Efficiency of Cytosolic Delivery with Poly(β-amino ester) Nanoparticles is Dependent on the Effective p Kaof the Polymer

Denis Routkevitch, Deepti Sudhakar, Marranne Conge, Mahita Varanasi, Stephany Y. Tzeng, David R. Wilson, Jordan J. Green

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanism by which cationic polymers containing titratable amines mediate effective endosomal escape and cytosolic delivery of nucleic acids is not well understood despite the decades of research devoted to these materials. Here, we utilize multiple assays investigating the endosomal escape step associated with plasmid delivery by polyethylenimine (PEI) and poly(β-amino esters) (PBAEs) to improve the understanding of how these cationic polymers enable gene delivery. To probe the role of these materials in facilitating endosomal escape, we utilized vesicle membrane leakage and extracellular pH modulation assays to demonstrate the influence of polymer buffering capacity and effective pKa on the delivery of the plasmid DNA. Our results demonstrate that transfection with PBAEs is highly sensitive to the effective pKa of the overall polymer, which has broad implications for transfection. In more acidic environments, PBAE-mediated transfection was inhibited, while PEI was relatively unaffected. In neutral to basic environments, PBAEs have high buffering capacities that led to dramatically improved transfection efficacy. The cellular uptake of polymeric nanoparticles overall was unchanged as a function of pH, indicating that microenvironmental acidity was important for downstream intracellular delivery efficiency. Overall, this study motivates the use of polymer chemical characteristics, such as effective pKa values, to more efficiently evaluate new polymeric materials for enhanced intracellular delivery characteristics.

Original languageEnglish (US)
Pages (from-to)3411-3421
Number of pages11
JournalACS Biomaterials Science and Engineering
Volume6
Issue number6
DOIs
StatePublished - Jun 8 2020

Keywords

  • endosome
  • gene delivery
  • nanoparticle
  • p K
  • poly(β-amino ester)
  • polyethylenimine

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering

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