ileal pH in a controlled manner. To evaluate the effectiveness of an oral delivery vehicle, T-HPMCP was used to deliver an M cell targeting protein antigen to mice through oral route. The antigens were mostly delivered and located in Peyer's patches in the ileum demonstrating the higher uptake of antigens through M-cells. Importantly, oral delivery of the antigen with T-HPMCP not only induced strong antibody mediated immune responses but also generated memory T cells in the spleen as adaptive immunity indicating a direct evidence of an effective delivery system. Thus, this study represents the first demonstration of HPMCP for ileum-specific delivery of protein vaccine through oral route.
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Bijay
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Sushila
authors.initials: S
authors.lastname: Maharjan
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute of Eco-friendly Animal Science, Institute of Green-Bio Science and Technology, Seoul National University, Kangwon-Do 232-916, Republic of Korea.
authors.forename: Sang-Kee
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea. Electronic address: cyjcow@snu.ac.kr.
authors.forename: Yun-Jaie
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea; Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea. Electronic address: chocs@snu.ac.kr.
authors.forename: Chong-Su
authors.initials: CS
authors.lastname: Cho
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D007082:Ileum / Q000276:immunology / Q000378:metabolism*; D008747:Methylcellulose / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D010581:Peyer's Patches / Q000276:immunology; D014612:Vaccines / Q000008:administration & dosage*
chemical_list: D014612:Vaccines; D008747:Methylcellulose; C053309:hydroxypropyl methylcellulose phthalate
keywords: M cells; Microparticles; Mucoadhesive; Targeted delivery; Thiolated HPMCP; pH-responsive