Structural Effects of Carbohydrate-Containing Polycations on Gene Delivery. 3. Cyclodextrin Type and Functionalization

Abstract

Linear cationic beta-cyclodextrin (beta-CD)-based polymers can form polyplexes with plasmid DNA and transfect cultured cells. The effectiveness of the gene delivery and the cellular toxicity has been related to structural features in these polycations. Previous beta-CD polycations were prepared from the cocondensation of 6(A),6(D)-dideoxy-6(A),6(D)-diamino-beta-CD monomers with other difunctionalized monomers such as dimethyl suberimidate (DMS). Here, the type of CD and its functionalization are varied by synthesizing numerous 3(A),3(B)-dideoxy-3(A),3(B)-diamino-beta- and gamma-CD monomers. Both alkyl- and alkoxydiamines are prepared in order to vary the nature of the spacing between the CD and the primary amines in the monomers. These diamino-CD-monomers are polymerized with DMS to yield amidine-based polycations. The nature of the spacer between the CD-ring and the primary amines of each monomer is found to influence both molecular weight and polydispersity of the polycations. When these polycations are used to form polyplexes with plasmid DNA, longer alkyl regions between the CD and the charge centers in the polycation backbone increase transfection efficiency and toxicity in BHK-21 cells, while increasing hydrophilicity of the spacer (alkoxy versus alkyl) provides for lower toxicity. Further, gamma-CD-based polycations are shown to be less toxic than otherwise identical beta-CD-based polycations.

Supramolecular Polymers Based on Cyclodextrins for Drug and Gene Delivery

“…The first CD-containing cationic polymer for gene delivery was reported in 1999 [104,105]. So far, the same group has developed a set of such CD-containing polymers and studied the structural effects of the polymers on gene delivery [27,28,106]. Generally, the CD-containing cationic polymers showed lower cytotoxicity and efficient gene transfection.…”

Cationic Polymers for the Delivery of Therapeutic Nucleotides

“…Cytotoxicity of these complexes has been found to be dependent on the alkyl chain length between CD units; it generally decreases with longer chain lengths (Hwang et al 2001). Further, polymers containing 4-10 carbon alkyl chains between CD units have been found to display less toxicity, higher transfection efficiency, but less water solubility (Popielarski et al 2003).…”

Medical Polymer-Based Gene Therapy

“…β-CD containing cationic polymers efficiently condensed DNA to small particles and showed nontoxic and high gene transfection efficiency. The same group has developed a set of such CD-containing polymers and studied the structural effects of the polymers on gene delivery (Popielarski, et al, 2003. In general, the CD-containing cationic polymers showed lower cytotoxicity and efficient gene transfection in vitro.…”