Proton sponge effect

Once internalized, the essential step for the polyplex is to escape rapidly the endosomal vesicle in order to release the nucleic acid in the cytosol and prevent its lysosomal degradation. As the endosomal and lysosomal pH presents values between 4.5 and 6.5 and therefore differs from the neutral pH of 7.4 in other biological compartments [58], some polycations containing protonable residues like PEI facilitate this step by the proton sponge effect [59, 60]. As not all cationic polymers display this attribute, another effective method for enhanced endosomal polyplex release is incorporation of specific endosomal membrane disrupting or pore-forming domains, such as lytic lipid moieties or endosomolytic peptides. 

A possible explanation was that the proton sponge effect, as discussed later, may be more efficient with larger complexes. Larger particles may also sediment to interact with cells more readily under in vitro culture conditions... 

Because the acetal-PEG-ODN conjugate is one of the homologs of PEG/polyanion block copolymers, it is expected that the conjugate will, based on the electrostatic interaction, mix with the appropriate polycation and, thus, form a PIC micelle. Linear-PEI was chosen as the counter polycation because it has often been used for the gene delivery of DNA/L-PEl complexes and displays high transfection efficiency, which is due to the buffer or proton-sponge effect (51). So that the PIC micelle... 

Poly(2-dimethylamino)ethyl methacrylate (pDMAEMA) is a water-soluble cationic pol3maer that contains tertiary amines and shows the proton sponge effect to some extent due to pKa=7.5. Approximately 50% of the amines are protonated at pH 7.2 impl3rmg that the other 50% participate in buffering. The absence of primary and secondary amines indicates that pDMAEMA binds relatively loosely to pDNA compared to polycations such as PEI-25K and other high MW PEI. It has been shown to condense pDNA into 150-180 nm size particles and mediate transfection in different cell types. However, complexes with pDMAEMA are not very stable in physiological salt and serum and since they do not possess attributes other than DNA condensation and modest endoso-mal buffering, attempts have been made to modify them (71)... 

The proton sponge effect was first proposed by Behr and co-workers. The proton sponge nature of PEI and other materials, which display relatively high transfection efficiencies, such as lipopolyamines, PAMAM den-drimers and various imidazole-containing polymers, is thought... 

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