title: Effects of base polymer hydrophobicity and end-group modification on polymeric gene delivery.
abstract: A new 320-member polymer library of end-modified poly(β-amino ester)s was synthesized. This library was chosen such that small differences to the structures of component backbone, side-chain, and end-group monomers could be systematically and simultaneously evaluated. The in vitro transfection efficacy and cytotoxicity of DNA nanoparticles formed from this library were assessed. This library approach not only enabled us to synthesize and test a large variety of structures rapidly but also provided us with a robust data set to analyze for the effect of small structural permutations to polymer chain structure. Small changes to the side chains, backbones, and end groups within this polymer library produced dramatic results, with transfection efficacy of CMV-Luc varying over 4 orders in a 96-well plate format. Increasing hydrophobicity of the base polymer backbone and side chain tended to increase transfection efficacy, but the most hydrophobic side chains and backbones showed the least requirement for a hydrophobic pair. Optimal PBAE formulations were superior to commercially available nonviral alternatives FuGENE HD and Lipofectamine 2000, enabling ~3-fold increased luminescence (2.2 × 10(6) RLU/well vs 8.1 × 10(5) RLU/well) and 2-fold increased transfection percentage (76.7% vs 42.9%) as measured by flow cytometry with comparable or reduced toxicity.
authors: Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, 400 N Broadway/Smith Building Room 5017, Baltimore, Maryland 21231, United States.
authors: Joel C
authors: JC
authors: Sunshine
authors: Marib I
authors: MI
authors: Akanda
authors: David
authors: D
authors: Li
authors: Kristen L
authors: KL
authors: Kozielski
authors: Jordan J
authors: JJ
authors: Green
mesh_terms: D000818:Animals; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D008156:Luciferases / Q000032:analysis; D049449:Luminescence; D008163:Luminescent Measurements; D053758:Nanoparticles; D011108:Polymers / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D011108:Polymers; D054852:Small Molecule Libraries; D004247:DNA; D008156:Luciferases