Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels

Ana Paula Perez1, Cecilia Mundi&ntilde;a-Weilenmann2, Eder Lilia Romero1, Maria Jose Morilla11Programa de Nanomedicinas, Departamento de Ciencia y Tecnolog&iacute;a, Universidad Nacional de Quilmes, Buenos Aires, 2Centro de Investigaciones Cardiovasculares, CCT-La Plata, CONICET, Fac...

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Autores principales:	Perez AP, Mundi&ntilde;a-Weilenmann C, Romero EL, Morilla MJ
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Lenguaje:	EN
Publicado:	Dove Medical Press 2012
Materias:	Medicine (General) R5-920
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spelling	oai:doaj.org-article:ba87569c8b3b482eb49a18afb54a5c742021-12-02T07:21:24ZIncreased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels1176-91141178-2013https://doaj.org/article/ba87569c8b3b482eb49a18afb54a5c742012-03-01T00:00:00Zhttp://www.dovepress.com/increased-brain-radioactivity-by-intranasal-32p-labeled-sirna-dendripl-a9455https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Ana Paula Perez1, Cecilia Mundi&ntilde;a-Weilenmann2, Eder Lilia Romero1, Maria Jose Morilla11Programa de Nanomedicinas, Departamento de Ciencia y Tecnolog&iacute;a, Universidad Nacional de Quilmes, Buenos Aires, 2Centro de Investigaciones Cardiovasculares, CCT-La Plata, CONICET, Facultad de Ciencias M&eacute;dicas, Universidad Nacional de La Plata, La Plata, ArgentinaBackground: 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 32P-small interference RNA (siRNA) complexed with poly(amidoamine) G7 dendrimers (siRNA dendriplexes) within in situ-forming mucoadhesive gels, was determined.Materials: 32P-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&deg;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 32P-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.Conclusion: The increased radioactivity within the olfactory bulb suggested that the combination above mentioned favored the mediation of a direct brain delivery.Keywords: nucleic acids, gel, dendrimers, mucosa, olfactory bulbPerez APMundi&ntilde;a-Weilenmann CRomero ELMorilla MJDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2012, Iss default, Pp 1373-1385 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Perez AP Mundi&ntilde;a-Weilenmann C Romero EL Morilla MJ Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels
description	Ana Paula Perez1, Cecilia Mundi&ntilde;a-Weilenmann2, Eder Lilia Romero1, Maria Jose Morilla11Programa de Nanomedicinas, Departamento de Ciencia y Tecnolog&iacute;a, Universidad Nacional de Quilmes, Buenos Aires, 2Centro de Investigaciones Cardiovasculares, CCT-La Plata, CONICET, Facultad de Ciencias M&eacute;dicas, Universidad Nacional de La Plata, La Plata, ArgentinaBackground: 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 32P-small interference RNA (siRNA) complexed with poly(amidoamine) G7 dendrimers (siRNA dendriplexes) within in situ-forming mucoadhesive gels, was determined.Materials: 32P-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&deg;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 32P-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.Conclusion: The increased radioactivity within the olfactory bulb suggested that the combination above mentioned favored the mediation of a direct brain delivery.Keywords: nucleic acids, gel, dendrimers, mucosa, olfactory bulb
format	article
author	Perez AP Mundi&ntilde;a-Weilenmann C Romero EL Morilla MJ
author_facet	Perez AP Mundi&ntilde;a-Weilenmann C Romero EL Morilla MJ
author_sort	Perez AP
title	Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels
title_short	Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels
title_full	Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels
title_fullStr	Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels
title_full_unstemmed	Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels
title_sort	increased brain radioactivity by intranasal 32p-labeled sirna dendriplexes within in situ-forming mucoadhesive gels
publisher	Dove Medical Press
publishDate	2012
url	https://doaj.org/article/ba87569c8b3b482eb49a18afb54a5c74
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Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels

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