title: Increased brain radioactivity by intranasal P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels.
abstract: BACKGROUND
  Molecules taken up by olfactory and trigeminal nerve neurons directly access the brain by the nose-to-brain pathway. In situ-forming mucoadhesive gels would increase the residence time of intranasal material, favoring the nose-to-brain delivery. In this first approach, brain radioactivity after intranasal administration of (32)P-small interference RNA (siRNA) complexed with poly(amidoamine) G7 dendrimers (siRNA dendriplexes) within in situ-forming mucoadhesive gels, was determined.
  
  
  METHODS
  (32)P-siRNA dendriplexes were incorporated into in situ-forming mucoadhesive gels prepared by blending thermosensitive poloxamer (23% w/w) with mucoadhesive chitosan (1% w/w, PxChi) or carbopol (0.25% w/w, PxBCP). Rheological properties, radiolabel release profile, and local toxicity in rat nasal mucosa were determined. The best-suited formulation was intranasally administered to rats, and blood absorption and brain distribution of radioactivity were measured.
  
  
  RESULTS
  The gelation temperature of both formulations was 23°C. The PxChi liquid showed non-Newtonian pseudoplastic behavior of high consistency and difficult manipulation, and the gel retained 100% of radiolabel after 150 minutes. The PxCBP liquid showed a Newtonian behavior of low viscosity and easy manipulation, while in the gel phase showed apparent viscosity similar to that of the mucus but higher than that of aqueous solution. The gel released 35% of radiolabel and the released material showed silencing activity in vitro. Three intranasal doses of dendriplexes in PxCBP gel did not damage the rat nasal mucosa. A combination of (32)P-siRNA complexation with dendrimers, incorporation of the dendriplexes into PxCBP gel, and administration of two intranasal doses was necessary to achieve higher brain radioactivity than that achieved by intravenous dendriplexes or intranasal naked siRNA.
  
  
  CONCLUSIONS
  The increased radioactivity within the olfactory bulb suggested that the combination above mentioned favored the mediation of a direct brain delivery.
authors.affiliation: Programa de Nanomedicinas, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Roque Saenz Peña 352, Bernal, Buenos Aires, Argentina.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Perez
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mundiña-Weilenmann
authors.forename: Eder Lilia
authors.initials: EL
authors.lastname: Romero
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Morilla
mesh_terms: D000281:Administration, Intranasal / Q000379:methods; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D048271:Chitosan / Q000737:chemistry; D050091:Dendrimers / Q000737:chemistry; D055119:Elastic Modulus; D005782:Gels / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006651:Histocytochemistry; D008297:Male; D009297:Nasal Mucosa / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D010759:Phosphorus Isotopes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013696:Temperature; D014783:Viscosity
chemical_list: D050091:Dendrimers; D005782:Gels; C104700:PAMAM Starburst; D010759:Phosphorus Isotopes; D034741:RNA, Small Interfering; D048271:Chitosan