Nonviral Vectors for the Delivery of Small Interfering RNAs to the CNS

Inmaculada Posadas; Francisco Javier Guerra; Valentín Ceña

Disclosures

Nanomedicine. 2010;5(8):1219-1236. 

In This Article

Natural Polymers: Chitosan & Collagen

Chitosans, a family of linear binary polysaccharides composed of β (1–4)-linked 2-amino-2-deoxy-β-D-glucose (D-unit) and the N-acetylated analog (A-unit), are naturally derived cationic polysaccharides that are highly attractive as drug and gene delivery candidates.[36]

The interest in chitosans arises from their availability, excellent safety profile, biodegradability, ease of modification and unique biological properties related to their polycationic nature. Chitosan is a weak polybase with a pKa approaching 6.6 at 25°C and physiological ionic strength.[37] Accordingly, the charge density of chitosan at pH 7.4 is very low and generic chitosans are insoluble. The broad variety of available chitosans and their structure-dependent sensitivity to pH and ionic conditions may be a reason for the highly variable efficacy of chitosan-based gene delivery systems reported in the literature.

However, this system has a significant limitation, owing to its low transfection efficiency.[38] The transfection efficiency of chitosan/DNA complexes is dependent on several factors, including the degree of deacetylation and MW of the chitosan, plasmid concentration, charge ratio of amine (chitosan) to phosphate (DNA), serum concentration, pH and cell type.[39] Although most chitosans are able to compact DNA into nanosized polyplexes, the stability and properties of the formed polyplexes strongly depend upon chitosan structural variables.[40,41] It has been suggested that the key to successful transfection with chitosan is to achieve a subtle balance between DNA protection and intracellular DNA release.[42,43]

Several studies have promoted the use of high-MW chitosans,[44] but others have found that lower MW chitosans were superior for gene transfer.[38] It has been shown that a chitosan with a MW of 10 kDa and a fraction of acetylated units (FA) 0.08–0.2 was particularly efficient, compared with chitosans with MW of 40 kDa and higher.[45] Besides these potential problems for therapeutic use, one of the promising fields for the use of chitosan-based NPs lies in its use in mucosal (intranasal) delivery of insulin[46] and DNA,[47] due to its high colloidal stability in biological fluids.

Collagen is another important natural polymer. Modified collagen, such as atelocollagen, which is obtained after removal of telopeptides, has been investigated for a wide range of drug and gene delivery methods. Complexation of pDNA and atelocollagen in an implanted pellet has been shown to prolong the residence time of applied pDNA.[48] Conversely, Wang et al. compared the transfection levels achieved between native collagen and methylated collagen complexed with a luciferase encoding plasmid, both in vitro and in vivo. Methylated collagen/DNA particles were more condensed and exhibited a higher charge density at pH 7.4 than native collagen/DNA particles at pH 3. Once at neutral pH, native collagen/DNA particles aggregated significantly and became destabilized, thus indicating the better transfection rates obtained when methylated collagen was used.[49]

Gelatin, the denatured form of collagen, has also been shown to be a viable gene delivery vehicle. In a cystic fibrosis model, in vitro transfection of human bronchial epithelial cells defective in cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transport, using a gelatin/CFTR plasmid (pCFTR), resulted in functional recovery of transport.[50]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....