title: Microsphere-Based Rapamycin Delivery, Systemic Versus Local Administration in a Rat Model of Renal Ischemia/Reperfusion Injury.
abstract: OBJECTIVE
  The increasing prevalence and treatment costs of kidney diseases call for innovative therapeutic strategies that prevent disease progression at an early stage. We studied a novel method of subcapsular injection of monodisperse microspheres, to use as a local delivery system of drugs to the kidney.
  
  
  METHODS
  We generated placebo- and rapamycin monodisperse microspheres to investigate subcapsular delivery of drugs. Using a rat model of acute kidney injury, subcapsular injection of placebo and rapamycin monodisperse microspheres (monospheres) was compared to subcutaneous injection, mimicking systemic administration.
  
  
  RESULTS
  We did not find any adverse effects related to the delivery method. Irrespective of the injection site, a similar low dose of rapamycin was present in the circulation. However, only local intrarenal delivery of rapamycin from monospheres led to decreased macrophage infiltration and a significantly lower amount of myofibroblasts in the kidney, where systemic administration did not. Local delivery of rapamycin did cause a transient increase in the deposition of collagen I, but not of collagen III.
  
  
  CONCLUSIONS
  We conclude that therapeutic effects can be increased when rapamycin is delivered subcapsularly by monospheres, which, combined with low systemic concentrations, may lead to an effective intrarenal delivery method.
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Jurjen
authors.initials: J
authors.lastname: Zandstra
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. m.m.van.beuge@umcg.nl.
authors.forename: Marike M
authors.initials: MM
authors.lastname: van Beuge
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Zuidema
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Arjen H
authors.initials: AH
authors.lastname: Petersen
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Staal
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Luisa F
authors.initials: LF
authors.lastname: Duque
authors.affiliation: Nanomi BV, Oldenzaal, The Netherlands.
authors.forename: Sergio
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: Nanomi BV, Oldenzaal, The Netherlands.
authors.forename: Audrey A R
authors.initials: AA
authors.lastname: Lathuile
authors.affiliation: Nanomi BV, Oldenzaal, The Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Veldhuis
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Steendam
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Bank
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Eliane R
authors.initials: ER
authors.lastname: Popa
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D008863:Microspheres; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000188:drug therapy*; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D020123:Sirolimus
keywords: ischemia reperfusion; kidney; local drug delivery; microspheres; rapamycin