title: Therapeutic advantage of inhaled tacrolimus-bound albumin nanoparticles in a bleomycin-induced pulmonary fibrosis mouse model.
abstract: Tacrolimus (Tac) is an immunosuppressant that inhibits translocation of nuclear factor of activated T cells and has therapeutic potential for pulmonary fibrosis. Here, we investigated the therapeutic efficacy of a sustained-release type inhaled Tac formulation for treating bleomycin-induced pulmonary fibrosis. Inhalation has many meaningful advantages over injections, such as improved patient compliance, safety, and therapeutic effect. To this end, we fabricated inhalable albumin nanoparticles with bound Tac (Tac Alb-NPs) at a daily therapeutic dose (60 μg/mouse) using a high-pressure homogenizer via nanoparticle albumin-bound technology. The Tac Alb-NPs were spherical, ∼ 182.1 ± 28.5 nm in size, with a zeta potential of -34.5 ± 0.3 mV, and the Tac incorporation efficiency was as high as ∼ 85.3%. The bound tacrolimus was released gradually from Tac Alb-NPs for ∼ 24 h, which was sufficient time for pulmonary delivery. Most of all, the inhaled Tac Alb-NPs displayed remarkable anti-fibrotic efficacy in mice with bleomycin-induced pulmonary fibrosis, which was much better than the efficacy resulting from intraperitoneal administration of Tac (60 μg/mouse) based on histopathological results (hematoxylin and eosin and Masson's trichrome staining). Furthermore, the inhaled Cy5.5-labelled Tac Alb-NPs were visualized throughout the lungs of mice for ∼ 48 h, indicating direct exposure to fibrotic tissues in lung lesions. In conclusion, Tac Alb-NPs offer great potential as an inhalation delivery formulation for treating pulmonary fibrosis. Additionally, these NPs would be particularly useful as an effective and safe prototype for delivering practically insoluble therapeutic agents into the lungs.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Jisoo
authors.initials: J
authors.lastname: Seo
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Changkyu
authors.initials: C
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Ha Shin
authors.initials: HS
authors.lastname: Hwang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Bomi
authors.initials: B
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
authors.forename: Le Quang
authors.initials: le Q
authors.lastname: Thao
authors.affiliation: Division of Biotechnology, The Catholic University of Korea, 43-1 Yeokgok 2-dong, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Republic of Korea.
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, 221 Heukseok dong, Dongjak-gu, Seoul 155-756, Republic of Korea.
authors.forename: Kyung Taek
authors.initials: KT
authors.lastname: Oh
authors.affiliation: CKD Research Institute, Chong Kun Dang Pharm Corp., 315-20, Dongbaekjukjeon-daero, Giheung-gu, Yongin-si, Gyeonggi-do 16995, Republic of Korea.
authors.forename: Jong-Lae
authors.initials: JL
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan, Gyeonggi-do 15588, Republic of Korea.
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea. Electronic address: ysyoun@skku.edu.
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
mesh_terms: D000280:Administration, Inhalation; D000418:Albumins / Q000737:chemistry*; D000818:Animals; D000963:Antimetabolites; D001761:Bleomycin; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D006909:Hydroxyproline / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016559:Tacrolimus / Q000008:administration & dosage* / Q000627:therapeutic use*
chemical_list: D000418:Albumins; D000963:Antimetabolites; D007166:Immunosuppressive Agents; D001761:Bleomycin; D006909:Hydroxyproline; D016559:Tacrolimus
keywords: Albumin nanoparticles; Bleomycin-induced fibrosis model; Inhalation; Pulmonary fibrosis; Tacrolimus