Structure-activity relationships of poly(L-lysines): effects of pegylation and molecular shape on physicochemical and biological properties in gene delivery.

The influence of shape, molecular weight and pegylation of linear, grafted, dendritic and branched poly-L-lysines on their DNA delivery properties were investigated. DNA binding, condensation, complex size and morphology, cell uptake and transfection efficiency were determined. Most polylysines condense DNA, linear polymers being more efficient than most dendritic ones. At low molecular weights of PLL DNA binding and condensation were less efficient, particularly with dendrimers. Pegylation did not decrease DNA condensation of PLLs at less than 60% (fraction of M(w)) of PEG. Pegylation stabilized the complexes sterically, but did not protect them from interaction with polyanionic chondroitin sulfate. Cell uptake of polylysine/DNA complexes was high and pegylation increased the transfection efficacy. However, overall transfection level of polylysines is low possibly due to inadequate escape of the complexes from endosomes or poor release of DNA from the complexes. Physicochemical and biological structure-property relationships of poly-L-lysines were demonstrated, but no clear correlations between the tested physicochemical determinants (size of complexes, zeta-potentials, condensation of DNA and the shape of complexes) and biological activities were seen. Transfection activity may be ultimately determined by intracellular factors and/or still unknown features of DNA complexation with the carriers. Copyright 2002 Elsevier Science B.V.