A Versatile Nanocarrier-Cubosomes, Characterization, and Applications

Abstract

The impact of nanotechnology on the exponential growth of several research areas, particularly nanomedicine, is undeniable. The ability to deliver active molecules to the desired site could significantly improve the efficiency of medical treatments. One of the nanocarriers developed which has drawn researchers' attention are cubosomes, which are nanosized dispersions of lipid bicontinuous cubic phases in water, consisting of a lipidic interior and aqueous domains folded in a cubic lattice. They stand out due to their ability to incorporate hydrophobic, hydrophilic, and amphiphilic compounds, their tortuous internal configuration that provides a sustained release, and the capacity to protect and safely deliver molecules. Several approaches can be taken to prepare this structure, as well as different lipids like monoolein or phytantriol. This review paper describes the different methods to prepare nanocarriers. As it is known, the physicochemical properties of nanocarriers are very important, as they influence their pharmacokinetics and their ability to incorporate and deliver active molecules. Therefore, an extensive characterization is essential to obtain the desired effect. As a result, we have extensively described the most common techniques to characterize cubosomes, particularly nanocarriers. The exceptional properties of the cubosomes make them suitable to be used in several applications in the biomedical field, from cancer therapeutics to imaging, which will be described. Taking in consideration the outstanding properties of cubosomes, their application in several research fields is envisaged.

Keywords: cubosomes; delivery systems; nanomedicine; nanotechnology.

Figure 1

Schematic representation of a polar lipid molecule. Polar lipidic molecules present two domains: a hydrophilic headgroup (polar) and a hydrophobic tail (apolar).

Figure 2

Most common self-assembly structures of amphiphilic molecules, including micelle, vesicle, bilayer, and bicontinuous phases. Reproduced from Florenzano et al., 1997 [30] (work licensed under a Creative Commons Attribution 4.0 International License, 2022).

Figure 3

Illustration of the P_s concept and relation with geometrical shapes. Adapted from Marques and Silva, 2013 [31].

Figure 4

Self-assembled structures radii. Left: sphere with both radii positive; Right: cylinder with a positive finite radius and an infinite radius. Adapted from Marques and Silva, 2013 [31].

Figure 5

Skeletal graphs of the water channels in the three bicontinuous cubic phases morphologies. (a) Ia3d (G-surface), (b) Pn3m (D-surface), (c) Im3m (P-surface). Adapted from Squires et al., 2006 [40].

Figure 6

Chemical structure of monoolein and phytantriol.

Figure 7

Aqueous phase behavior of the monoolein–water system. L_c and L_∝ represent the lamellar phases (crystalline and fluid, respectively). Ia3d and Pn3m are the inverted bicontinuous cubic phases. L₂ and H_II correspond to the inverted micellar and hexagonal phase, respectively. Adapted from Kulkarni et al., 2011 [46].

Figure 8

Phase diagram of the phytantriol–water system. L_c and L_∝ represent the lamellar phases (crystalline and fluid, respectively). Ia3d and Pn3m are the inverted bicontinuous cubic phases. L₂ and H_II correspond to the inverted micellar and hexagonal phase, respectively. Adapted from Barauskas and Landh, 2003 [47].

Figure 9

Conceptual representation of the work by Patil et al., 2021. Bedaquiline-loaded cubosomes were designed for inhalatory administration in the context of cancer therapy. Reproduced with permission from reference [97]. Copyright 2022 Elsevier.

Figure 10

Conceptual representation of the work by Sarkar et al., 2021. Cubosomes loaded with GFP-antisense siRNA are shown to reduce the expression of GFP in vitro using Chinese Hamster Ovary cells. Reproduced with permission from reference [139], 2022.