An in situ gelling liquid crystalline system based on monoglycerides and polyethylenimine for local delivery of siRNAs

Autor(es):Mostrar menos -

Borgheti-Cardoso, Livia Neves ^[1] ; Depieri, Livia Vieira ^[1] ; Kooijmans, Sander A. A. ^[2] ; Diniz, Henrique ^[1] ; Junqueira Calzzani, Ricardo Alexandre ^[3] ; Moura de Carvalho Vicentini, Fabiana Testa ^[1] ; van der Meel, Roy ^[2] ; de Abreu Fantini, Marcia Carvalho ^[4] ; Iyomasa, Mamie Mizusaki ^[5] ; Schiffelers, Raymond M. ^[2] ; Lopes Badra Bentley, Maria Vitoria ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Med Ctr Utrecht, Lab Clin Chem & Haematol, Utrecht - Netherlands

^[3] Univ La Frontera, Temuco - Chile

^[4] Univ Sao Paulo, Inst Fis, BR-01498 Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Fac Odontol Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmaceutical Sciences; v. 74, p. 103-117, JUL 10 2015.
• Citações Web of Science: 22

Resumo

The development of delivery systems able to complex and release siRNA into the cytosol is essential for therapeutic use of siRNA. Among the delivery systems, local delivery has advantages over systemic administration. In this study, we developed and characterized non-viral carriers to deliver siRNA locally, based on polyethylenimine (PEI) as gene carrier, and a self-assembling drug delivery system that forms a gel in situ. Liquid crystalline formulations composed of monoglycerides (MO), PEI, propylene glycol (PG) and 0.1 M Tris buffer pH 6.5 were developed and characterized by polarized light microscopy, Small Angle X-ray Scattering (SAXS), for their ability to form inverted type liquid crystalline phases (LC2) in contact with excess water, water absorption capacity, ability to complex with siRNA and siRNA release. In addition, gel formation in vivo was determined by subcutaneous injection of the formulations in mice. In water excess, precursor fluid formulations rapidly transformed into a viscous liquid crystalline phase. The presence of PEI influences the liquid crystalline structure of the LC2 formed and was crucial for complexing siRNA. The siRNA was released from the crystalline phase complexed with PEI. The release rate was dependent on the rate of water uptake. The formulation containing MO/PEI/PG/Tris buffer at 7.85:0.65:76.5:15 (w/w/w/w) complexed with 10 mu M of siRNA, characterized as a mixture of cubic phase (diamond-type) and inverted hexagonal phase (after contact with excess water), showed sustained release for 7 days in vitro. In mice, in situ gel formation occurred after subcutaneous injection of the formulations, and the gels were degraded in 30 days. Initially a mild inflammatory process occurred in the tissue surrounding the gel; but after 14 days the tissue appeared normal. Taken together, this work demonstrates the rational development of an in situ gelling formulation for local release of siRNA. (C) 2015 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 10/11736-0 - Sistemas de liberação de geleificação in situ para veiculação de siRNA: desenvolvimento, caracterização e estudos in vitro e in vivo em modelo animal
• Beneficiário: Lívia Neves Borgheti Cardoso
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 04/09465-7 - Laboratório multiusuário de caracterização de sistemas de liberação micro - e nanodispersos de fármacos
• Beneficiário: Maria Vitória Lopes Badra Bentley
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários
• Processo FAPESP: 13/02132-1 - Avaliação in vivo de sistema de geleificação in situ no tratamento do carcinoma de células escamosas após administração intratumoral
• Beneficiário: Lívia Neves Borgheti Cardoso
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado