Synthetic cationic polymers

Synthetic polymers include macromolecules formed from monomers by chemical polymerization reactions. Synthetic polymers possess some significant advantages over natural polymers, such as high purity and better reproducibility. The properties of synthetic polymers, such as degradation rate, hydrophobicity and drug release rate, can be manipulated easily by structural modifications or formulation parameters. Synthetic polymers can be modified and functionalized easily and they allow production of tailor-made nanocarriers. These nanocarriers sustain the release of the encapsulated therapeutics over a period of hours to weeks in an adjustable manner.  

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

Studies show that PEI-grafted methacrylate nanocarriers are capable of transfection and DNA delivery. PEI (MW 25 kDa) also has immu-notherapeutic effects. Studies have showed that PEI reverses TAM polarization and evokes therapeutic anti-tumor immunity in a murine allograft tumor model like cationic dextran derivatives.  

On the other hand, PEI nanocarriers have some toxicity problems. They are reported to show two types of toxicity one of them is immediate toxicity due to free PEI. Free PEI interacts with serum proteins which have a negative charge and also erythrocytes. This interaction results in precipitation in huge clusters, adherence to the cell membrane and damage to the plasma membrane. The other type is delayed toxicity as a consequence of cellular processing of the PEI polyplexes. Another toxicity problem also arises from the linear structure of PEI. When PEI polyplexes were administered via the intravenous route to mice, lethal side effects were observed. On the other hand, linear PEIs have higher transfection efficiency and lower cytotoxicity than branched PEIs, according to several studies.  

To solve these challenges, PEI is conjugated with hydrophilic polymers like PEG. Nanocarriers produced from PEG-PEI copolymers also have a longer circulation time since PEG conjugation prevents opsonization. PEG-PEI (800 kDa) polyplexes were manufactured through grafting of transferrin to PEG and this modification resulted in a five-fold increase in transfection efficiency and decreased toxicity.  

1 Susceptibility of Staphylococcus aureus and Staphylococcus epidermidis Strains to Poly[2-(dimethylaminoethyl)methacrylate] 

Agar diffusion assays were performed to estimate the susceptibility of 11 Staphylococcus aureus and 11 Staphylococcus epidermidis strains. At each of the three concentrations of pDMAEMA tested, Staphylococcus epidermidis was significantly more sensitive than Staphylococcus aureus. Although pDMAEMA (20 mg/ml) partially inhibited the growth of Staphylococcus aureus, such high concentrations are not physiologically relevant [24]. 

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Synthetic cationic polymers have been used in water-based drilling fluids to control shale problems. Recent applications include the use of low molecular weight poly amines (48, 49) some of these cationic polymers are also used for water treatment (48). The use of low molecular weight polyols and glycols has recently been advocated with claims that they act to control both fluid loss and shale hydration (50). 

Plasmid and liposome complexes are easy to produce and are safer, but they have low gene-transfer efficiency. However, novel lipid formulations and synthetic cationic polymer carriers have clearly improved the effectiveness of plasmid-mediated gene transfer [7-9]. 

Polyethylenimine (PEI) is the most outstanding example for synthetic cationic polymers because of its wide range of applications. It can be synthesized in linear (LPEI) as well as in branched (BPEI) structures. LPEI possesses primary and secondary amino groups, whereas BPEI also features tertiary amino groups. BPEI usually has a ratio of primary to secondary to tertiary amino functionalities of 1 2 1 and up to 25% of these amino groups are protonated under physiological conditions. Such buffer capability can also be utilized for endosomal escape mechanisms. The amino... 

In the literature, chitosan nanoparticles have been shown to neutralize the surface charge of liver cancer eells, deerease the membrane potential of mitochondria and indicate lipid peroxidation thus they eause neerotic death. Chitosan nanoparticles form either polyplexes or eneapsulate aetive molecules in their nanoparticle matrix.However, chitosan nanoparticles have lower transfection efficiency than synthetic cationic polymers sueh as polyethylenimine because of their lower endosomal escape. ... 

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. 

Polyamidoamine (PAMAM), polyethylenimine (PEI) and poly[2-(dimethyl-amino)ethyl methacrylate] (PDMAEMA) are widely used as non-viral vectors because of their ability to condense DNA and to form complexes (polyplexes) for more efficient uptake through endoc)d osis. However, it is difficult for these cationic polymers to enter the brain tissue by crossing the BBB. A list of synthetic cationic polymers enabling in vivo and ex vivo transfection to the CNS is provided in Table 17.4. 

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. 

The synthetic cationic polymers are of three types ammonium (primary, secondary, tertiary, and quaternary), sulfonium, and phosphonium compounds (Fig. 14) [25]. Of these, the ammonium-based polymers constitute a large class of materials with diverse applications [papermaking, mineral processing, petroleum recovery, stabilizers for emulsion poly-... 

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