Synthetic cationic polymers gene delivery

Cationic polymers are of particular interest carriers in drug and gene deliveiy because of their ability to promote cellular uptake.This holds also for the delivery of proteins, especially for those that possess an overall anionic charge at pH values above the isoelectric point (p/). These proteins can form soluble, nanosized, polyelectrolyte complexes with natural or synthetic cationic polymers by simply mixing the oppositely charged protein and polymer that self-assemble by electrostatic attraction, as represented in Scheme 14.1. 

The subject of this review is complexes of DNA with synthetic cationic polymers and their application in gene delivery [1 ]. Linear, graft, and comb polymers (flexible, i.e., non-conjugated polymers) are its focus. This review is not meant to be exhaustive but to give representative examples of the various types (chemical structure, architecture, etc.) of synthetic cationic polymers or polyampholytes that can be used to complex DNA. Other interesting synthetic architectures such dendrimers [5-7], dendritic structures/polymers [8, 9], and hyperbranched polymers [10-12] will not be addressed because there are numerous recent valuable reports about their complexes with DNA. Natural or partially synthetic polymers such as polysaccharides (chitosan [13], dextran [14,15], etc.) and peptides [16, 17] for DNA complexation or delivery will not be mentioned. 

Nonviral vector systems are usually either composed of a plasmid based expression cassette alone ( naked DNA), or are prepared with a synthetic amphipathic DNA-complexing agent (84, 88). Gene delivery systems based on nonviral vectors mainly comprise cationic liposomes, DNA-polymer-protein complexes, and mechanic administration of naked DNA. An idealized/optimized multifunctional nonviral gene delivery system is depicted in Figure 13.4. 

The structure of cationic lipids and polymers is readily amenable to chemical modification [35, 36] allowing the exploration of a virtually unlimited number of combinations and strategies at the mercy of chemists creative abilities. Various reviews have been focused on cationic lipids, dendrimers and polymers in terms of their chemical structures and their transfection properties [36—41], in an attempt to shed some light on the chemical requirements necessary to mediate gene delivery. The focus of this chapter will be to explore these carriers from a synthetic perspective, with a description of the chemical strategies used for the preparation via synthetic organic chemistry (excluding polymer synthesis) of cationic lipids and dendrimers. 

Synthetic polymer. Among the cationic synthetic polymers used for gene delivery are polyethylenimine (PEI), polyamidoamine dendrimers, and poly(2-dimethylaminoethyl methacrylate).161-164 Depending on the flexibility (or rigidity) of the polymers, they form either a small (<100 nm) DNA polyplex or a large (>1 to 10 pm) DNA polyplex.165 More detailed physicochemical properties and their transfection efficacy are to be discussed. 

Dextran can be modified easily and cationic derivatives are obtained by reaction with diethylaminoethyl (DEAE) reagents or spermine. DEAE-dextran is one of the pioneer cationic polymers for gene delivery. However, PLL and other synthetic polymers have replaced dextran these days because of low transfection efficiency and toxicity problems of DEAE-dextran. Spermine-dextran (MW 9000-11 000 g mol ) is used as an siRNA delivery agent to cancer cells, with low toxicity and high loading capacity on HeLa-Zwc cells, and was proved to be a safe and effective acid-sensitive carrier for gene delivery by Cohen et al. Researchers showed that cationic dextran derivatives (MW 70 kDa) have also reverse tumor-associated macrophage (TAM) polarization, promote IL-12 expression in tumor TAMs and thereby enhance the tumoricidal capacity of TAMs. ... 

Cationic synthetic polymers such as PEI, PEL and PMA are widely studied for drug and gene delivery systems. ... 

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