Liposomes to Cubosomes: The Evolution of Lipidic Nanocarriers and Their Cutting-Edge Biomedical Applications

Abstract

Lipidic nanoparticles have undergone extensive research toward the exploration of their diverse therapeutic applications. Although several liposomal formulations are in the clinic (e.g., DOXIL) for cancer therapy, there are many challenges associated with traditional liposomes. To address these issues, modifications in liposomal structure and further functionalization are desirable, leading to the emergence of solid lipid nanoparticles and the more recent liquid lipid nanoparticles. In this context, "cubosomes", third-generation lipidic nanocarriers, have attracted significant attention due to their numerous advantages, including their porous structure, structural adaptability, high encapsulation efficiency resulting from their extensive internal surface area, enhanced stability, and biocompatibility. Cubosomes offer the potential for both enhanced cellular uptake and controlled release of encapsulated payloads. Beyond cancer therapy, cubosomes have demonstrated effectiveness in wound healing, antibacterial treatments, and various dermatological applications. In this review, the authors provide an overview of the evolution of lipidic nanocarriers, spanning from conventional liposomes to solid lipid nanoparticles, with a special emphasis on the development and application of cubosomes. Additionally, it delves into recent applications and preclinical trials associated with cubosome formulations, which could be of significant interest to readers from backgrounds in nanomedicine and clinicians.

Keywords: cancer therapeutic; cubosomes; lipidic nanoparticles; liposomes; solid lipid nanoparticles.

Figure 1

(A). Transmission electron micrographs of Au-ILs. (B) Au-IL nanoparticles had maximum distribution in the MC area compared to the other formulations. (C) Transmission electron micrographs of sections of kidneys treated with AuNPs, Au-LNHys, or Au-ILs. (D) HE staining assay of mouse heart, liver, spleen, lung, and kidney tissue sections after administration of DXMS/siRNA, DXMS/siRNA@Au-LNHy, or DXMS/siRNA@Au-ILs for analyzing in vivo toxicity. Adapted with permission from ref (63). Copyright 2021 American Chemical Society.

Figure 2

Representation of liposomes used for several types of drug delivery as well as gene delivery due to their unique properties. A wide variety of hydrophilic and hydrophobic diagnostics or therapeutic agents are easily encapsulated with a sustained release capability. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 3

(A) Scanning electron microscope images of SLNPs. (B) In vitro siRNA activity as compared between untreated (free siRNA) and SLNs encapsulated siRNA activity on Human 293FT cells that were cotransfected with pTD138 (a plasmid that expresses click beetle luciferase CBL). (C) Normalized total flux versus time shows in vivo release of unencapsulated siGLO Red (black solid line) and siGLO Red encapsulated in SLNPs (red lines); (D) In vivo activity of siRNA released from SLNs as from red fluorescence of siGLO Red in mice paws after day 1, day 4, and day 11 of administration. Adopted with the permission from ref (91). Copyright 2011 American Chemical Society.

Figure 4

Schematic representation of cubosome preparation by different methods. Here the solvent evaporation method, spray drying process, and top-down and bottom-up mechanisms are elaborated. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 5

Various biomedical applications of cubosomes are described. Encapsulating drugs in cubosomes enhances antifungal, antibacterial, wound healing, and dermatological medication by improving skin retention, sustaining drug release, resisting enzymatic degradation, increasing drug loading capacity, targeting drug delivery, increasing bioavailability, and many more. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 6

Detailed mechanism of therapeutic loaded cubosomes for various types of cancer treatment including brain, skin, lungs, colon, and breast cancer. Therapeutic activity was enhanced for drugs loaded on cubosomes, with targeted drug delivery and lower toxicities detected as well as increased apoptosis in cancer cells. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 7

(A) Cryo-TEM image of cubosome showing its structure and morphology. (B–D) Efficacy of tumor growth reduction in the Affimer targeted delivery, nontargeted delivery and control group. (E, F) Body weight change and survivability of the three groups of mice showing significantly high therapeutic efficacy in the Affimer targeted group. Adopted from ref (13). Available under a CC-BY 4.0 license.

Figure 8

Summary of the three generations of lipidic nanocarriers with their advantages and drawbacks. Figures have been reproduced with permission from ref (165), (166), and (13). Copyright 2014 Elsevier, 2018 Elsevier, and 2022 American Chemical Society.