Post-nuclear gene delivery events for transgene expression by biocleavable polyrotaxanes

Abstract

2 ABSTRACTA quantitative comparison between nuclear DNA release from carriers and their transfection activity would be highly useful for improving the effectiveness of non-viral gene vectors. We previously reported that, for condensed DNA particles, a close relationship exists between the efficiency of DNA release and transfection activity, when biocleavable polyrotaxanes (DMAE-SS-PRX), in which the cationic density can be easily controlled. In this study, we first investigated the efficiencies of DNA release from condensed DNA particles with various types of DMAE-SS-PRX. The findings indicate that an optimal cationic density in DMAE-SS-PRX exists for DNA release. We then packaged condensed DNA particles in a multifunctional envelope-type nano device (MEND), and evaluated their transfection activities. The results showed that the transfection activity was increased and this increase was, to some extent, dependent on the efficiency of the DNA release. However, transfection activity decreased, when the value for the efficiency of DNA release was higher than a certain value. An investigation of the fate of intranuclear DNA indicated that a very high efficiency of DNA release has a positive influence on transcription, however, it would inhibit the post-transcription process; nuclear mRNA export, translation and related processes.Such information provides a new viewpoint for the development of cationic polymer-based vectors.

Hyaluronic acid controls the uptake pathway and intracellular trafficking of an octaarginine-modified gene vector in CD44 positive- and CD44 negative-cells

“…However, the values were decreased in the case of both the HA-R8/GALA-MEND and the R8/GALA-MEND, when 1 μg of pDNA was transfected to the cell. A previous report showed that excess free cations 26 released from the gene vectors inhibited the post-transcription process including nuclear mRNA export and the translation process, resulting in low transgene expression [21].…”

Threaded macromolecules as a versatile framework for biomaterials

“…In addition to the biocleavable DMAE-SS-PRX, various PRXs or pseudopolyrotaxanes, such as Pluronic/β-CD, PEG/α-CD, PPG/β-CD, poly[(ethylene glycol)-ran-(propylene glycol)]/α-CD, ionene/α-CD, and linear PEI/γ-CD, have been studied for pDNA delivery. [118][119][120][121][122][123][124][125] These cationic PRX-based carrier systems have been utilized in the delivery of siRNA. For example, PEG/α-CD and ionene/α-CD PRXs have been reported to demonstrate the potential ability of cationic PRXs in siRNA delivery.…”

Cationic α-Cyclodextrin:Poly(ethylene glycol) Polyrotaxanes for siRNA Delivery

“…Cationic α-CD PR have been synthesized where the endcaps are linked via disulfide bonds, rendering them degradable in the reducing environment of the cell 26-28 . PR:pDNA complexes also have been encapsulated within a lipid bilayer to improve their biological performance.…”