title: Local therapeutic efficacy with reduced systemic side effects by rapamycin-loaded subcapsular microspheres.
abstract: Kidney injury triggers fibrosis, the final common pathway of chronic kidney disease (CKD). The increase of CKD prevalence worldwide urgently calls for new therapies. Available systemic treatment such as rapamycin are associated with serious side effects. To study the potential of local antifibrotic therapy, we administered rapamycin-loaded microspheres under the kidney capsule of ureter-obstructed rats and assessed the local antifibrotic effects and systemic side effects of rapamycin. After 7 days, microsphere depots were easily identifiable under the kidney capsule. Both systemic and local rapamycin treatment reduced intrarenal mTOR activity, myofibroblast accumulation, expression of fibrotic genes, and T-lymphocyte infiltration. Upon local treatment, inhibition of mTOR activity and reduction of myofibroblast accumulation were limited to the immediate vicinity of the subcapsular pocket, while reduction of T-cell infiltration was widespread. In contrast to systemically administered rapamycin, local treatment did not induce off target effects such as weight loss. Thus subcapsular delivery of rapamycin-loaded microspheres successfully inhibited local fibrotic response in UUO with less systemic effects. Therapeutic effect of released rapamycin was most prominent in close vicinity to the implanted microspheres.
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, The Netherlands.
authors.forename: Lucas L
authors.initials: LL
authors.lastname: Falke
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, The Netherlands.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: van Vuuren
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: Filis
authors.initials: F
authors.lastname: Kazazi-Hyseni
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: Farshad
authors.initials: F
authors.lastname: Ramazani
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, The Netherlands.
authors.forename: Tri Q
authors.initials: TQ
authors.lastname: Nguyen
authors.affiliation: Nanomi B.V., Oldenzaal, The Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Veldhuis
authors.affiliation: Department of Clinical Pharmacy, University Medical Centre Utrecht, The Netherlands.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Maarseveen
authors.affiliation: Department of Pathology and Laboratory Medicine, University Medical Centre Groningen, University of Groningen, The Netherlands.
authors.forename: Jurjen
authors.initials: J
authors.lastname: Zandstra
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Zuidema
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Luisa F
authors.initials: LF
authors.lastname: Duque
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Steendam
authors.affiliation: Department of Pathology and Laboratory Medicine, University Medical Centre Groningen, University of Groningen, The Netherlands.
authors.forename: Eliane R
authors.initials: ER
authors.lastname: Popa
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: Robbert Jan
authors.initials: RJ
authors.lastname: Kok
authors.affiliation: Department of Pathology, University Medical Centre Utrecht, The Netherlands. Electronic address: R.Goldschmeding@umcutrecht.nl.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002214:Capsules; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011916:Rats, Inbred F344; D020123:Sirolimus / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome; D014517:Ureteral Obstruction / Q000188:drug therapy / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D002214:Capsules; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Chronic kidney disease; Fibrosis; Microsphere; Rapamycin; Subcapsular delivery; mTOR