“Single–Single” Amphiphilic Janus Dendrimers Self-Assemble into Uniform Dendrimersomes with Predictable Size

Abstract

An accelerated modular synthesis of six libraries containing 29 amphiphilic Janus dendrimers, employed to discover and predict functions via primary structures, is reported. These dendrimers were constructed from a single hydrophobic and a single hydrophilic dendron, interconnected with l-Ala to form two constitutional isomeric libraries, with Gly to produce one library, and with l-propanediol ester to generate two additional constitutional isomeric libraries. They are denoted "single-single" amphiphilic Janus dendrimers. Assemblies obtained by injection of their ethanol solution into water were analyzed by dynamic light scattering and cryogenic transmission electron microscopy. A diversity of complex structures including soft and hard dendrimersomes, cubosomes, solid lamellae, and rod-like micelles were obtained in water. It was discovered that the "single-single" amphiphilic Janus dendrimers containing three triethylene glycol groups in the hydrophilic dendron favored the formation of dendrimersomes. Assemblies in bulk analyzed by differential scanning calorimetry and powder X-ray diffraction revealed that the amphiphilic Janus dendrimers with melting point or glass transition below room temperature self-assemble into soft dendrimersomes in water, while those with higher temperature transitions produce hard assemblies. In the range of concentrations where their size distribution is narrow, the diameter of the dendrimersomes is predictable by the d-spacing of their assemblies in bulk. These results suggested the synthesis of Library 6 containing two simpler constitutional isomeric benzyl ester based amphiphilic Janus dendrimers that self-assemble in water into soft dendrimersomes and multidendrimersome dendrimersomes with predictable dimensions.

Self-assembly of amphiphilic Janus dendrimers into uniform onion-like dendrimersomes with predictable size and number of bilayers

“…Regardless of the nature of the solvent, it was determined by cryo-TEM that the thickness of the bilayer of the onion-like dendrimersomes was about 5.55 nm, which is almost equal to that of the bilayer determined by X-ray diffraction in bulk (SI Appendix, Table S3 and Fig. S11) (28). Less-regular shapes with nonuniform spacing between bilayers were obtained from isopropanol and ethanol.…”

“…2). "Single-single" amphiphilic Janus dendrimer refers to a compound constructed from a "single" hydrophilic and a "single" hydrophobic dendron (28), rather than from "twin" hydrophilic and "twin" hydrophobic dendrons (26,27). This modular synthetic approach involves coupling of the hydrophilic acids 3b and 5a-e with the hydrophobic amine minidendron (41) 8a, or hydrophobic acid minidendron 3a with the hydrophilic amine 8b.…”

“…By using a constitutional isomeric library approach elaborated previously (28,35), six primary structures of single-single amphiphilic Janus minidendrimers that self-assemble into uniform onion-like dendrimersomes by simple injection in water and buffers have been discovered. These onion-like vesicles were assembled by two extremely easy-to-handle direct and reverse injection methods.…”

“…and short notations of these single-single (28) amphiphilic Janus dendrimers are summarized in Fig. 2.…”

“…Polymersomes (21)(22)(23)(24) assembled from amphiphilic block copolymers exhibit better mechanical properties and permeability, but are not always biocompatible and are polydisperse. Dendrimersomes (25)(26)(27)(28) self-assembled from amphiphilic Janus dendrimers and minidendrimers (26)(27)(28) have also been elaborated to mimic single-bilayer biological membranes. Amphiphilic Janus dendrimers take advantage of multivalency both in their hydrophobic and hydrophilic parts (23, [29][30][31][32].…”