Cubosome Dispersions Research Articles

Cubosomes hydrogel containing silver based organometallic compounds for enhanced wound healing of burns: In vitro and in vivo studies

The aim of this study is to investigate the treatment of burn wounds and bacterial infections, specifically focusing on silver(I) N-heterocyclic carbene (Ag-NHC) loaded into cubosomes. Ag-NHC is an organometallic complex of silver (Ag) and can be considered an active pharmaceutical ingredient for the topical treatment of burns. A novel nanoparticle system, cubosome dispersions, was formulated using high pressure homogenization methods with different concentrations of lipid phase glyceryl monooleate (GMO), surfactants such as poloxamer 407 (F-127), and polyvinyl alcohol (PVA). The optimized formulation (U6) was characterized by in vitro drug release profile (90.54 ± 1.17 %), particle size (126.7 ± 0.98 nm), zeta potential (−21.6 ± 6.83 mV), entrapment efficiency (89.30 ± 1.46 %), and morphology as observed by transmission electron microscopy (TEM). The U6 formulation was incorporated into a hydrogel containing Carbopol 940 to form a cubosomal hydrogel (cubogel). The cubogel was characterized by the in vitro release of Ag-NHC (92 %), entrapment efficiency (>90 %), pH (5.3), viscosity (1.2 cP), spreadability, and TEM. From the in vitro drug release pattern, it was concluded that the U6 formulation showed slow and sustained drug release over 24 h, and demonstrated superior burn healing compared to marketed products. The in vivo wound healing study revealed that the cubogel demonstrated a superior burn healing rate compared to commercially available products (Quench® and Clotrimazole®). The in vivo histopathological results showed that the prepared cubogel was effective in treating second-degree burns, with no side effects or skin irritation, compared to commercial products. Additionally, Ag-NHC-loaded cubogel facilitated sustained release for treating burn wounds without any bacterial infections. The current findings provide a strong basis for the initiating phase 0 clinal trials, highlighting significant potential for the further research to benefit the pharmaceutical industry.

Development, characterization and pharmacokinetic evaluation of selegiline HCl loaded cubosomal thermoreversible mucoadhesive gel for nose to brain delivery

Selegiline HCl (SGH) is MAO-B inhibitor with limited bioavailability due to extensive hepatic metabolism. Thus, this work aims to formulate and evaluate SGH loaded intranasal thermoreversible cubosomal gel in order to enhance its bioavailability and ensure efficient brain targeting. Experimental design and Artificial Neural Network (ANN) were explored to optimize the formulation. Gellan gum and konjac gum were used as gelling agent and mucoadhesive agent respectively to formulate mucoadhesive in situ nasal gel. Optimized formulation of SGH loaded cubosomal dispersion exhibits average particle size (166.8 ± 3.12 nm), entrapment efficiency (72.85 ± 1.50 %), and drug release at 6 h (89.15 ± 1.04 %). In vitro drug release analysis demonstrated the sustained release pattern. In vivo pharmacokinetic studies in Swiss Albino mice showed approximately 1.90-fold increase in Cmax and AUC(0-t) in brain after intranasal administration. The Cmax and AUC for drug solution was found to be 4.3828 ± 0.02 ng/mL, 19.4166 ± 0.06 ng min/mL and for cubosomal gel it was 11.7665 ± 0.32 ng/mL, 36.9216 ± 0.41 ng min/mL respectively. Furthermore, the stability study was executed for estimation of shelf life of optimized formulation. The shelf life of SGH loaded cubosmal gel was found to be 20.64 months which demonstrate its long-term stability. The in vitro and in vivo evaluation endorsed that the fabricated cubosomal in situ nasal gel could be the promising approach for nose to brain delivery of SGH in Parkinson's therapy.

Mucoadhesive Chitosan Composite Sponge as a Carrier for β-Sitosterol Cubosomes for Thermal Burn Treatment

Our study aimed to explore the potential of using nanostructured lipid carriers (NLCs) to enhance the topical administration of β-sitosterol, a bioactive that is poorly soluble in water. Here, we have taken advantage of the unique characteristics that cubosomes have to provide as a drug delivery system. These characteristics include a large surface area, thermal stability, and the capacity to encapsulate molecules that are hydrophobic, amphiphilic, and hydrophilic. The cubosomal formulation was optimized by building a central composite design. The optimum dispersion exhibited a particle size of 88.3 nm, a zeta potential of -43, a polydispersity index of 0.358, and drug entrapment of 95.6%. It was composed of 15% w/w oleic acid and 5% w/w pluronic F127. The optimized cubosome dispersion was incorporated into a sponge formulation. The optimized cubosome sponge achieved a higher drug release compared with the cubosome dispersion. The SEM micrograph of the selected sponge showed that it has an interwoven irregular fibrous lamellar structure with low density and high porosity. The in-vivo data revealed that topical application of the β-sitosterol cubosomal sponge showed significant higher wound closure percentage relative to the β-sitosterol product (Mebo)®.Graphical

Cubosomes: An Emerging and Promising Drug Delivery System for Enhancing Cancer Therapy.

Cancer and other diseases can be treated with cubosomes, which are lyotropic nonlamellar liquid crystalline nanoparticles (LCNs). These cubosomes can potentially be a highly versatile carrier with theranostic efficacy, as they can be ingested, applied topically, or injected intravenously. Recent years have seen substantial progress in the synthesis, characterization, regulation of drug release patterns, and target selectivity of loaded anticancer bioactive compounds. However, its use in clinical settings has been slow and necessitates additional proof. Recent progress and roadblocks in using cubosomes as a nanotechnological intervention against various cancers are highlighted. In the last few decades, advances in biomedical nanotechnology have allowed for the development of "smart" drug delivery devices that can adapt to external stimuli. By improving therapeutic targeting efficacy and lowering the negative effects of payloads, these well-defined nanoplatforms can potentially promote patient compliance in response to specific stimuli. Liposomes and niosomes, two other well-known vesicular systems, share a lipid basis with cubosomes. Possible applications include a novel medication delivery system for hydrophilic, lipophilic, and amphiphilic drugs. We evaluate the literature on cubosomes, emphasizing their potential use in tumor-targeted drug delivery applications and critiquing existing explanations for cubosome self-assembly, composition, and production. As cubosome dispersion has bioadhesive and compatible features, numerous drug delivery applications, including oral, ocular, and transdermal, are also discussed in this review.

Potentiation of Brain Bioavailability Using Thermoreversible Cubosomal Formulation.

The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 μg/mL), Cmax (368.07 ± 0.23 μg/mL), Tmax (4 h), and t1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.

Preparation and in vivo evaluation of nano sized cubosomal dispersion loaded with Ruta graveolens extracts as a novel approach to reduce asthma-mediated lung inflammation

Asthma is a chronic disease affecting people of all ages. Asthma medications are associated with adverse effects restricting their long-term usage, demanding newer alternative therapies. This study aimed to investigate the anti-asthmatic properties of Ruta graveolens extract and its prepared nano-cubosomal dispersion (Ruta-ND). Firstly, the R. graveolens methanolic extract exhibited higher anti-inflammatory activity on Lipopolysaccharide (LPS)-activated BEAS-2B cells. To ensure best bioavailability and hence best cellular uptake, R. graveolens extract was loaded in nano-cubosomal dispersion (ND). Then, the anti-asthmatic effects of Ruta extract and ND were simultaneously evaluated in rats’ model with ovalbumin-induced allergic asthma. R. graveolens extract and Ruta-ND subsided asthma score and improved lung function by restoring FEV1/FVC ratio to the expected values in control rats. Also, it showed strong antioxidant and anti-inflammatory activities manifested by lowering levels of malondialdehyde (MDA), IL-4, IL-7, TGF-β, and Ig-E, and increasing levels of superoxide dismutase (SOD) and INF-γ in bronchoalveolar lavage fluid. Our research findings also indicate autophagy induction and apoptosis inhibition by Ruta extract and Ruta-ND. Finally, the HPLC MS/MS phytochemical profiling of R. graveolens extract evident production of various alkaloids, flavonoids, coumarins, and other phenolics with reported pharmacological properties corresponding to/emphasize our study findings. In conclusion, R. graveolens exhibited promise in managing Ova-induced allergic asthma and could be developed as an alternative anti-allergic asthma drug.

Celecoxib-Loaded Cubosomal Nanoparticles as a Therapeutic Approach for Staphylococcus aureus In Vivo Infection.

There is a great need for novel approaches to treating bacterial infections, due to the vast dissemination of resistance among pathogenic bacteria. Staphylococcus aureus are ubiquitous Gram-positive pathogenic bacteria and are rapidly acquiring antibiotic resistance. Here, celecoxib was encapsulated into cubosomal nanoparticles, and the particle morphology, size distribution, zeta potential, entrapment efficiency, and celecoxib release were evaluated in vitro. Also, a systemic infection model in mice elucidated the in vivo antibacterial action of the celecoxib cubosomes. Cubosomes are a nanotechnology-based delivery system which can adhere to the external peptidoglycan layers of Gram-positive bacteria and penetrate them. The size distribution investigation revealed that the prepared celecoxib-loaded cubosomes had a mean particle size of 128.15 ± 3.04 nm with a low polydispersity index of 0.235 ± 0.023. The zeta potential measurement showed that the prepared cubosomes had a negative surface charge of -17.50 ± 0.45, indicating a highly stable nanodispersion formation with little susceptibility to particle aggregation. The cubosomal dispersion exhibited an entrapment efficiency of 88.57 ± 2.36%. The transmission electron micrograph for the prepared celecoxib-loaded cubosomes showed a narrow size distribution for the cubosomal nanoparticles, which had a spherical shape and were non-aggregated. The tested cubosomes diminished the inflammation in the treated mice's liver and spleen tissues, as revealed by hematoxylin and eosin stain and Masson's trichrome stain. The immunostained tissues with nuclear factor kappa B and caspase-3 monoclonal antibodies revealed a marked decrease in these markers in the celecoxib-treated group, as it resulted in negative or weak immunostaining in liver and spleen that ranged from 4.54% to 17.43%. This indicates their inhibitory effect on the inflammatory pathway and apoptosis, respectively. Furthermore, they reduced the bacterial burden in the studied tissues. This is alongside a decrease in the inflammatory markers (interleukin-1 beta, interleukin-6, cyclooxygenase-2, and tumor necrosis factor-alpha) determined by ELISA and qRT-PCR. The IL-1β levels were 16.66 ± 0.5 pg/mg and 17 ± 0.9 pg/mg in liver and spleen, respectively. Also, IL-6 levels were 85 ± 3.2 pg/mg and 84 ± 2.4 pg/mg in liver and spleen, respectively. In conclusion, the current study introduced cubosomes as an approach for the formulation of celecoxib to enhance its in vivo antibacterial action by improving its oral bioavailability.

Cubosome-based thermosensitive in situ gelling system for intranasal administration of lamotrigine with enhanced antiepileptic efficacy

Lamotrigine (LTG) is a second-generation antiepileptic drug that belongs to Biopharmaceutics Classification System (BCS) class II. LTG has a low probability of crossing the BBB if administered orally. This study was designed to fabricate LTG cubosomal dispersion that is further loaded in a thermosensitive in situ gel to increase nasal residence time and enhance drug absorption across the nasal mucosal membrane. LTG-loaded cubosomes exhibited an entrapment efficiency ranging from 24.83% to 60.13%, a particle size ranging from 116.2 to 197.6 nm, and a zeta potential ≤ −25.5 mV. The selected LTG-loaded cubosomal formulation was loaded in a thermosensitive in situ gel (cubogel) employing different concentrations of poloxamer 407. In vitro release study revealed sustained drug release from cubosomal and cubogel compared with free drug suspension. In vivo studies revealed enhanced antiepileptic efficacy of LTG cubogel and LTG cubosomes compared with free drug in rats with pilocarpine-induced epilepsy by stimulating the release of gamma-aminobutyric acid (GABA), total antioxidant capacity (TAC), and serotonin and by inhibiting the release of Ca2+, dopamine, acetylcholine (Ach), C-reactive protein (CRP), and glial fibrillary acidic protein (GFAP). LTG cubogel exhibited superior activity over LTG cubosomes. These findings reveal that the developed cubosomal thermosensitive in situ gel can enhance the antiepileptic efficacy of LTG via the intranasal route.

Ifosfamide-Loaded Cubosomes: An Approach to Potentiate Cytotoxicity against MDA-MB-231 Breast Cancer Cells

Background: Ifosfamide (IFS) is proved efficacious against breast cancer, an enormously diagnosed cancer across the globe. However, the clinical efficacy of IFS is limited owing to its hydrophilicity, less stability, and dose-dependent toxicities. Therefore, the primary goal of the present research was to develop IFS-loaded cubosomes with improved anticancer efficacy and reduced dose-dependent toxicities.
 Methods: The IFS-cubosomes were optimized using a 32 factorial design based on IFS content and zeta potential. The optimized cubosomal dispersion was further assessed for particle size, in vitro IFS release, haemolysis, cytotoxicity, cellular uptake and physical stability.
 Results: The optimized IFS-cubosomal dispersion exhibited maximum IFS content (89.75±4.3%) and better zeta potential value (-40.0±1.6 mV), and size in nanometer. Moreover, IFS-cubosomes retarded IFS release (about 91 %) after 12 h than plain IFS solution (>99 % within 2 h). The IFS-cubosomes displayed lower haemolysis (3.7±0.79%) towards human RBCs. Besides, the in vitro cytotoxicity of IFS-cubosomes was noticed to be substantially higher (IC50: 0.64±0.08 µM) than plain IFS solution (IC50: 1.46±0.21 µM) against multi-drug resistant (MDR) breast cancer (MDA-MB-231) cells. DAPI staining revealed death of IFS-cubosomes treated cells mainly by apoptosis. The cubosomes showed increased uptake by cancer cells. Furthermore, IFS-cubosomes were found to be more stable at refrigeration temperature than at room temperature.
 Conclusion: Thus, IFS-cubosomes could be a novel avenue in the treatment of breast cancer with improved anticancer efficacy and reduced toxicity. However, further in vivo investigations are desired to validate these claims.

Cubosomes: Design, Development, and Tumor-Targeted Drug Delivery Applications.

Because of the extraordinary advancements in biomedical nanotechnology over the last few decades, traditional drug delivery systems have been transformed into smart drug delivery systems that respond to stimuli. These well-defined nanoplatforms can boost therapeutic targeting efficacy while reducing the side effects/toxicities of payloads, which are crucial variables for enhancing patient compliance by responding to specific internal or external triggers. Cubosomes are lipid-based nano systems that are analogous to well-known vesicular systems, such as lipo- and niosomes. They could be used as part of a unique drug delivery system that includes hydro-, lipo-, and amphiphilic drug molecules. In this review, we critically analyze the relevant literature on cubosomesregarding theories of cubosomeself-assembly, composition, and manufacturing methods, with an emphasis on tumor-targeted drug delivery applications. Due to the bioadhesive and -compatible nature of cubosome dispersion, this review also focuses on a variety of drug delivery applications, including oral, ophthalmic and transdermal.

Formulation and evaluation of a novel cubosomal emulgel for topical delivery of luliconazole

Abstract Despite numerous remarkable developments in clinical therapy, the world remains firmly in the grip of fungal infections. While conventional approaches to antifungal therapy are failing, dermatophytes continue to affect people’s daily lives, especially in humid and tropical areas, and pose a major medical problem. Cubosomes, the liquid crystalline nanostructures, are among the recently developed lipid nanoparticles that could potentially overcome the hurdles of conventional therapy. In the present study, cubosomes containing luliconazole, an antifungal drug, were formulated to overcome the limitation of poor water solubility and poor bioavailability of the drug for the main purpose of treating fungal infections. Various formulations of luliconazole loaded cubosomes were prepared with different ratios of lipid (glyceryl monooleate) and surfactant (poloxamer 407) using emulsification method. The prepared formulations were optimised and the optimised cubosomal dispersion was loaded into a carbomer-934 gel to form an emulsifying gel. All cubosomal dispersions had particle sizes ranging from 124 nm to 221.1 nm, optimal zeta potential and polydispersity index, and were found to be stable. The drug entrapment efficiency of the cubosomes was over 90%. The in vitro diffusion study showed that the developed formulation had a higher release rate than the marketed formulation. The in vitro antifungal activity study confirmed that the prepared emulsion formulation was also effective against Candida albicans. The novel drug delivery system developed in this study, the cubosomal emulgel, could thus be a favourable approach for the topical delivery of luliconazole for the treatment of fungal infections.

Lornoxicam-Loaded Cubosomes: - Preparation and In vitro Characterization.

Cubosomes are nanosized structures self-assembled nanostructured materials used for controlling the release of the entrapped drug molecule. Lornoxicam (LXM) is a potent analgesic nonsteroidal anti-inflammatory (NSAID) drug with a short half-life (3-4) hours. The present study aims to prepare LXM-loaded cubosomes with well-defined morphology, particle size, PDI, high entrapment efficiency, sustained drug release, and high zeta potential value, as a transdermal drug delivery system.
 Twelve formulas of LXM-loaded cubosomal dispersions were prepared by a solvent dilution method using Glyceryl monooleate ( GMO) as polar lipid with different stabilizers as Pluronic® F127 or tween 80 and different types of hydrotrope as ethanol or propylene glycol. These formulas were evaluated for their particle size analysis & PDI, E.E. %, and in-vitro drug release to select a group of the optimum formulas, that further characterized by transmission electron microscopy (TEM) and zeta potential analyzer to select the optimum dispersion. FTIR study was used to investigate the compatibility of the drug with excipients.
 The obtained results indicated that F3, composed of GMO, Pluronic® F127, ethanol, drug, and phosphate buffer solution pH 7.4 in the following per cents 7.28%, 1.82%, 8%, 2%, and 80.9% w/w, respectively, prepared in 20min agitation period, as the optimum formula for its high E.E. % (94.30±0.002%), small particle size (16.3±0.19nm), low PDI (0.06±0.02), and high zeta potential value (-65.9±0.05mV), and well-defined cubic structure. FTIR study indicated no interaction between LXM and other formulas components.
 This study's conclusion illustrated that LXM-loaded cubosomal dispersion could be considered a promising nano-carrier for transdermal drug delivery.

“Plurol will not miss the boat”: A new manifesto of galantamine conveyance

Liquid crystalline nanoparticles (LCNPs) are lipid self-assembled nanostructures that meet plenty of advantageous features. The commonly used substrates for LCNPs preparation are glyceryl monooleate. The impact of other LCNPs forming substrates like Plurol® has not been extensively explored. Galantamine (GAL) is used as a typical therapy to control the symptoms of Alzheimer's disease (AD). The existing study intends to study Plurol® as an emerging cart for the conveyance of GAL to the brain after nasal application. Different stabilizers; Poloxamer 407, Myri 53 and Myrj 59 have been studied along with different water content in order to select the best formula that can permeate both the nasal mucosa and the BBB. In vitro and in vivo examinations had been performed to test for the applicability of the fabricated formulae. Results revealed the successful encapsulation of GAL into the developed Plurol-based cubosomes. The optimized formula had a particle size of 205 ± 4.38 nm, PDI of 0.356 ± 0.016, zeta potential of 2.44 ± 0.947 and entrapment efficiency of 60.8%. Y-maze task results showed that GAL LCNPs treated resulted in 39% boost in percentage alternation relative to the Streptozotocin (STZ) group. In addition, results of Morris water maze task showed that mice received GAL cubosomal gel settled longer in the target quadrant (time increased by 34.67 s relative to that recorded for the STZ group). The ex vivo and in vivo results point to the better performance of the cubic gel in terms of enhanced permeation through nasal mucosa and reversed STZ-induced cognitive impairment compared to the cubosomal dispersion.

Advantages of Cubosomal Formulation for Gatifloxacin Delivery in the Treatment of Bacterial Keratitis: In Vitro and In Vivo Approach Using Clinical Isolate of Methicillin-Resistant Staphylococcus aureus.

The objective of this study was to enhance the corneal permeation of gatifloxacin (GTX) using cubosomal nanoparticle as a delivery system. Cubosomal nanoparticle loaded with GTX was prepared and subjected for in vitro and in vivo investigations. The prepared GTX-loaded cubosomal particles exhibited nanoparticle size of 197.46 ± 9.40 nm and entrapment efficiency of 52.8% ± 2.93. The results of ex vivo corneal permeation of GTX-loaded cubosomal dispersion show approximately 1.3-fold increase compared to GTX aqueous dispersion. The incorporation of GTX into cubosomal particles resulted in a fourfold reduction in the minimum inhibitory concentration (MIC) value for the GTX cubosomal particles relative to GTX aqueous dispersion. Furthermore, the enhanced corneal penetration of GTX-loaded cubosomal dispersion compared was evident by a significant decrease in the area % of corneal opacity in MRSA infected rats. Moreover, these results were confirmed by photomicrographs of histological structures of corneal tissues from rats treated with GTX-cubosomal dispersion which did not present any change compared to that of the normal rat corneas. In conclusion, treatment of ocular bacterial infections and reduction in the probability of development of new resistant strains of MRSA could be accomplished with GTX-loaded cubosomal nanoparticles.

Fabrication and Evaluation of Lidocaine Hydrochloride loaded Cubosomes

Topical delivery of local anaesthetic drugs such as Lidocaine HCl using carriers and novel nanotechnology can enhance effective drug permeation through the skin into deeper layers and exhibit desirable duration of action. The present study was aimed to formulate and evaluate Lidocaine HCl loaded cubosomes (LHLCs) for sustained therapeutic topical action. Cubosomes emanated as favourable means for the delivery of the drug. LHLCs were prepared by top-down technique using lipid and polymer. Eight formulations of LHLCs were prepared using different concentrations of glyceryl monooleate (GMO) and Poloxamer 407 (P-407). Local anaesthetics create loss of sensation in particular region of the body by inhibiting impulse generation and propagation. Lidocaine HCl is most commonly used amino amide local anaesthetic. It is used as local, topical, intravenous, epidural, peripheral and spinal anaesthesia. The prepared cubosomal dispersions were evaluated to determine surface morphology, particle size, poly dispersibility index (PDI), zeta potential, entrapment ability, tissue distribution studies, and in vitro drug release studies. Scanning Electron Microscopic analysis confirmed that drug was encapsulated in bicontinuous structure. The maximum entrapment efficiency was found to be 89.85±1.1% with vesicle size as 228±2.1nm, charge as -5.68±2.7, PDI as 0.295 and 98.83%± 0.12 in vitro drug release at the end of 12 hr for F7 formulation, which was confirmed as optimized cubosomal dispersion.

Cubosomes: A Potential Drug Delivery System

The discovery of cubosomes is a classic story and deals with food science, differential geometry, biological membranes and digestive processes. Cubosomes are highly balanced and nanoparticles in design formed primarily from the lipid cubic state and protected by a polymer-based outer circle. Hydrating a surfactant that designates cubic phase and then disperses a solid state into smaller particles, typically forms cubosomes. They behave concretely like rheology with unique properties of practical interest. Cubosome formation can be optimized to engineer pore size or consist of bioactive lipids, polymers can be used for targeting to the outer circle and they are highly secure under physiological conditions. This type of network structure gives them greater drug trapping potential. Related to liposomes, the structure adds a significantly more enhanced membrane surface area to trap membrane proteins and small drug entities. Cubosome may increase the solubility of poorly soluble drugs. Due to modern advances, nanoparticles patterns include drug delivery, membrane bioreactors, artificial cells and biosensors and can be engineered both in vitro. This review, focused on modern advances in cubosome technology, not only facilitates their work but also contributes to standard procedures for the rational design of innovative systems for biomedical applications. Due to the nature of cubosome dispersion being bio-adhesive and biocompatible, as well as having different properties, cubosomes are functional systems, administered in a variety of ways, such as orally and parenterally. Cubosome structure is investigated through electron microscopy, light scattering, X-rays, and NMR, although some researchers are studying the potential of cubosomes as a delivery system.

Albendazole-loaded cubosomes interrupt the ERK1/2-HIF-1α-p300/CREB axis in mice intoxicated with diethylnitrosamine: A new paradigm in drug repurposing for the inhibition of hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. It was suggested that albendazole (ABZ) is a powerful inhibitor of several carcinoma types. However, the bioavailability of ABZ is very poor. Additionally, the mechanisms underlying the antitumor effects of ABZ may go beyond its tubulin-inhibiting activity. Therefore, we aimed to examine the effects of ABZ suspension (i.p. and p.o.) and ABZ-loaded cubosomes (LC) on the diethylnitrosamine-induced HCC in mice. ABZ-loaded nanoparticles exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 93.26 ± 2.48% of ABZ. The in vivo absorption study confirmed a two-fold improvement in the relative bioavailability compared with aqueous ABZ suspension. Furthermore, the oral administration of ABZ cubosomal dispersion demonstrated regression of tumor production rates that was comparable with ABZ (i.p.). ABZ relieved oxidative stress, improved liver function, and decreased necroinflammation score. The antiangiogenic activity was evident as ABZ effectively downregulated tissue expression of CD34, mRNA expression of CD309 and VEGF at the protein expression level. Besides, lower levels of MMP-9 and CXCR4 indicated antimetastatic activity. ABZ showed a considerable level of apoptotic activity as indicated by increased mRNA expression level of p53 and the increased Bax/BCL-2 ratio and active caspase-3. Additionally, Ki-67 expression levels were downregulated showing an antiproliferative potential. These protective effects contributed to increasing survival rate of diethylnitrosamine-treated mice. These effects found to be mediated via interrupting ERK1/2-HIF-1α-p300/CREB interactions. Therefore, our findings revealed that disrupting ERK1/2-HIF-1α-p300/CREB interplay might create a novel therapeutic target for the management of HCC.

Intranasal versus intraperitoneal Myrj 59-stabilized cubosomes: A potential armamentarium of effective anti-diabetic therapy

The present study is concerned with the suitability of using Myrj 59, out-performing the commonly used stabilizer i.e., poloxamer, for preparation of cubosomes on one hand and gives an insight into the need for distinctive choice of delivery system and administration route towards better diabetes pharmacotherapy on the other hand. In light, repaglinide (REP) cubosomal dispersion and in-situ gel forms were prepared and physicochemically characterized. The selected cubosomal forms were tested for in-vitro drug release and administered via intranasal (IN) and intraperitoneal (IP) routes and compared with Intravenous (IV) REP solution regarding in-vivo antidiabetic efficacy. The results confirmed the formation of cubic nanostructures (170−233 nm), entrapping high REP amounts (93.2–95.66 %). Sustained REP release from selected cubosomal forms was realized with no burst release. Upon in-vivo assessment, IN and IP REP cubosomes and cubosomal gel exhibited superior long-acting in-vivo traits over IV REP solution, respecting percentages of maximum reduction, total decrease in BG levels, and the pharmacological availability. Moreover, IP REP cubosomes and cubosomal gel revealed higher values of the aforementioned parameters than IN counterparts. In conclusion, IN and IP administration of the newly developed cubosomal forms could proffer feasible options for an optimal control of BG levels.

In vitro and in vivo evaluation of cubosomal nanoparticles as an ocular delivery system for fluconazole in treatment of keratomycosis.

The objective of the present study was to enhance ocular antifungal activity of fluconazole (FCZ) in treatment of keratomycosis through incorporation into cubosomal nanoparticles. FCZ-loaded cubosomal dispersions were prepared by emulsification method according to 23 full factorial design. Design-Expert® software was used to study the effects of different formulation factors on properties of FCZ-loaded cubosomal dispersions and select the optimal formulation. Eight FCZ-loaded cubosomal dispersions were prepared and were in vitro and in vivo evaluated. In vitro, the results revealed that the optimum formula exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 85.70 ± 2.56% of FCZ. The ex vivo permeation study confirmed a two-fold enhancement in FCZ permeation through rabbit cornea compared to aqueous FCZ solution. Furthermore, in vivo ocular tolerance and histopathological studies proved the efficacy and safety FCZ-loaded cubosomal dispersion in treatment of induced keratomycosis in rats compared to aqueous FCZ solution after topical ocular application. In conclusion, the obtained results indicated that cubosomes could be promising ocular drug delivery system for enhancing antifungal activity of FCZ in treatment of fungal keratitis in rats. Graphical abstract.

Stabilizing excipients for engineered clopidogrel bisulfate procubosome derived in situ cubosomes for enhanced intestinal dissolution: Stability and bioavailability considerations

Clopidogrel bisulfate (CB) is a golden antiplatelet treatment, yet its benefits are limited by its low bioavailability (<50%) caused by poor intestinal solubility and absorption. The present study aims to improve CB intestinal solubility and absorption through developing a novel stable dry CB procubosomes tablets ready to disintegrate and re-disperse upon dilution in the GIT forming in situ CB cubosome nanoparticles while simultaneously overcome the poor stability of conventional cubosome dispersion at room temperature. Glyceryl monooleate based CB cubosome dispersion was prepared using Poloxamer 407 as surfactant, freeze dried using different stabilizing excipients (dextrose, mannitol and avicel) then compressed into procubosome tablets. The effect of excipient's physicochemical properties on the flowability, in vitro dissolution and stability at accelerated conditions (40 ± 2 °C/75 ± 5% RH) were evaluated. The prepared procubosomes exhibited an excipient type dependent dissolution profile where Avicel based procubosome tablet CF2 showed the highest in vitro dissolution profile among other excipients used during the freeze drying process. Upon transition to intestinal pH of 6.8 to mimic the drug absorption site, CF2 procubosome Avicel tablet, was able to preserve the enhanced CB release profile (99.6 ± 6.92%) compared to commercial Plavix® where, CB dissolved % dropped dramatically to 79.1 ± 2.45%. After storage for six months, CF2 retained the fresh tablet drug content of 98.5 ± 5.82% and dissolution properties. Moreover, following oral administration in rabbits, CF2 showed higher relative bioavailability (153%) compared to commercial Plavix® with significant higher Cmax,shorter tmax, as well as enhanced antiplatelet activity.