Cyclodextrin-Containing Polymers: Versatile Platforms of Drug Delivery Materials

Table 4

Parameters and result summaries for early investigations of polymer structure-activity relationships (SARs).

Parameter	Variants tested	Results/trends	Reference(s)
Carbohydrate size	(i) Trehalose; (ii) α-CD; (iii) β-CD; (iv) γ-CD; (v) (hexane)	(i) The absence of a carbohydrate produces high toxicity and reduces water solubility; (ii) CD-containing species had comparable properties	[29]
Carbohydrate distance from charge centers (spacer length) and hydrophilicity of the spacer	(i) 4, 5, 6, 7, and 8 versus 10 methylene units (ii) alkyl versus alkoxy spacers	(i) Transfection efficiency is dependent on distance from charge centers, with up to 20-fold difference among β-CD-containing polymers	[28, 29, 31]
		(ii) As the charge center is further removed from the carbohydrate unit, the toxicity is increased
		(iii) Optimum transfection is achieved with a spacer length of 6 methylene units
		(iv) Increasing hydrophilicity of the spacer (alkoxy versus alkyl) provides for lower toxicity
Cyclodextrin functionalization	(i) 6^A,6^D-Dideoxy-6^A,6^D-Diamino-β-CD (ii) 3^A,3^D-Dideoxy-3^A,3^D-Diamino-β-CD (iii) 3^A,3^B-Dideoxy-3^A,3^B-Diamino-γ-CD	(i) The structure of diaminated CD monomers was found to influence both the molecular weight and polydispersity of polycations resulting from reaction of these compounds with dimethylsuberimidate (DMS)	[31]
		(ii) Longer alkyl regions in the polycation backbone increased transfection efficiency and toxicity, while increasing hydrophilicity was toxicity reducing
		(iii) γ-CD polycations were shown to be less toxic than otherwise identical β-CD polycations
Charge center type	(i) Amidine(ii) Quaternary ammonium	(i) Quaternary ammonium analogues exhibit lower gene expression values and similar toxicities to their amidine analogues	[30]
Termini	(i) Primary amine (ii) Histidine (iii) Imidazole	(i) Incorporation of pH-buffering moiety to polymer termini increases gene delivery, buffers acidification experienced by nanoparticles, and enhances intracellular release of nucleic acid payload	[33–35]