Lyotropic Liquid Crystalline Nanostructures as Drug Delivery Systems and Vaccine Platforms

Abstract

Lyotropic liquid crystals result from the self-assembly process of amphiphilic molecules, such as lipids, into water, being organized in different mesophases. The non-lamellar formed mesophases, such as bicontinuous cubic (cubosomes) and inverse hexagonal (hexosomes), attract great scientific interest in the field of pharmaceutical nanotechnology. In the present review, an overview of the engineering and characterization of non-lamellar lyotropic liquid crystalline nanosystems (LLCN) is provided, focusing on their advantages as drug delivery nanocarriers and innovative vaccine platforms. It is described that non-lamellar LLCN can be utilized as drug delivery nanosystems, as well as for protein, peptide, and nucleic acid delivery. They exhibit major advantages, including stimuli-responsive properties for the "on demand" drug release delivery and the ability for controlled release by manipulating their internal conformation properties and their administration by different routes. Moreover, non-lamellar LLCN exhibit unique adjuvant properties to activate the immune system, being ideal for the development of novel vaccines. This review outlines the recent advances in lipid-based liquid crystalline technology and highlights the unique features of such systems, with a hopeful scope to contribute to the rational design of future nanosystems.

Keywords: controlled drug release; cubosomes; drug delivery nanosystems; lipid nanoparticles; lyotropic liquid crystals; stimuli-responsive; vaccines.

Figure 1

Left panel: Kinetically stabilized oil-in-water (O/W) and water-in-oil (W/O) nanostructured emulsions comprising a self-assembled lipid nanostructure. Apart from the illustrated hexagonal H₂ nanostructure, other types of nanostructures, including bicontinuous cubic Pn3m or Im3m, micellar cubic Fd3m, hexagonal (H₂), or inverse micelles (L₂), can be formed in these emulsions. Right panel: Chemical structures of the commonly used lipids and stabilizer. Adapted from Kulkarni [3].

Figure 2

(A) Thermodynamically stable self-assembled lipid nanostructures. Adapted from Kulkarni [3]. (B) Three-dimensional organizations of cubic liquid crystalline phases: (a) primitive cubic (Im3m/Q^IIP), (b) bicontinuous double diamond cubic (Pn3m/Q^IID), and (c) bicontinuous gyroid cubic (Ia3d/Q^IIG) types. Adapted from Rakotoarisoa et al. [13].

Figure 3

(a–c) Cryo-TEM images of hexosomes (all scale bars represent 100 nm); (d) SAXS profiles of the lipid-based liquid crystals without (black) and with undecylenic acid (red). Black, down arrows show the reflections of the Im3m cubic phase; blue, up arrows show the reflections of the Pn3m cubic phase. The reflections are annotated above the Bragg peaks. Adapted by Mionić Ebersold et al. [51].

Figure 4

(a) Phase behavior of the PHYT-PG-water system. ▲ Isotropic solution; ♢ emulsion; ☆ emulsion + lamellar phase; ♦ lamellar phase; × lamellar + cubic phase; ∆ cubic phase. (b) Drug release studies of minocycline hydrochloride-loaded in situ cubic liquid crystal and Periocline^®. Adapted by Yang et al. [128].

Figure 5

(Left Panel, a–d) Cryo-TEM images of liquid crystalline nanosystems with PDMAEMA-b-PLMA. (Right Panel, a–d) Physicochemical characteristics of the nanosystems depending on the pH of the dilution medium. Adapted by Chountoulesi et al. [38].