Srinivas College of Pharmacy, Valachil, Mangalore- 574143.
Osteoarthritis (OA) is a chronic joint disorder characterized by cartilage degradation, inflammation, and pain, leading to impaired mobility. Conventional treatments, such as NSAIDs, corticosteroids, and hyaluronic acid injections, often provide only temporary relief and are associated with systemic side effects. Cubosomes, self-assembled nanostructured lipid carriers, have emerged as a promising drug delivery system for OA treatment due to their biocompatibility, sustained drug release, and ability to encapsulate both hydrophilic and hydrophobic drugs. They offer targeted delivery of anti-inflammatory agents, regenerative molecules, and analgesics, reducing systemic exposure while enhancing therapeutic efficacy. Additionally, cubosomes can be engineered for cartilage regeneration and gene therapy applications to slow OA progression. Despite challenges such as stability and large-scale production, ongoing research aims to optimize cubosome-based formulations for intra-articular drug delivery. This nanotechnology-driven approach holds significant potential for improving OA management, reducing side effects, and enhancing long-term joint health.
Osteoarthritis (OA) is the most common arthritis type, impacting millions of individuals around the globe. It is a long-lasting condition of joints characterized by the gradual wearing away of cartilage, the smooth tissue that serves as a buffer at the bones in a joint. Painful symptoms, stiffness, swelling, and reduced mobility are accompanied as bones start to grate against one another because of the cartilage wearing down (1). Any joint can be affected by Osteoarthritis however, knees, hips, hands, and spine are the most common areas of impact. OA is known colloquially as “wear and tear” disease because it is said to form due to the cumulative impact of aging and overusing joints throughout years. Despite that, it’s now widely accepted that osteoarthritis is a multifaceted condition that is affected by numerous factors such as genetics, obesity, joint traumas, and even metabolic disorders (2). It was previously considered a solely mechanical problem, but studies indicate that inflammation triggers are part of its progression. Rest results alleviation of symptoms, while pain brought on by movement is one of the most distinctive characteristics of osteoarthritis. Morning rigidity after lengthy intervals of stillness is quite common. Progressing through the stages of the disease makes performing daily activities, like walking, stair climbing or gripping onto objects with hands, increasingly more difficult(3). In extreme instances, a person's quality of life may be scarred due to irreparable joint deformities along with advanced stages of degeneration which inflict immense suffering that practically caps all functions. The diagnosis is primarily based on integrating the clinical assessment with the patient’s medical history and physical examination. Imaging techniques like X-ray and MRI scans also enhance the accuracy of diagnosis. Joint space narrowing alongside formation of bone spurs (osteophytes) and alteration in bone density can be visible via X-ray whilst MRI scans yield much detailed images of cartilage and soft tissues (4). Various strategies and options aimed at symptom alleviation are accessible, even though cures for this disease are non-existent, and it is a progressive ailment on one’s body. These options align with conservative treatment approaches that include changes in lifestyle, undergoing training from physiotherapists, weight loss, as well as intake of medicines which range from pain relief medication to anti-inflammatory drugs. In some intermediate cases, joint injections of corticosteroid drugs or hyaluronic acid can offer short-term relief. On the other hand, when these become ineffective, surgery in the form of joint replacements are offered as alternatives. Losing weight and keeping active allows one to avoid the excessive stress on one’s joints, which, combined with managing existing health conditions that lead to one’s joints deteriorating, prevents osteoarthritis from developing (5) Regular physical activity helps to improve the range of movement of joints, especially swimming and cycling, which are low impact (6). Osteoarthritis is among the top five leading contributors to global disability, with its occurrence forecasted to increase due to aging societies and rising obesity levels. While it is not fatal, the disorder can greatly impact a person’s day to day activities and mobility. There is ongoing research work that continues to improve knowledge on osteoarthritis, which is developing new treatment strategies and possibilities for disease modifying treatment (7). Cubosomes have emerged as a new class of nanostructured particles with argueable interest in drug delivery, cosmetics, and biomedicine. They are liquid crystalline self-assembled nanoparticles with a distinctive bicontinuous cubical phase characterized by two unconnected water channels separated by lipid bilayers (8). Such construction enables cubosomes to encapsulate both hydrophilic and hydrophobic molecules, thus serving as versatile carriers for an extensive range of bioactive materials (9). Cubosomes form mainly with the aid of amphiphilic lipids like glyceryl monooleate (GMO) and phytantriol which automatically transform into cubic phases upon hydration in an aqueous medium. In order to control Pluronic F127 surfactant aggregates and stabilizing the nanoparticles in good dispersion, a Pluronic surfactant F127 is normally included. This surfactant self-assemble is able to achieve self-assemble is able to achieve self-assemble is able to achieve self-assemble create nanoparticles with good stiffness and biocompatibility(10).
Structural Characteristics of Cubosomes.
Figure 1: Cubosomes with various drug loading strategies displaying their interior & the cubic shape as well as membrane
Figure 2: Honeycombed-shaped structure of cubosomes
Cubosomes comprise curved bicontinuous lipid bilayers that are organised in three The cubosomes structure is composed of a lipid bilayer that is continuously curled in three directions and divides two congruent networks of aqua channels, thus accommodating hydrophilic, amphiphilic and hydrophobic components. This structure can serve as an efficient device for delivering low-molecular-weight drugs, proteins, peptides, nucleic acids, and amino acids. Extensive research on such systems have supported the claim of the existence of three cubic geometry of lipid bilayer structures with Gyroid (Ian3d), Diamond (Pn3m), and Primitive (Im3m) surfaces(11). shapes as having honeycomb features and separated into two internal aqueous chambers which may be utilized by different bioactive agents, including chemical drugs, peptides, and proteins. Because of sheding characteristics like: thermodynamic stability and bioadhesion; bioadhension; the ability of incorporating hydrophilic, hydrophobic and amphiphilic substances; as well as through the functionalization of the compounds, cubosomes are considered favorable for different routes of administration. Cubosomes are individual and nanosized particles created by the disintegration and steric stabilization of inverse bicontinuous cubic phase of lipids. Hence, cubosomes have much larger specific surface areas and still retain inner structures of the sustained release drug delivery system (12).
Components Of Cubosmes
Amphiphilic lipids
GlycerylMonooleate(GMO)
A lipophilic lipid class formed through the glycerol and oleic acid methyl ester synthesis includes: GMO. The head of the lipid is lipophilic while the tail is hydrophobic (13). Moreover, GMOs are also applied in the lipid food emulsification processes in the manufacturing of food. GMO is a clear, colorless polar lipid with unsaturation at the monoglyceride level. It possesses a melting and storage temperature of 35-37 degrees Celsius and-20 degrees Celsius, respectively. Its HLB value is 3 (14).
Phytantriol(PHTY)
Stabilizers
Surfactants are able to offer colloidal stability which is vital for the formation of cubosomes. The encasement of cubosomes generates the bulk cubic phase. The electrostatic-repulsive barrier that the stabilizer is capable of creating between the cubosomes and incoming particles is permissive of avoidance of unwanted interactions with the hydrophobic regions of cubosomes as it does interact with particles without destroying the cubic structure. It follows that the stabilizer is an important component in the generation of cubosomes (19, 20). Most common stabilizers used are Pluronics, especially F127 (Poloxamer 407) which is termed as the “gold standard”. Pluronics are water-solu Block copolymers composed of polypropylene (PPO) and polyethylene oxide (PEO) where ? shaped polymers containing a PEO-PPO-PEO structure possessing hydrophilic and hydrophobic are organized.. Pluronics are water-soluble (21).
Method of preparation of Cubosomes
Figure3: A diagrammatic representation of the methods for manufacturing cubosomes.
Top-down approach
In most research, the bulk cubic phase is first synthesized and then converted into Cubosomes nanoparticles through high energy processing. Cubic bulk phases looks like a liquid crystalline domain while the cubic phase appears as a transparent, stiff gel which is a cross linked polymer chains swollen with water. Due to the greater quantity of oils and surfactants that yield bilayers, the cubical phases yield stress centrifuges increase. These lipids and stabilisers form the bulk viscous cubic phase which is later dispersed into water by high energy input (such as High-Pressure Homogenization [HPH], sonication, or shear) to produce Lyotropic Liquid Crystals (LLC) nanoparticles. This HPH method most frequently utilized to create LLC nanoparticles. Vesicles (dispersed nanoparticles of lamellar liquid crystalline phase) or entities that resemble vesicles always coexist alongside them. (22,23)
Bottom-up approach
This process relies fundamentally on a single hydrotrope, which can transform water-insoluble lipids into liquid precursors. With a less energy-consuming process than the top-down method, this approach utilizes cubosome-splitting, which is achieved via emulsion. The results showed a spontaneous self-assembly of block copolymers into mesophases such as micelles, vesicles, or cubosomes, and many discrete vesicles are formed along with cubosomes (24,25).
Heat treatment
Increasing the temperature only assists the noncubic vesicles transform into highly organized cubical particles; therefore, it cannot be viewed as an overall approach toward cubosome synthesis in a strict sense. tendency could suggest that integrating a basic method comprising homogenization and thermal treatment could be applied to formulate dispersed particles. The results suggest that enhanced thermal treatment increases the size of the cubic phases to form narrow ranges of well-dispersed colloidal particles, while the smaller particle size that corresponds to vesicles is reduced (26). It is apparent that these changes happen during the heat treatment stage of the full preparation process. The change in solubility and stability as temperature increases may have resulted in formation. Because of the surfactant's high solubility at temperatures below cloud point, the particles could exist in a stable form with little fusion. The vesicles quickly fused when the surfactant solubility dropped below a certain threshold (27,28).
Cubosomes As Transdermal and Topical Drug Delivery System
Due to their greater bio-adhesiveness, cubic phases are excellent for medication delivery as well as topical and mucosal depositions. Topical delivery systems are made possible by the special qualities of liquid crystal (LC) and liquid crystal nanoparticle (LCNP) technologies. Because they create bioadhesive LC systems in situ, topical drug delivery systems are unique in that they provide regulated and efficient drug delivery to mucosal surfaces (buccal, ophthalmic, vaginal, and others). This intriguing method effectively protects irritated and sensitive skin temporarily by forming a thin surface coating at mucosal surfaces made of a liquid crystal matrix, whose nanostructure may be adjusted to create an ideal delivery profile (29). Cubosomes have a high potential as mucosal and transdermal drug delivery systems due to their well- defined shape, particle size, and compatibility with human tissues and cells. The medicine contained in cubosomes can easily permeate the epidermis of mucosal and skin because of the similarities between the inner structure of cubosomes and the epithelial cells and the high permeability of cubosomes. This increases drug bioavailability (30). Due to its huge body surface area and ability to provide excellent and numerous drug administration sites, administration of drugs through the skin is a promising alternative to traditional drug administration routes. Additionally, the first-pass metabolism is avoided when medications are administered through the skin, increasing their bioavailability and lowering their negative effects. Due to its structure, content, and physicochemical characteristics, the stratum corneum (SC) serves as the body's primary barrier of defence against external agents and serves as the primary impediment to the administration of drugs through the skin (31,32). Hence the cubosome based drug delivery system which can able to overcome the limitation. The application of treatments directly to the skin's surface is referred to as topical medication delivery. The topical distribution of numerous medicinal compounds, including peptides, vitamins, and vaccine components, has found use for lipid-based crystalline nanoparticles (33).
Drug permeation through stratum corneum
The process by which molecules cross the layers of skin is known as percutaneous or dermal absorption. Three stages make up this process: (1) penetration, which is the access of a substance to one of the skin's layers; (2) permeation, which is the penetration of one layer into another; and (3) reabsorption, which refers to uptake by the circulatory system. The drug enters the SC through passive diffusion after being released from the vehicle through three different pathways: (1) transcellular, (2) intercellular, also known as paracellular, and (3) the appendage, which consists of the eccrine glands, which include the sweat and/or hair follicles (34,35).The medication diffuses through the SC's keratinized dead cells when administered transcellularly. The poor diffusion coefficient of this layer of cells serves as the primary barrier. Drug penetration is thought to be mostly accomplished via the intercellular pathway. The intercellular distances along this path are estimated to be between 19 and 75 nm, and the diffusion path's maximum length is 900 m (36). The molecular weight and Log P 1-4 of the nonpolar molecules required to permeate the SC must be less than 500 Da. Drugs are displaced through this pathway by successive diffusion with polar group and intercellular lipid alkyl chain partitioning. The appendage pathway is also not thought to be a significant channel for medication penetration (37).
CONCLUSION
Cubosomes are innovative nanocarriers with a unique bicontinuous cubic structure, enabling efficient encapsulation and controlled release of both hydrophilic and hydrophobic molecules. Their high biocompatibility, stability, and sustained-release capabilities make them ideal for drug delivery, cosmetics, and biomedical applications. Ongoing research into novel lipids, surfactants, and surface modifications continues to enhance their performance. With their ability to improve solubility, bioavailability, and targeted therapy, cubosomes represent a major advancement in nanotechnology, holding great promise for future biomedical innovations.
REFERENCES
Swasthika S.*, Bhavyashree T., A. R. Shabaraya, Cubosomes: A Novel Nanotechnology-Based Drug Delivery System for Osteoarthritis Treatment, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 5, 2907-2914. https://doi.org/10.5281/zenodo.15450305
10.5281/zenodo.15450305
