title: Examination of the effect of increasing the number of intra-disulfide amino functional groups on the performance of small molecule cyclic polyamine disulfide vectors.
abstract: Establishing structure-activity relationships is vital if the efficacy of non-viral vectors is to match that of their viral counter-parts. Recently, we reported on the ability of a series of small molecule, cyclic polyamine disulfides to condense and cage plasmid DNA (pDNA) by a process of thermodynamically controlled templated polymerization, leading to a series of corresponding pDNA-polyplex nanoparticles able to mediate high levels of transfection with no associated cytotoxicities. The leading cyclic polyamine disulfide was shown to be the spermine tetra-amine disulfide (TetraN-3,4,3). Herein we report on the significantly more challenging syntheses of cyclic disulfides with longer polyamine motifs. Two new cyclic polyamine disulfides, based on hexa- and octa-amine inserts, were prepared and their transfection efficacies and cytotoxicities compared with our previously reported cyclic tri- and tetra-amine disulfides. The new cyclic hexa- and octa-amine disulfides prove more effective at transfection in vitro, especially of lung epithelial A549 cell line. By contrast, our original cyclic tetra-amine disulfide remains the most efficient agent for the transfection of lung epithelial cells in vivo following intra-nasal administration. Hypothetical mechanistic reasons are presented to explain this outcome. Our data in toto support the concept of shorter cyclic polyamine disulfides as preferred agents for polycation-mediated controlled condensation and functional delivery of pDNA to lung epithelial cells in vivo.
authors: Department of Chemistry, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK. chris.drake@ucsf.edu
authors: Christopher R
authors: CR
authors: Drake
authors: Abderrahim
authors: A
authors: Aissaoui
authors: Orestis
authors: O
authors: Argyros
authors: Maya
authors: M
authors: Thanou
authors: Joachim H G
authors: JH
authors: Steinke
authors: Andrew D
authors: AD
authors: Miller
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010957:Plasmids; D011073:Polyamines / Q000737:chemistry*; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D004220:Disulfides; D011073:Polyamines; D004247:DNA; D008156:Luciferases; D001616:beta-Galactosidase; D000111:Acetylcysteine
keywords: Cyclic polyamine disulfide; Gene therapy; Non-viral vector; Reducible