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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: European Journal of Pharmaceutical Sciences; v. 74, p. 103-117, JUL 10 2015.
• Web of Science Citations: 22

Abstract

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)

• FAPESP's process: 10/11736-0 - In situ gelling delivery systems for siRNA: development, characterization and study of in vitro and in vivo in animal model
• Grantee: Lívia Neves Borgheti Cardoso
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 13/02132-1 - In vivo evaluation of in situ gelling systems to treatment of squamous cell carcinoma after intratumoral administration
• Grantee: Lívia Neves Borgheti Cardoso
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate