Polymer Structure, Cytotoxicity and Biocompatibility Relationships

The cytotoxicity of cationic polymers is seen as a major limiting factor in their success as drug or gene delivery vectors. Mechanisms of cytotoxicity caused by polycations is not yet fully understood however, mechanisms are thought to be influenced by different properties of the polymers, such as (i) MW, (ii) charge density and type of the cationic functionalities, (iii) structure and sequence, such as block, random, linear and branched, and finally (iv) conformational flexibility.  

The second phase, proposed by Moghimi et al., was said to occur 24 h after exposure, and consisted of a loss of mitochondrial membrane potential which was revealed by translocation of phosphatidylserine as a consequence of PEI-induced channel formation. This led to release of the pro-apoptotic cytochrome c and subsequent activation of caspases-3 triggering apoptosis. Mitochondrial-mediated apoptotic events induced by polycations have also been reported in cell lines treated with high MW PLL in free form, DNA polyplexes and PAMAM dendrimers. In the study by Lee et al., PAMAM dendrimers around 45 nm in size exhibited mitochondrial co-localization, decreased expression of mitochondrial genes and mitochondria membrane 

There have been a number of strategies to reduce the cytotoxicity of cationic polymers for their use in various drug and gene delivery systems (Table 18.2). 

Compliment activation Reduce chain length/mask surface charge 129 

Inflammatory response PEGylation to shield surface charge 147 

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