Multiple Routes to Bicontinuous Cubic Liquid Crystal Phases Discovered by High-Throughput Self-Assembly Screening of Multi-Tail Lipidoids

Abstract

Bicontinuous cubic phases offer advantageous routes to a broad range of applied materials ranging from drug delivery devices to membranes. However, a priori design of molecules that assemble into these phases remains a technological challenge. In this article, high-throughput synthesis of lipidoids which undergo protonation-driven self-assembly (PrSA) into liquid crystalline phases is conducted. With this screening approach we discover 12 different multi-tail lipidoid structures capable of assembling into the bicontinuous double gyroid phase. The large quantity of morphological data uncovers unexpected design criteria that enable phase selection as a function of lipidoid headgroup size and architecture, tail length and architecture and counterion identity. Surprisingly, combining branched headgroups with bulky tails forces lipidoids to adopt unconventional pseudo-disc conformations that pack into double gyroid networks, entirely distinct from other synthetic or biological amphiphiles within bicontinuous cubic phases. From a multitude of possible applications, we demonstrate two examples of functional materials from lipidoid LCs. Firstly, the fabrication of highly aligned lipidoid gyroid films by interfacial PrSA, which are rapidly responsive to the external medium. Secondly, we show that colloidally-dispersed lipidoid cubosomes, e.g. for drug-delivery, are easily assembled using top-down solvent evaporation methods.

High-throughput screening of cationic lipidoids reveals how molecular conformation affects membrane-targeting antimicrobial activity

“…Inverse hexagonal phases were observed in our earlier study in lipidoids protonated by either sulfuric or hydrochloric acids. 24 However, the phase was only previously seen for protonated lipidoids with non-linear tails and branched headgroups. In addition, such protonated lipidoids more readily formed the double gyroid phase, a cubic phase consists of interpenetrating 3D networks with low interfacial curvature relative to the hexagonal phase.…”

“…25,26 In this study we focused on lipidoid structures with 3 or more amines per headgroup and 4 or more hydrophobic tails, following our previously optimized synthetic procedure. 23,24 Headgroups were selected from either linear, branched, or cyclic arrangements of amines with variable hydrocarbon spacer groups between the amines (Figure 1A). One gemini lipidoid was also prepared for comparison, using a primary diamine fully substituted with four tails.…”

“…Lipidoid compounds designed for this study have a high number of hydrophobic tails (4 -6) and relatively small hydrophilic headgroups, therefore were poorly soluble in a variety of aqueous solutions, including bacterial growth media. We previously found that protonation of lipidoid headgroups using strong acids resulted in the formation of liquid crystalline mesophases, 23,24 but notably these charged liquid crystals are difficult to disperse in aqueous medium without an emulsifier. Instead, lipidoid dispersion in aqueous media was facilitated by introducing permanent positive charges into the headgroup using methyliodide.…”

“…The liquid crystalline phase behavior of multi-tailed lipidoids gives a strong indications of their molecular conformations and the preferred interfacial/spontaneous curvatures of the molecules. 23,24 Thus, we sought to understand how the different conformations of lipidoids could relate to their antimicrobial activity. Self-assembly of the 27 different lipidoids from Table 1 was analyzed by SAXS, using the dispersions of methylated lipidoids in LB growth medium at 1mM.…”

“…In this study, we take a combinatorial approach to explore the membrane activity of synthetic lipid-like compounds (lipidoids) based on polyamine headgroups and ≥4 hydrophobic tails. Such lipidoids were recently discovered to self-assemble into diverse liquid crystalline nanostructures upon protonation, 23,24 relating to unique molecular conformations that result from having a multitude of hydrophobic tails. In particular, the propensity of some of these lipidoids to form aggregates with highly-curved topologies suggests a high membrane-disrupting potential.…”