Self-Assembling Nucleic Acid Delivery Vehicles via Linear, Water-Soluble, Cyclodextrin-Containing Polymers

Abstract

Non-viral (synthetic) nucleic acid delivery systems have the potential to provide for the practical application of nucleic acid-based therapeutics. We have designed and prepared a tunable, non-viral nucleic acid delivery system that self-assembles with nucleic acids and centers around a new class of polymeric materials; namely, linear, water-soluble cyclodextrin-containing polymers. The relationships between polymer structure and gene delivery are illustrated, and the roles of the cyclodextrin moieties for minimizing toxicity and forming inclusion complexes in the self-assembly processes are highlighted. This vehicle is the first example of a polymer-based gene delivery system formed entirely by self-assembly.

Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles

“…The imidazolated polymer is used because the imidazole moiety has been shown to enhance endosomal escape, thereby increasing delivery efficiency. 9 CDP-Imid self-assembles with the DNAzyme by electrostatic interactions to form small particles called polyplexes. Complete DNAzyme loading in the polyplexes is confirmed by gel electrophoresis.…”

“…Here, AD-gluglu-PEG-gal (gluglu is the anionic segment) is employed to modify the nature of the surface charge of the formulated particles since we have already reported that this component can work well to vary particle zeta potentials. 9 The extent of DNAzyme complexation was monitored by gel electro-phoresis. Polyplexes were prepared as described above.…”

“…9 The first component of this system is a short (approximately five repeat units giving on average ten charges per polymer chain), cyclodextrin-containing polycation (CDP, Fig. 1A) that can self-assemble with nucleic acids via electrostatic interactions and form uniformly sized, sub-100 nm particles termed "polyplexes" 10 ( Fig.…”

“…[29][30][31] For example, DNAzymes targeting the translation initiation region of c-myc RNA have been reported to site-selectively cleave full length RNA and downregulate c-myc gene expression in smooth muscle cells. 30,31 The objective of this work is to assess the ability of the cyclodextrincontaining polycation delivery system 9,11,16 to provide for the in vivo delivery of anti-c-myc DNAzymes 30,31 to subcutaneous tumors in mice. The study focuses on the preparation of transferrin-modified polyplexes and their biodistribution in tumor-containing nude mice.…”

Bifunctional compounds for targeted hepatic gene delivery

“…These include various cationic lipids, 1-3 different forms of polyethyleneimine (PEI), 4-9 modified polylysine, 10,11 dendrimers, [12][13][14] chitosan, [15][16][17][18] block copolymers, [19][20][21] and cyclodextrincontaining polycations. 22,23 The predominant role of these synthetic or naturally occurring compounds is to form nuclease-resistant complexes with DNA that can be effectively endocytosed by a cell. The delivery efficiency of these gene carriers varies depending on their chemical structure, target cell type and excipients included in the formulation.…”