Self‐Assembled Nanostructured Lipid Systems: Is There a Link between Structure and Cytotoxicity?

Abstract

Self‐assembly of lipid‐based liquid crystalline (LLC) nanoparticles is a formulation art arising from the hydrophilic–lipophilic qualities and the geometric packing of amphiphilic lipid molecules in an aqueous environment. The diversity of commercialized amphiphilic lipids and an increased understanding of the physicochemical factors dictating their membrane curvature has enabled versatile architectural design and engineering of LLC nanoparticles. While these exotic nanostructured materials are hypothesized to form the next generation of smart therapeutics for a broad field of biomedical applications, biological knowledge particularly on the systemic biocompatibility or cytotoxicity of LLC materials remains unclear. Here, an overview on the interactions between LLCs of different internal nanostructures and biological components (including soluble plasma constituents, blood cells, and isolated tissue cell lines) is provided. Factors affecting cell–nanoparticle tolerability such as the type of lipids, type of steric stabilizers, nanoparticle surface charges, and internal nanostructures (or lipid phase behaviors) are elucidated. The mechanisms of cellular uptake and lipid transfer between neighboring membrane domains are also reviewed. A critical analysis of these studies sheds light on future strategies to transform LLC materials into a viable therapeutic entity ideal for internal applications.

Nature‐Inspired Design and Application of Lipidic Lyotropic Liquid Crystals

“…One remaining hurdle in the deployment of lipidic lyotropic liquid crystals in drug delivery is uncertainty over the interactions of particles of these materials with cells, a topic reviewed recently . It is still not yet known what is the interplay between internal complex nanostructure, external surface structure as “seen” by cellular targets, and the inherent biocompatibility or toxicity of the lipid components.…”

Monocytic Cell-Induced Phase Transformation of Circulating Lipid-Based Liquid Crystalline Nanosystems

“…Phase characteristics at equilibrium were further established using the synchrotron-based SAXS technique. As opposed to the existing SAXS profiling of the LLC dispersed systems that typically employed lipid concentrations at > 10 mg/mL, we attempted to identify the lowest possible lipid concentrations that meet both, the SAXS instrument detection limits and the biocompatibility levels (i.e., < 1 mg/mL per 10 6 cells), according to previous cytotoxicity studies across different cell lines [11]. As shown in Figure 2b, the LLC phase-specific diffraction peaks were reliably acquired for each system at 1 mg/mL lipid level (i.e., ideal for 10 7 cells in the subsequent studies).…”

“…On the other hand, lipid molecules with CPPs of 0.5-1 produce positively curved, lamellar vesicles (LV, or more commonly known as liposomes) [11]. (Figure 1a).…”

“…(Figure 1a). On the other hand, lipid molecules with CPPs of 0.5-1 produce positively curved, lamellar vesicles (LV, or more commonly known as liposomes) [11]. While liposomal formulations have long-found clinical use for therapeutic delivery [12], a few non-lamellar systems (i.e., the Camurus products) have recently reached regulatory approval for internal applications [13].…”

“…However, their phase behaviour under physiological systemic conditions have been underexplored, to date. A majority of their bio-interaction studies have placed emphasis on cytotoxicity, cellular uptake and intracellular distribution [11,26]. Only a few reports focusing on protein corona effects revealed that biological fluids (e.g., blood serum and artificial cell culture media) could alter the lattice parameters of the LLC systems [27,28], and possibly trigger a slow transition from one phase to the other [29].…”