Small interfering RNA (siRNA) has garnered much attention in recent years as a promising avenue for cancer gene therapy due to its ability to silence disease-related genes. Effective gene silencing is contingent upon the delivery of siRNA into the cytosol of target cells and requires the implementation of delivery systems possessing multiple functionalities to overcome delivery barriers. The present work explores the multifunctional properties and biological activity of a recently developed cationic lipid carrier, (1-aminoethyl)iminobis[N-(oleicylcysteinyl-1-amino-ethyl)propionamide]) (ECO). The physicochemical properties and biological activity of ECO/siRNA nanoparticles were assessed over a range of N/P ratios to optimize the formulation. Potent and sustained luciferase silencing in a U87 glioblastoma cell line was observed, even in the presence of serum proteins. ECO/siRNA nanoparticles exhibited pH-dependent membrane disruption at pH levels corresponding to various stages of the intracellular trafficking pathway. It was found that disulfide linkages created during nanoparticle formation enhanced the protection of siRNA from degradation and facilitated site-specific siRNA release in the cytosol by glutathione-mediated reduction. Confocal microscopy confirmed that ECO/siRNA nanoparticles readily escaped from late endosomes prior to cytosolic release of the siRNA cargo. These results demonstrate that the rationally designed multifunctionality of ECO/siRNA nanoparticles is critical for intracellular siRNA delivery and the continuing development of safe and effective delivery systems.
Small interfering RNA (siRNA) has garnered much attention in recent years as a promising avenue for cancer gene therapn>y due to its ability to silence disease-related genes. Effective gene silencing is contingent upon the delivery of siRNA into the cytosol of target cells and requires the implementation of delivery systems possessing multiple functionalities to overcome delivery barriers. The present work explores the multifunctional properties and biological activity of a recently developed cationic n>an class="Chemical">lipid carrier, (1-aminoethyl)iminobis[N-(oleicylcysteinyl-1-amino-ethyl)propionamide]) (ECO). The physicochemical properties and biological activity of ECO/siRNA nanoparticles were assessed over a range of N/P ratios to optimize the formulation. Potent and sustained luciferase silencing in a U87glioblastoma cell line was observed, even in the presence of serum proteins. ECO/siRNA nanoparticles exhibited pH-dependent membrane disruption at pH levels corresponding to various stages of the intracellular trafficking pathway. It was found that disulfide linkages created during nanoparticle formation enhanced the protection of siRNA from degradation and facilitated site-specific siRNA release in the cytosol by glutathione-mediated reduction. Confocal microscopy confirmed that ECO/siRNA nanoparticles readily escaped from late endosomes prior to cytosolic release of the siRNA cargo. These results demonstrate that the rationally designed multifunctionality of ECO/siRNA nanoparticles is critical for intracellular siRNA delivery and the continuing development of safe and effective delivery systems.
Authors: Jie Wei; Jeffrey Jones; Jing Kang; Ananda Card; Michael Krimm; Paula Hancock; Yi Pei; Brandon Ason; Elmer Payson; Natalya Dubinina; Mark Cancilla; Mark Stroh; Julja Burchard; Alan B Sachs; Jerome H Hochman; W Michael Flanagan; Nelly A Kuklin Journal: Mol Pharmacol Date: 2011-03-22 Impact factor: 4.436
Authors: Kai Xiao; Yuanpei Li; Juntao Luo; Joyce S Lee; Wenwu Xiao; Abby M Gonik; Rinki G Agarwal; Kit S Lam Journal: Biomaterials Date: 2011-02-04 Impact factor: 12.479
Authors: Sean C Semple; Akin Akinc; Jianxin Chen; Ammen P Sandhu; Barbara L Mui; Connie K Cho; Dinah W Y Sah; Derrick Stebbing; Erin J Crosley; Ed Yaworski; Ismail M Hafez; J Robert Dorkin; June Qin; Kieu Lam; Kallanthottathil G Rajeev; Kim F Wong; Lloyd B Jeffs; Lubomir Nechev; Merete L Eisenhardt; Muthusamy Jayaraman; Mikameh Kazem; Martin A Maier; Masuna Srinivasulu; Michael J Weinstein; Qingmin Chen; Rene Alvarez; Scott A Barros; Soma De; Sandra K Klimuk; Todd Borland; Verbena Kosovrasti; William L Cantley; Ying K Tam; Muthiah Manoharan; Marco A Ciufolini; Mark A Tracy; Antonin de Fougerolles; Ian MacLachlan; Pieter R Cullis; Thomas D Madden; Michael J Hope Journal: Nat Biotechnol Date: 2010-01-17 Impact factor: 54.908
Authors: Devika S Manickam; Jing Li; David A Putt; Qing-Hui Zhou; Chao Wu; Lawrence H Lash; David Oupický Journal: J Control Release Date: 2009-08-29 Impact factor: 9.776
Authors: Amita M Vaidya; Zhanhu Sun; Nadia Ayat; Andrew Schilb; Xujie Liu; Hongfa Jiang; Da Sun; Josef Scheidt; Victoria Qian; Siyuan He; Hannah Gilmore; William P Schiemann; Zheng-Rong Lu Journal: Bioconjug Chem Date: 2019-02-21 Impact factor: 4.774
Authors: Jenny G Parvani; Maneesh D Gujrati; Margaret A Mack; William P Schiemann; Zheng-Rong Lu Journal: Cancer Res Date: 2015-04-09 Impact factor: 12.701
Authors: Nadia R Ayat; Zhanhu Sun; Da Sun; Michelle Yin; Ryan C Hall; Amita M Vaidya; Xujie Liu; Andrew L Schilb; Josef H Scheidt; Zheng-Rong Lu Journal: Nucleic Acid Ther Date: 2019-05-28 Impact factor: 5.486
Authors: Adina Brett-Morris; Bradley M Wright; Yuji Seo; Vinay Pasupuleti; Junran Zhang; Jun Lu; Raffaella Spina; Eli E Bar; Maneesh Gujrati; Rebecca Schur; Zheng-Rong Lu; Scott M Welford Journal: Cancer Res Date: 2014-10-02 Impact factor: 12.701
Authors: Mehdi Bin Samad; Krishnaiah Maddeboina; Nathalia Rodrigues de Almeida; Martin Conda-Sheridan Journal: J Vis Exp Date: 2018-06-25 Impact factor: 1.355