title: Surface modified poly(β amino ester)-containing nanoparticles for plasmid DNA delivery.
abstract: The use of biodegradable polymers provides a potentially safe and effective alternative to viral and liposomal vectors for the delivery of plasmid DNA to cells for gene therapy applications. In this work we describe the formulation of a novel nanoparticle (NP) system containing a blend of poly(lactic-co-glycolic acid) and a representative poly(beta-amino) ester (PLGA and PBAE respectively) for use as gene delivery vehicles. Particles of different weight/weight (wt/wt) ratios of the two polymers were characterized for size, morphology, plasmid DNA (pDNA) loading and surface charge. NPs containing PBAE were more effective at cellular internalization and transfection (COS-7 and CFBE41o-) than NPs lacking the PBAE polymer. However, along with these delivery benefits, PBAE exhibited cytotoxic effects that presented an engineering challenge. Surface coating of these blended particles with the cell-penetrating peptides (CPPs) mTAT, bPrPp and MPG via a PEGylated phospholipid linker (DSPE-PEG2000) resulted in NPs that reduced surface charge and cellular toxicity to levels comparable with NPs formulated with only PLGA. Additionally, these coated nanoparticles showed an improvement in pDNA loading, intracellular uptake and transfection efficiency, when compared to NPs lacking the surface coating. Although all particles with a CPP coating outperformed unmodified NPs, respectively, bPrPp and MPG coating resulted in 3 and 4.5× more pDNA loading than unmodified particles and approximately an order of magnitude improvement on transfection efficiency in CFBE41o- cells. These results demonstrate that surface-modified PBAE containing NPs are a highly effective and minimally toxic platform for pDNA delivery.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Fields
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Elias
authors.initials: E
authors.lastname: Quijano
authors.forename: Caroline
authors.initials: C
authors.lastname: Weller
authors.forename: Nina
authors.initials: N
authors.lastname: Kristofik
authors.forename: Nha
authors.initials: N
authors.lastname: Duong
authors.forename: Christopher
authors.initials: C
authors.lastname: Hoimes
authors.forename: Marie E
authors.initials: ME
authors.lastname: Egan
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects / Q000737:chemistry*; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D004337:Drug Carriers / Q000009:adverse effects / Q000737:chemistry*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000235:genetics; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry*; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics; D011108:Polymers / Q000009:adverse effects / Q000737:chemistry*; D012995:Solubility; D013499:Surface Properties; D014162:Transfection
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D011108:Polymers; C507253:poly(beta-amino ester); D049452:Green Fluorescent Proteins; D004247:DNA; D008156:Luciferases