Introducing small cationic groups into 4-armed PLLAePEG copolymers leads to preferred micellization over thermo-reversible gelation

Starting from bis-MPA, PEGePLLA triblock copolymers (bis-MPA-(PLLAePEG)2), comprising a central Nhydroxysuccinimide active ester, were synthesized. Reacting the corresponding active ester with a,udiamines afforded four-armed (PEGePLLA)2eRe(PLLAePEG)2 copolymers with central a,u-diamide groups (R). Applying the a,u-diamines, hexamethylene-diamine, spermine or norspermidine none, one or two secondary amine groups, respectively, were introduced into the linking moiety R. Whereas a copolymer containing no secondary amine groups showed fully thermo-reversible gelation behavior, copolymers comprising a central moiety containing one or two secondary amine groups retained the ‘sol’ state after a few heating and cooling cycles. Dynamic light scattering revealed that the copolymer containing no secondary amine groups showed a thermo-reversible shift in micellar size and small aggregates (57 and 877 nm at 25 C and 40 and 152 nm at 50 C). Conversely, copolymers comprising a central moiety containing secondary amine groups show a temperature independent distribution mainly consisting of micelles. It is proposed that the protonated amine groups preferably are located at the corona of the micelles and micellar aggregates and/or shielded by the PEG blocks, hindering the formation of hydrogels by PEG entanglements upon a change in temperature.