Synthesis of a Series of Folate-Terminated Dendrimer‑b‑PNIPAM Diblock Copolymers: Soft Nanoelements That Self-Assemble into Thermo- and pH-Responsive Spherical Nanocompounds

A series of well-defined bifunctional dendrimers bearing one azide and 5, 15, and 44 folate termini were synthesized via the divergent approach. Poly­(N-isopropylacrylamide) homopolymers PNIPAM-7k, PNIPAM-19k, and PNIPAM-64k were prepared using the reversible addition-fragmentation chain-transfer polymerization (60–67% yield) followed by end functionalization with a cyclooctyne derivative. A grafting-to approach through strain-promoted azide alkyne cycloaddition between the dendrimers and the PNIPAM afforded a series of dendrimer-b-PNIPAM diblock copolymers containing folates (G1-11k, G2-30k, and G3-95k). Investigation of the self-assembly process in aqueous media revealed the formation of thermo- and pH-responsive core–shell spherical micelles within the 70–160 nm size range with low polydispersities. Within the nanoperiodic concept, these dendrimer-b-PNIPAM copolymers behave as S1-type nanoelements that self-assemble into soft:soft spherical nanocompounds with a linear relationship between the molecular weight of the copolymers and the hydrodynamic diameter of the self-assembled nanospheres. The thermo- and pH-responsiveness of the micelles formed by the dendrimer-b-PNIPAM diblock copolymers bearing folates make them promising candidates for targeted drug delivery.