Research Paper

Pharmaceutical Research

, Volume 27, Issue 11, pp 2260-2273

First online:

pH-Sensitive Multi-PEGylated Block Copolymer as a Bioresponsive pDNA Delivery Vector

  • Tsz Chung LaiAffiliated withDivision of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin – Madison
  • , Younsoo BaeAffiliated withDivision of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky
  • , Takayuki YoshidaAffiliated withAstellas Pharma Inc.
  • , Kazunori KataokaAffiliated withDepartment of Materials Engineering, Graduate School of Engineering, The University of Tokyo
  • , Glen S. KwonAffiliated withDivision of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin – Madison Email author 

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ABSTRACT

Purpose

A reversibly-PEGylated diblock copolymer, poly(aspartate-hydrazide-poly(ethylene glycol))-block-poly(aspartate-diaminoethane) (p[Asp(Hyd-PEG)]-b-p[Asp(DET)]) was reported here for enhanced gene transfection and colloidal stability. The diblock copolymer possessed a unique architecture based on a poly(aspartamide) backbone. The first block, p[Asp(Hyd)], was used for multi-PEG conjugations, and the second block, p[Asp(DET)], was used for DNA condensation and endosomal escape.

Methods

p[Asp(Hyd-PEG)]-b-p[Asp(DET)] was synthesized and characterized by 1H-NMR. Polyplexes were formed by mixing the synthesized polymers and pDNA. The polyplex size, ζ-potential, and in vitro transfection efficiency were determined by dynamic light scattering, ζ-potential measurements, and luciferase assays, respectively. pH-dependent release of PEG from the polymer was monitored by cationic-exchange chromatography.

Results

The polyplexes were 70–90 nm in size, and the surface charge was effectively shielded by a PEG layer. The transfection efficiency of the reversibly PEGylated polyplexes was confirmed to be comparable to that of the non-PEGylated counterparts and 1,000 times higher than that of the irreversibly PEGylated polyplexes. PEG release was demonstrated to be pH-sensitive. Fifty percent of the PEG was released within 30 min at pH 5, while the polymer incubated at pH 7.4 could still maintain 50% of PEG after 8 h.

Conclusion

The reversibly PEGylated polyplexes were shown to maintain polyplex stability without compromising transfection efficiency.

KEY WORDS

non-viral gene delivery PEG pH-sensitive polyplex