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

Abstract

RNA interference has broad therapeutic potential due to its high specificity and ability to potentially evade drug resistance. Three cationic α-cyclodextrin:poly(ethylene glycol) polyrotaxanes derived from polymer axle different sizes (MW 2000, 3400 and 10000) have been synthesized for delivering siRNA. These polyrotaxanes are able to condense siRNA into positively charged particles that are < 200 nm in diameter, enabling their facile internalization into mammalian cells. The cationic polyrotaxanes display cytotoxicity profiles that are >102-fold lower than the commercial standard bPEI and gene silencing efficiencies that are comparable to both Lipofectamine 2000 and bPEI. Our findings suggest that the cationic polyrotaxanes display a size-activity relationship, wherein, the higher molecular weight polyrotaxanes (PEG3400 and 10000) are able to condense and deliver siRNA better than the lower molecular weight material (PEG2000).

Poly(ethylene glycol)-block-cationic polylactide nanocomplexes of differing charge density for gene delivery

“…A variety of biodegradable CPs such as poly(b-amino ester)s [14e17], poly[a-(4-aminobutyl)-L-glycolic acid] [18], poly(4-hydroxy-L-proline ester) [19], poly(D-glucaramidoamine) [20], cationic poly(a-hydroxy acid) [21], and cationic cyclodextrin [22] have been successfully synthesized and used in gene delivery studies. In addition to protecting therapeutic genes from nuclease degradation, synthetic design of CPs can be directed to optimize their biodegradability and improve their biocompatibility for repeated administration of gene-based therapies [23,24]. In particular, the intracellular cleavage of the biodegradable polymer backbone aids nanocomplexes in unpacking gene payloads, and effective cytosolic release of nucleic acids from nanocomplexes was reported to be positively correlated with enhanced gene transfection [25,26].…”

Recent progress in gene therapy to deliver nucleic acids with multivalent cationic vectors

“…20 cationic polymer derivatives from PEI [127], PAA [103] or POEAA [144], chitosan [197], amphiphatic homopolymers [198], diblock copolymers [105], dendrimers [199,200], glycopolycations [104,108], pendant polymer-cationic cyclodextrins [167] and cationic polymer-cyclodextrin polyrotaxanes [88,168]. In general, biological activity (as silencing vectors) reported by lipoplexes (with GCLs or MVCLs) is higher than that reported by polyplexes.…”

“…Fig. 4 shows, as an example, tipical SAXS diffractograms (intensity vs q factor) of the (C 16 Am) 2 C 2 /DOPE-pDNA lipoplex [54] polycations [40,136,165,166], or cationic polyrotaxanes [89]; and (b) siRNA with cationic polymers [167], or polyrotaxanes [88,168]. Fig.…”

“…Fig. 9 shows a plot of the % GFP for several α-CD:PEG-siRNA polyplexes that informs about the knockdown efficacy of the several cationic polyrotaxanes (CDPR + ) [168]. Results show that CDPR + based on 10k PEG with 1−2 cationic charges per CD may be a promising siRNA delivery agent for sensitive cell types.…”

“…22 polycation derivatives from calixarene [40,192] or cyclodextrin [106,134,142,164,193]; (v) pendant polymer-cationic cyclodextrins [129,167]; and (vi) cationic polymercyclodexdtrin polyrotaxanes [88,89,168]. These studies have reported that: a) GCLs and MVCLs offer a better cell viability than the positive controls (Lipo2000 or PEI)…”