title: Delivery of kinesin spindle protein targeting siRNA in solid lipid nanoparticles to cellular models of tumor vasculature.
abstract: The ideal siRNA delivery system should selectively deliver the construct to the target cell, avoid enzymatic degradation, and evade uptake by phagocytes. In the present study, we evaluated the importance of polyethylene glycol (PEG) on lipid-based carrier systems for encapsulating, and delivering, siRNA to tumor vessels using cellular models. Lipid nanoparticles containing different percentage of PEG were evaluated based on their physical chemical properties, density compared to water, siRNA encapsulation, toxicity, targeting efficiency and gene silencing in vitro. siRNA can be efficiently loaded into lipid nanoparticles (LNPs) when DOTAP is included in the formulation mixture. However, the total amount encapsulated decreased with increase in PEG content. In the presence of siRNA, the final formulations contained a mixed population of particles based on density. The major population which contains the majority of siRNA exhibited a density of 4% glucose, and the minor fraction associated with a decreased amount of siRNA had a density less than PBS. The inclusion of 10 mol% PEG resulted in a greater amount of siRNA associated with the minor fraction. Finally, when kinesin spindle protein (KSP) siRNA was encapsulated in lipid nanoparticles containing a modest amount of PEG, the proliferation of endothelial cells was inhibited due to the efficient knock down of KSP mRNA. The presence of siRNA resulted in the formation of solid lipid nanoparticles when prepared using the thin film and hydration method. LNPs with a relatively modest amount of PEG can sufficiently encapsulate siRNA, improve cellular uptake and the efficiency of gene silencing.
authors.affiliation: Northeastern University, Bouvé College of Health Sciences, Department of Pharmaceutical Sciences, 360 Huntington Avenue, Boston, MA 02115, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Ying
authors.affiliation: Northeastern University, Bouvé College of Health Sciences, Department of Pharmaceutical Sciences, 360 Huntington Avenue, Boston, MA 02115, United States. Electronic address: robert.campbell@mcphs.edu.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Campbell
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology*; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D051379:Mice; D053769:Nanocapsules / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D014162:Transfection / Q000379:methods*
chemical_list: D053769:Nanocapsules; D010743:Phospholipids; D034741:RNA, Small Interfering; C521052:Kif11 protein, mouse; D016547:Kinesins
keywords: Cancer; Liposomes; Nanoparticles; Polyethyleneglycol; siRNA