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

Starting from bis-MPA, PEG–PLLA triblock copolymers (bis-MPA-(PLLA–PEG)2), comprising a central N-hydroxysuccinimide active ester, were synthesized. Reacting the corresponding active ester with α,ω-diamines afforded four-armed (PEG–PLLA)2–R–(PLLA–PEG)2 copolymers with central α,ω-diamide groups (R). Applying the α,ω-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.