Accessing Lipophilic Ligands in Dendrimer‐Based Amphiphilic Supramolecular Assemblies for Protein‐Induced Disassembly

Abstract

Supramolecular nanoassemblies that respond to the presence of proteins are of great interest, as aberrations in protein concentrations represent the primary imbalances found in a diseased state. We present here a molecular design, syntheses, and study of facially amphiphilic dendrimers that respond to the presence of the protein, immunoglobulin G. It is of particular interest that the ligand functionality, utilized for causing the binding-induced disassembly, be lipophilic. Demonstration of binding with lipophilic ligands greatly expands the repertoire of binding-induced disassembly, since this covers a rather large class of ligand moieties designed for proteins and these provide specific insights into the mechanistic pathways that are available for the binding-induced disassembly process. Here, we describe the details of the binding induced disassembly, including the change in size of the assembly in response to proteins, concurrent release of noncovalently encapsulated guest molecules, and the specificity of the disassembly process.

Experimental and theoretical investigations in stimuli responsive dendrimer-based assemblies

“…To test this possibility, we also designed a dendrimer system using dinitrophenyl (DNP) moiety as the hydrophobic ligand functionality, which is complementary to anti-DNP immunoglobulin G (IgG). 118 Indeed, we were able to show that the binding induced disassembly possibility does exist and is likely due to the equilibrium between the unimeric and the aggregated states of the amphiphilic dendrimer assembly. Even though such equilibrium should heavily favour the aggregated state of the amphiphile, a Le Chatelier type effect should be sufficient to funnel the bound dendrons towards the disassembled state.…”

Stimuli sensitive amphiphilic dendrimers

“…Studies with ligand on the hydrophobic side of the dendrimer also resulted in protein-induced disassembly, highlighting the role that the dendrimer-aggregate equilibrium can play in the disassembly process. 91 …”

Protein AND Enzyme Gated Supramolecular Disassembly

“…Therefore, protein-responsive disassembly has been of recent interest. 11 Considering the decisive advantages of multi-stimuli responsive assemblies, we were interested in addressing the challenge of designing a system that not only responds to proteins, but also that would respond only due to the concurrent presence of two different proteins. We demonstrate a versatile new molecular design that allows for such a supramolecular disassembly, illustrated in Figure 1.…”

“…We have previously shown that micelle-like supramolecular aggregates, from facially amphiphilic molecules, can be disassembled due to a ligand-protein binding event. 11c The disassembly occurs due to the change in the hydrophilic-lipophilic balance caused by the protein binding, i.e . the protein binding causes the equilibrium to shift to the monomeric state of the amphiphile (represented as equilibrium b in Figure 1).…”

“…However, analogous assemblies do have a hydrophobic core and are solid structures. 11a,c,e,12 The assembly size was monitored for a 24 hour time period and the size of the assembly in solution did not change over this time period (Figure S2 a,b). Probing these by transmission electron microscopy (TEM) showed that these molecules indeed form spherical assemblies (Figure S2c).…”