Lipid nanoparticle-mediated drug delivery experiences rapid developments in the field of liquid crystalline colloidal carriers, e.g., cubosomes, spongosomes, hexosomes and vesicles [1,2,3,4,5,6,7]. In addition to the expansion of liposomes as advanced drug delivery systems [8,9,10], a plethora of research has been dedicated to diverse mesoporous liquid crystalline materials and nanostructures intended as drug delivery devices [11,12,13,14,15,16]. Lipid-based cubic mesophases are increasingly implemented in noninvasive drug delivery applications [17,18,19]. The liquid crystalline structure of cubosomes, consisting of well-defined networks of aqueous channels and lipid bilayer membranes, organized in periodic 3D topologies, presents advantages over other delivery systems [20]. Scientific and technological advances have been achieved in the fabrication of biocompatible systems for encapsulation of natural and synthetic lipophilic, hydrophilic and hydrophobic drug molecules, a variety of macromolecular drugs (peptides, proteins, DNA, siRNA, etc.) and imaging agents [1,2,3,4,5,6,7,11,12,13,14,15,16,17,18,19,21,22,23,24]. Complex cubic lattice networks of high surface areas provide enhanced protection of the incorporated payload from degradation as well as the prolonged and sustained release of the entrapped bioactive molecules [25,26].

Current demands for improved performance and specificity of drug delivery carriers require the use of intelligent materials, which respond to various environmental stimuli [27]. In this context, the cubosome assemblies present further advantages because the transformations between the different liquid crystalline organizations, e.g., Pn3m, Im3m and Ia3d, besides the inverted hexagonal phases (Figure 1), can be tuned and controlled by changes in temperature, ionic strength or pH of the environment of the targeted application sites [28,29,30,31,32,33,34].

In the present work, we review recent advances in cubosome nanocarriers and bulk cubic mesophases with a particular emphasis on the pH effects on the structures and topologies of the designed drug delivery systems. This interest is motivated by the fact that pH represents an inherent physiological condition of all biological organisms and that pathological (inflamed or infected) areas can embed target sites for pH-sensitive nanomedicines. This has led to the emergence of pH-responsive drug delivery carriers and nanomaterials, some of which are reviewed here below.

Acidic compartments of the cells are the endosomes (pH 5–6) and the lysosomes (pH 5). Depending on the application site, pH changes of the biological medium may comprise a profitable condition to boost the target release of encapsulated drugs from the pH-responsive nanocarriers. In this context, lipid-based pH-sensitive cubosomes have been produced by the assembly of traditional cubic-phase-forming amphiphiles monoolein or phytantriol with charged or ionizable lipids [35,36,37,38,39,40,41,42]. Incorporation of drugs like doxorubicin, for which the redox process (Figure 1) provokes pH-dependent structural changes, may also lead to pH-responsiveness of the host cubic phase carriers. Furthermore, the association of lipids with polyelectrolytes and charged surfactants was employed as a means to generate highly pH-sensitive cubosomes and other types of nanocarriers [43,44,45,46,47]. A summary of the published works, exploiting small-angle X-ray scattering (SAXS) analyses of liquid crystalline nanostructures and nanoparticles, is presented in Table 1 below.

 

Oral delivery of peptides, recombinant proteins and other nanomedicines is of a primary therapeutic interest [48,49,50,51,52]. The oral drug administration represents several challenges. One of the most prominent is the considerable pH variation in the gastrointestinal tract (Figure 1, bottom panel). With this concern in mind, we discuss the perspectives of cubosomes development in oral drug delivery applications with special attention to composite nanocarriers, i.e., cubosomes with pH-responsive characteristics provided by polyelectrolyte shells [46,47,52]. The latter may ensure the structural stability of the carriers in adverse media, for instance under the strong acidic condition of the stomach.

Increased oral drug bioavailability can be expected due to the mucoadhesive features of the cubic-phase forming lipids. Prolonged-release mucoadhesive formulations have been obtained thanks to the fusogenic properties of monoolein enabling permeation enhancer activity of the nanocarriers [1,17,18,19]. The mucoadhesive controlled release formulations interact with the mucosal components such as mucin (Figure 1, bottom panel). The enhanced adsorption on the intestinal epithelia ideally promotes a sustained drug release.

Salentinig et al. have emphasized that the hydrolysis of monoolein in the zones of the gastrointestinal tract will produce oleic acid [37], the ionization state of which determines the structural properties of the carriers, through the lipid packing, and hence their fusion dynamics with the membranes [20].

pH-responsive lyotropic liquid crystalline phases and nanoparticles have received tremendous interest in view of applications in anticancer nanomedicine [3,4,11,18,28,29,31]. Although the pH of normal tissues and blood is around 7.4, the tumor environment exhibits acidic pH owing to the metabolic production of lactic acid under the conditions of fast cell growth and deficiency of oxygen and nutrients. The use of pH-sensitive cubosomes as drug delivery systems for cancer treatments presents an advantage of the pH difference between the tumor environment and the normal physiological condition [53,54]. In chemotherapy, pH-responsive drug delivery nanocarriers have been shown to accumulate in the tumor tissue via the enhanced permeability and retention (EPR) effect [53]. The release of anticancer drugs may be triggered in response to extracellular or intracellular chemical stimuli including pH-stimuli [53].