Biocleavable Polyrotaxane−Plasmid DNA Polyplex for Enhanced Gene Delivery

Abstract

A biocleavable polyrotaxane, having a necklace-like structure consisting of many cationic alpha-cyclodextrins (alpha-CDs) and a disulfide-introduced poly(ethylene glycol) (PEG), was synthesized and examined as a nonviral gene carrier. The polyrotaxane formed a stable polyplex having positively charged surface even at low charge ratio. This is likely to be due to structural factors of the polyrotaxane, such as the mobile motion of alpha-CDs in the necklace-like structure. Rapid endosomal escape was observed 90 min after transfection. The positively charged surface and the good buffering capacity are advantageous to show the proton sponge effect. The pDNA decondensation occurred through disulfide cleavage of the polyrotaxane and subsequent supramolecular dissociation of the noncovalent linkages between alpha-CDs and PEG. Transfection of the DMAE-SS-PRX polyplex is independent of the amount of free polycation. Those properties played a key role for delivery of pDNA clusters to the nucleus. Therefore, the polyplex nature and the supramolecular dissociation of the polyrotaxane contributed to the enhanced gene delivery.

Cellular delivery of polynucleotides by cationic cyclodextrin polyrotaxanes

“…PEG-based polyrotaxanes have been further modified with cationic dimethylaminoethyl groups by a statistic approach [25].…”

“…Especially those cationic CD polyrotaxanes, in which stopper groups had been linked via bioreducible disulfide bonds, were specifically effective for intracellular delivery of pDNA [25,26].…”

pH-responsive dendritic polyrotaxane drug-polymer conjugates forming nanoparticles as efficient drug delivery system for cancer therapy

“…[27][28][29][30][31][32] Among the various supramolecular assemblies, CD-based (Pseudo) polyrotaxanes have been extensively studies for their uses as carriers in drug delivery, such as thermo-/pH-sensitive hydrogels, [33][34][35] vesicles and micelles, as carriers for the controlled drug release 36 and gene carriers. [37][38][39] However, (Pseudo) polyrotaxanes, self-assembled from cyclodextrins (CDs) and polyesters, were apt to form crystallized precipitate in most of the solvent, especially in water, which profoundly limited their development in biomedical applications. In this article, amphiphilic block copolymers with novel architecture, a pH-sensitive amphiphilic dendritic polyrotaxane polymer-drug conjugate (PR-g-DOX), were successfully developed through a highly efficient approach.…”

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

“…To date, we reported on the development of an innovative gene delivery system [10,11], prepared by integrating a multifunctional envelope-type nano device (MEND) [5,[12][13][14] and a biocleavable polyrotaxane (DMAE-SS-PRX) [15][16][17] (Fig. 1B).…”

“…On the other hand, DMAE-SS-PRX is an artificial DNA condenser [15][16][17], which can condense pDNA and then release it under intracellular reductive conditions. We concluded that DMAE-SS-PRX would be an appropriate model polycation for investigating the relationship between the DNA release in nucleus and transfection activity, because the cationic density in a DMAE-SS-PRX-molecule can be easily controlled, thus permitting the efficiency of DNA release to be adjusted [16].…”