Formation of Dendrimer Nanoassemblies by Oligomerization-Induced Liquid-Liquid Phase Separation

Dendrimers are hyperbranched macromolecules with applications in host-guest chemistry, self-assembly, nanocatalysis, and nanomedicine. We show that dendrimer-based globular nanoparticles are formed by using dendrimer oligomerization to isothermally induce liquid-liquid phase separation (LLPS). We first determined that LLPS of aqueous mixtures of the fourth-generation amino-functionalized poly(amido amine) dendrimer is observed by lowering temperature in the presence of sodium sulfate. In relation to LLPS, we experimentally characterized the effect of salt and dendrimer concentrations on the LLPS temperature and salt-dendrimer isothermal partitioning. Our results were theoretically examined using a two-parameter thermodynamic model. We then showed that the addition of a small amount of glutaraldehyde, which leads to the formation of soluble dendrimer oligomers by chemical cross-linking, increases the LLPS temperature. This implies that a dendrimer aqueous mixture, which is initially homogeneous at room temperature and exhibits LLPS only at relatively low temperatures, can exhibit LLPS at room temperature due to dendrimer oligomerization. The high dendrimer concentration inside the nanodroplets, produced from LLPS, accelerates dendrimer cross-linking, thereby yielding stable globular nanoparticles. These nanomaterials retain the host-guest properties of the initial dendrimers, indicating potential applications as nanocatalysts, extracting agents and drug carriers. Our work provides the basis for a new approach for obtaining dendrimer-based nanoassemblies by employing low-generation dendrimers as building blocks.