Vesicular drug delivery systems have recently gained attention as a way of improving dosing accuracy for drugs with poor transdermal permeation. The current study focuses on utilization of the natural biocompatible vesicles to formulate vardenafil nanoethosomes (VRD-NE), for the enhancement of their transdermal permeation and bioavailability. Fifteen formulations were prepared by thin-layer evaporation technique according to Box-Behnken design to optimize formulation variables. The effects of lipid composition, sonication time, and ethanol concentration on particle size and encapsulation efficiency were studied. The diffusion of vardenafil (VRD) from the prepared nanoethosomes specified by the design was carried out using automated Franz diffusion cell apparatus. The optimized formula was investigated for in vivo pharmacokinetic parameters compared with oral VRD suspension. Confocal laser scanning microscopy images were used to confirm enhanced diffusion release of VRD in rat skin. The results showed that the optimized formula produced nanoethosomes with an average size of 128 nm and an entrapment efficiency of 76.23%. VRD-NE provided a significant improvement in permeation with an enhancement ratio of 3.05-fold for a film made with optimally formulated VRD-NE compared with a film made with VRD powder. The transdermal bioavailability of VRD from the nanoethosome film was approximately twofold higher than the oral bioavailability from an aqueous suspension. VRD-NE thus provide a promising transdermal drug delivery system. As a result, management of impotence for a longer duration could be achieved with a reduced dosage rate that improves patient tolerability and compliance for the treatment of erectile dysfunction.

To determine the use of antidepressants (ADs) in people with sub-threshold depression (SD); the lifetime prevalence of mania and hypomania in SD and the link between ADs use, bipolarity and anxiety disorders in SD.

Dysregulation of the transforming growth factor-β1 (TGF-β1)/selected small mother against decapentaplegic (SMAD) pathway can be implicated in development of age-related macular degeneration (AMD), and the delivery of TGF-β1 could be beneficial for AMD. We developed a new ophthalmic formulation of TGF-β1 assessing the ocular pharmacokinetic profile of TGF-β1 in the rabbit eye. Small unilamellar vesicles (SUV) loaded with TGF-β1 were complemented with Annexin V and Ca2+, and the vitreous bioavailability of TGF-β1 was assessed after topical ocular administration by a commercial ELISA kit. We detected high levels of TGF-β1 (Cmax 114.7 ± 12.40 pg/mL) in the vitreous after 60 min (Tmax) from the topical application of the liposomal suspension. Ocular tolerability was also assessed by a modified Draize's test. The new formulation was well tolerated. In conclusion, we demonstrated that the novel formulation was able to deliver remarkable levels of TGF-β1 into the back of the eye after topical administration. Indeed, this TGF-β1 delivery system may be useful in clinical practice to manage ophthalmic conditions such as age-related macular degeneration, skipping invasive intraocular injections.

Behavioral and psychological symptoms of dementia are symptoms of disturbed perception, mood, behavior, and thought content that occurred frequently. These symptoms, which include apathy, depression, anxiety, psychosis, agitation, and aggression, can serve as predictors of and early clinical diagnostic markers for Alzheimer's disease (AD) and are common precipitants of institutional care. Agitation and psychosis are associated with accelerated disease progression and increased tau phosphorylation in patients with AD. Current guidelines recommend the use of second-generation antipsychotics for the treatment of agitation and psychosis in AD, but only after first-line non-pharmacological interventions and for no longer than 12 weeks because long-term use of these drugs is associated with an increased risk of mortality and an increased frequency of cerebrovascular events. Therefore, new antipsychotic drugs with improved efficacy and safety are needed as an alternative to current antipsychotic drugs. In this report, we discuss some of the most relevant advances in the field of agitation and psychosis in AD and focus on the recent positive clinical evidence observed with two new antipsychotics drugs: brexpiprazole and pimavanserin. Brexpiprazole is a receptor partial agonist (D2, D3, 5-HT1A), receptor antagonist (5-HT2A/B, α1B/α2C) according to the neuroscience-based nomenclature. Two recent phase III clinical trials have shown that brexpiprazole 2 mg/day is effective for the treatment of agitation in patients with AD and has an improved tolerability and safety profile compared with currently available second-generation antipsychotics. Pimavanserin is a receptor antagonist (5-HT2A, 5-HT2C) that has been given market authorization for psychosis occurring in Parkinson's disease. Recent phase II studies suggest that this drug is effective in AD patients with more severe psychosis, although further long-term studies are needed to better define the efficacy and long-term safety profile of pimavanserin for the treatment of psychosis in AD.

Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery.

Successful gene therapy requires the development of vectors that enable efficient delivery of genetic materials (e.g., pDNA or siRNA) to targeted cells, without degradation of the genetic materials. We have shown that nanoparticles formed by combining cell-penetrating peptide and pDNA (CPP-pDNA) into complexes and condensing them with calcium chloride can provide gene nanoparticles with high transfection efficiency and low cytotoxicity. In this work, we compare in situ measurements of the membrane insertion potential of three arginine-based gene nanoparticles (RW9-NPs, R9-NPs, and RH9-NPs) using four lipid compositions and two types of model membrane (Langmuir monolayers vs. supported bilayers) with their transfection efficiency in two human cancer cell lines. Using a Langmuir trough, we measured the membrane insertion potential of our gene nanoparticles to model membrane monolayers. A Quartz Crystal Microbalance with Dissipation (QCM-D) technique was used to monitor the adsorption of these nanoparticles to lipid bilayers of various compositions. Finally, gene expression using these nanoparticles was measured in breast cancer and cervical cancer cell lines. Our cell culture studies indicate that although R9-NPs and RW9-NPs show a significant increase in transfection efficiency compared to free pDNA, RH9-NPs do not show any significant difference. Both the Langmuir monolayer and QCM-D bilayer studies show that these results are best reflected in the in situ measurement assays when lipid systems containing a mixture of phospholipids, cholesterol, and sphingolipids are used. It is important to note that the mechanism of penetration is expected to differ for RW9 vs. R9; however, gene nanoparticles containing either of these CPPs show similar transfection efficiency. Our results therefore demonstrate that the design of predictive assays for gene therapy using CPPs must involve carefully chosen model lipid membrane systems that accurately represent the varying compositions of cell membranes.

The last decades of biological, toxicological, and pharmacological research have deeply changed the way researchers select the most appropriate 'pre-clinical model'. The absence of relevant animal models for many human diseases, as well as the inaccurate prognosis coming from 'conventional' pre-clinical models, are among the major reasons of the failures observed in clinical trials. This evidence has pushed several research groups to move more often from a classic cellular or animal modeling approach to an alternative and broader vision that includes the involvement of microfluidic-based technologies. The use of microfluidic devices offers several benefits including fast analysis times, high sensitivity and reproducibility, the ability to quantitate multiple chemical species, and the simulation of cellular response mimicking the closest human in vivo milieu. Therefore, they represent a useful way to study drug-organ interactions and related safety and toxicity, and to model organ development and various pathologies 'in a dish'. The present review will address the applicability of microfluidic-based technologies in different systems (2D and 3D). We will focus our attention on applications of microchip electrophoresis (ME) to biological and toxicological studies as well as in drug discovery and development processes. These include high-throughput single-cell gene expression profiling, simultaneous determination of antioxidants and reactive oxygen and nitrogen species, DNA analysis, and sensitive determination of neurotransmitters in biological fluids. We will discuss new data obtained by ME coupled to laser-induced fluorescence (ME-LIF) and electrochemical detection (ME-EC) regarding the production and degradation of nitric oxide, a fundamental signaling molecule regulating virtually every critical cellular function. Finally, the integration of microfluidics with recent innovative technologies-such as organoids, organ-on-chip, and 3D printing-for the design of new in vitro experimental devices will be presented with a specific attention to drug development applications. This 'composite' review highlights the potential impact of 2D and 3D microfluidic systems as a fast, inexpensive, and highly sensitive tool for high-throughput drug screening and preclinical toxicological studies.

Peptic ulcer disease is an injury of the alimentary tract that leads to a mucosal defect reaching the submucosa. This study aimed to formulate and optimize omega-3 oil as a self-nanoemulsifying drug delivery system (SNEDDS) to achieve oil dispersion in the nano-range in the stomach to augment omega-3 oil gastric ulcer protection efficacy. Three SNEDDS components were selected as the design factors: the concentrations of the oil omega-3 (X1, 10-30%), the surfactant tween 20 and Kolliphor mixture (X2, 20-40%), and the cosurfactant transcutol (X3, 40-60%). The mixture experimental design proposed twenty-three formulations with varying omega-3 SNEDDS formulation component percentages. The optimized omega-3 SNEDDS formula was investigated for gastric ulcer protective effects by evaluating the ulcer index and by the determination of gastric mucosa oxidative stress parameters. Results revealed that optimized omega-3-SNEDDS achieved significant improvement in the gastric ulcer index in comparison with pure omega-3 oil. Histopathological findings confirmed the protective effect of the formulated optimized omega-3 SNEDDS in comparison with omega-3 oil. These findings suggest that formulation of omega-3 in the form of a SNEDDS would be more effective in gastric ulcer protection than the administration of omega-3 as a crude oil.

Flibanserin (FLB) is a multifunctional serotonergic agent that was recently approved by the FDA for the oral treatment of premenopausal women with hypoactive sexual desire disorder. FLB is a centrally acting drug that has a low oral bioavailability of 33% owing to its exposure to the hepatic first-pass effect, as well as its pH-dependent solubility, which could be an obstacle hindering the drug dissolution and absorption via mucosal barriers. Thus, this work aimed at overcoming the aforementioned drawbacks and promoting the nose-to-brain delivery of FLB via the formulation of an intra-nasal in situ niosomal gel. The Box-Behnken design was employed to study the impact of Span® 85 concentration (X1), hydration time (X2), and pH of the hydrating buffer (X3) on the vesicle size and drug entrapment. The optimized formulation exhibited a spherical shape with a vesicular size of 46.35 nm and entrapment efficiency of 92.48%. The optimized FLB niosomes integrated into gellan gum-based in situ gel exhibited enhanced ex vivo permeation and improved plasma and brain concentrations after nasal administration in rats compared to raw FLB. These findings highlight the capability of the proposed intra-nasal FLB niosomal in situ gel to boost the drug bioavailability and to promote its direct delivery to the brain.

Staphylococcus aureus is a Gram-positive bacterium responsible for a variety of mild to life-threatening infections including bone infections such as osteomyelitis. This bacterium is able to invade and persist within non-professional phagocytic cells such as osteoblasts. In the present study, four different S. aureus strains, namely, 2SA-ST239-III (ST239), 5SA-ST5-II (ST5), 10SA-ST228-I (ST228), and 14SA-ST22-IVh (ST22), were tested for their ability to modulate cell viability in MG-63 osteoblast-like cells following successful invasion and persistence. Methicillin-sensitive S. aureus (MSSA) ATCC-12598-ST30 (ST30) was used as control strain. Despite being proven that ST30, ST239, and ST22 have a similar ability to internalize and persist in MG-63 osteoblast-like cells under our experimental conditions, we demonstrated that the observed decrease in cell viability was due to the different behavior of the considered strains, rather than the number of intracellular bacteria. We focused our attention on different biochemical cell functions related to inflammation, cell metabolism, and oxidative stress during osteoblast infections. We were able to show the following: (1) ST30 and ST239 were the only two clones able to persist and maintain their number in the hostile environment of the cell during the entire period of infection; (2) ST239 was the only clone able to significantly increase gene expression (3 and 24 h post-infection (p.i.)) and protein secretion (24 h p.i.) of both interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in MG-63 osteoblast-like cells; (3) the same clone determined a significant up-regulation of the transforming growth factorbeta 1 (TGF-β1) and of the metabolic marker glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNAs at 24 h p.i.; and (4) neither the MSSA nor the four methicillin-resistant S. aureus (MRSA) strains induced oxidative stress phenomena in MG-63 cells, although a high degree of variability was observed for the different clones with regard to the expression pattern of nuclear factor E2-related factor 2 (Nrf2) and its downstream gene heme oxygenase 1 (HO-1) activation. Our results may pave the way for an approach to S. aureus-induced damage, moving towards individualized therapeutic strategies that take into account the differences between MSSA and MRSA as well as the distinctive features of the different clones. This approach is based on a change of paradigm in antibiotic therapy involving a case-based use of molecules able to counteract pro-inflammatory cytokines activity such as selective cytokine signaling inhibitors (IL-6, TNF-α).

Prostate cancer (PC) is emerging as one of the leading causes of mortality and morbidity worldwide. Curcumin (CUR) is a well-known phytochemical, and scorpion venom (SV) is a natural peptide with proven anticancer properties. However, these natural bioactive agents are limited by low solubility, low bioavailability, poor thermal stability, and short half-lives. Therefore, the aim of this study was to fabricate SV-conjugated CUR phytosomes as promising functionalized nanovesicles and assess their anticancer efficacy in human prostatic cancer PC3 cells. CUR-Phytosome-SV was fabricated using experimental design software in which the zeta potential and particle sizes were used as dependent variables. The anticancer effect of the fabricated formulation was determined by performing a tetrazolium (MTT) assay, cell cycle analysis, annexin V staining, and examining the expression levels of Bcl-associated X-protein (Bax), p53, caspase-3, B-cell lymphoma 2 (Bcl-2), nuclear factor kappa beta (NF-kB), and tumor necrosis factor alpha (TNF-α). The particle size of the nanoconjugates was found to be in the range of 137.5 ± 7.9 to 298.4 ± 11.9 nm, and the zeta potential was 2.9 ± 0.1 to 26.9 ± 1.2 mV. The outcome of the MTT assay showed that curcumin-Phospholipon®-scorpion venom (CUR-PL-SV) exhibited a satisfactory level of cytotoxicity, and the IC50 was found to be lower than CUR and PL-SV individually. Cell cycle analysis showed predominantly cell cycle arrest at the G2-M and pre-G1 phases. In contrast, annexin V staining showed significant early and late apoptosis events in addition to increased necrosis when PC3 cells were treated with CUR-PL-SV. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed a reduction in expression of Bax, p53, caspase-3, NF-kB, TNF-α, and an increase in Bcl-2 expression. Moreover, a MMP analysis showed a reduction in mitochondrial permeability and hence confirmed the superior anticancer potential of CUR-PL-SV. Thus, the present study showed significant anticancer potency of SV-conjugated CUR phytosomes against human prostatic cancer PC3 cells, making it a novel treatment approach for PC.

In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor's clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging the real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields, including psychiatry and neurology. In order to illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer's disease, schizoaffective disorder, and autism spectrum disorders. To facilitate a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom-agnostic, categorization models in clinical neurology and psychiatry for precision medicine solutions, we engage in a speculative intellectual exercise gravitating around BACE-related science, which is used as a paradigmatic case here. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by highthroughput techniques embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in neurology and psychiatry.

Impaired diabetic wound healing is a major concern for health care professionals worldwide, imposing an intense financial burden and reducing the quality of life of patients. A dysregulation of this process can be responsible for the development of intractable ulcers and the formation of excessive scars. Therefore, the identification of novel pharmacological strategies able to promote wound healing and restore the mechanical integrity of injured tissue becomes essential. In the present study, fluoxetine ecofriendly nanoemulsion (FLX-EFNE) was prepared and its potential efficacy in enhancing wound healing was tested in diabetic rats. The Box-Behnken response surface design was used to select the optimized formulation that was prepared by the high-shear homogenization-based technique. A Zetasizer was used for the characterization of the optimized formulation, providing a FLX-EFNE with a globule size of 199 nm. For the in vivo study, a wound was induced by surgical methods, and diabetic rats (streptozotocin-induced) were divided into five groups: untreated control, vehicle-treated, FLX, FLX-EFNE, and positive control receiving a commercially available formula. The treatment continued from the day of wound induction to day 21. Then, the animals were sacrificed and skin tissues were collected at the site of wounding and used for biochemical, histopathological, immunohistochemical, and mRNA expression assessments. In the FLX-EFNE treated group, the rate of wound contraction and signs of healing were significantly higher compared to all other groups. In addition, angiogenesis, proliferation, and collagen deposition were enhanced, while oxidative stress and inflammation decreased. The present data highlight the enhanced wound healing activity of the optimized FLX-EFNE formulation.

Icariin (ICA), a main active compound of the Epimedium genus, is used as an aphrodisiac in traditional Chinese herbal medicine. Despite its therapeutic efficacy, ICA displays reduced oral absorption, and therefore, low bioavailability hindered its clinical application. Implementing nanotechnology in the field of formulation has been a focus to improve the efficacy of ICA. In this regard, polymeric nanoparticles find a potential application as drug delivery systems. A nanosphere formula was designed, aiming to improve the drug's efficacy. The proposed ICA nanosphere formula (tocozeinolate) was optimized using D-optimal response surface design. The concentrations of ICA (X1), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, X2), zein (X3), and sodium deoxycholate (SDC, X4) expressed as percentages were investigated as quantitative independent variables. As per the experimental design, 23 formulations were developed, which were investigated for particle size (PS, nm), zeta potential (ZP, mV), and entrapment efficiency (EE, %) as response parameters. Numerical optimization and desirability approach were employed to predict the optimized variable levels that, upon combination, could result in minimized size and maximized zeta potential and ICA entrapment. The optimized ICA-tocozeinolate nanospheres showed a particle size of 224.45 nm, zeta potential of 0.961 mV, and drug entrapment of 65.29% that coincide well with the predicted values. The optimized ICA-tocozeinolate nanospheres were evaluated for sexual behavior in Wistar male rats compared to raw ICA at equivalent doses (20 mg/kg). In vivo assessment results showed significant sexual behavior enhancement by the optimized formulation, as evidenced by decreased average time of both mount latency (ML) and ejaculation latency (EL) to almost half those of raw ICA. Additionally, intromission latency (IL) time was reduced by 41% compared to the raw ICA. These results highlighted the potential of the proposed ICA-tocozeinolate nanospheres as a promising platform for improving the delivery and efficacy of therapeutic agents.

The present study aimed to design and optimize, a nanoconjugate of gabapentin (GPN)-melittin (MLT) and to evaluate its healing activity in rat diabetic wounds. To explore the wound healing potency of GPN-MLT nanoconjugate, an in vivo study was carried out. Diabetic rats were subjected to excision wounds and received daily topical treatment with conventional formulations of GPN, MLT, GPN-MLT nanoconjugate and a marketed formula. The outcome of the in vivo study showed an expedited wound contraction in GPN-MLT-treated animals. This was confirmed histologically. The nanoconjugate formula exhibited antioxidant activities as evidenced by preventing malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic exhaustion. Further, the nanoconjugate showed superior anti-inflammatory activity as it inhibited the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This is in addition to enhancement of proliferation as indicated by increased expression of transforming growth factor-β (TGF- β), vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor receptor-β (PDGFRB). Also, nanoconjugate enhanced hydroxyproline concentration and mRNA expression of collagen type 1 alpha 1 (Col 1A1). In conclusion, a GPN-MLT nanoconjugate was optimized with respect to particle size. Analysis of pharmacokinetic attributes showed the mean particle size of optimized nanoconjugate as 156.9 nm. The nanoconjugate exhibited potent wound healing activities in diabetic rats. This, at least partly, involve enhanced antioxidant, anti-inflammatory, proliferative and pro-collagen activities. This may help to develop novel formulae that could accelerate wound healing in diabetes.

(1) Background: 2-Methoxyestradiol (2ME) is a metabolite of estrogens and possesses promising anti-proliferative and cytotoxic activities. However, it suffers unfavorable pharmacokinetic characteristics such as absorption after oral administration. The aim of this study was to prepare an optimized 2ME self-nanoemulsifying drug delivery system (2ME-SNEDDS) and evaluate its cytotoxicity and pro-apoptotic activities in MCF-7 breast cancer cells. (2) Methods: For optimization of the 2ME-SNEDDS, a three-component system was used in the D-optimal mixture experimental study. MCF-7 cells were incubated with the 2ME-SNEDDS and subjected to an assessment of growth inhibition, cell cycle progression, annexin V staining, caspase-3 concentration, Bax, Bcl-2, and cyclin D1 mRNA expression, and reactive oxygen species (ROS) generation. (3) Results: The optimized formula had a globule size of 94.97 ± 4.35 nm. Zeta potential was found to be -3.4 ± 1.2 mV with a polydispersity index (PDI) of 0.34. In addition, 96.3  ± 4.3% of 2ME was released from the 2ME-SNEDDS within 24 h using the activated analysis bag technique. Moreover, the prepared 2ME-SNEDDS exhibited a significant enhancement of the anti-proliferative activity against MCF-7 cells in comparison to raw 2ME. This was associated with cyclin D1 expression down-regulation and the accumulation of cells in the G0/G1 and G2/M phases. The pro-apoptotic activities of the 2ME-SNEDDS were confirmed by annexin V staining, which indicated enhanced early and late cell death. This accompanied modulation of the mRNA expression of Bax and Bcl-2 in favor of apoptosis. The 2ME-SNEDDS significantly enhanced cleaved caspase-3 concentration in comparison to raw 2ME. In addition, the 2ME-SNEDDS significantly increased the generation of ROS in MCF-7 cells. (4) Conclusions: The 2ME-SNEDDS exhibits enhanced cytotoxicity and pro-apoptotic activity in MCF-7 cells. This is mediated by, at least partially, ROS generation.

The outbreak of the COVID-19 pandemic in China has become an urgent health and economic challenge. There is a current race for developing strategies to treat and/or prevent COVID-19 worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes COVID-19. The aim of the present work was to evaluate the efficacy of the combined complex (nano-conjugates) of two FDA-approved drugs, sitagliptin (SIT) and glatiramer acetate (GA), against a human isolate of the SARS-CoV-2 virus. SIT-GA nano-conjugates were prepared according to a full three-factor bilevel (23) factorial design. The SIT concentration (mM, X1), GA concentration (mM, X2), and pH (X3) were selected as the factors. The particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for the Fourier-transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM) was carried out. In addition, the half-maximal inhibitory concentration (IC50) in Vero-E6 epithelial cells previously infected with the virus was investigated. The results revealed that the optimized formula of the prepared complex was a 1:1 SIT:GA molar ratio at a pH of 10, which met the required criteria with a desirability value of 0.878 and had a particle size and zeta potential at values of 77.42 nm and 27.67 V, respectively. The SIT-GA nano-complex showed antiviral potential against an isolate of SARS-CoV-2 with IC50 values of 16.14, 14.09, and 8.52 µM for SIT, GA, and SIT-GA nano-conjugates, respectively. Molecular docking has shown that the formula's components have a high binding affinity to the COVID 3CL protease, essential for coronavirus replication, paralleled by 3CL protease inhibition (IC50 = 2.87 µM). An optimized formulation of SIT-GA could guarantee both enhanced deliveries to target cells and improved cellular uptake. Further clinical studies are being carried out to validate the clinical efficacy of the optimized formulation against SARS-CoV-2.

Research on statins highlights their potent cytotoxicity against cancer cells and their potential for cancer prevention. The aim of the current study was to examine whether loading lovastatin (LVS) in zein (ZN) nanoparticles (NPs) would potentiate the anti-proliferative effects of LVS and enhance its proliferation-inhibiting activity in HepG2 cells. LVS-ZN NPs were prepared and showed excellent characteristics, with respect to their particle size, zeta potential, diffusion, and entrapment efficiency. In addition, they showed the most potent anti-proliferative activity against HepG2 cells. ZN alone showed an observable anti-proliferative that was significantly higher than that of raw LVS. Furthermore, LVS uptake by HepG2 cells was greatly enhanced by the formulation in ZN. A cell cycle analysis indicated that LVS induced a significant cell accumulation in the G2/M and pre-G phases. In this regard, the LVS-ZN NPs exhibited the highest potency. The accumulation in the pre-G phase indicated an enhanced pro-apoptotic activity of the prepared formula. The cells incubated with the LVS-ZN NPs showed the highest percentage of cells with annexin-V positive staining. In addition, the same incubations showed the highest content of caspase-3 enzyme in comparison to raw LVS or ZN. Thus, the loading of LVS in ZN nanoparticles enhances its anti-proliferative activity against HepG2 cells, which is attributed, at least partly, to the enhanced cellular uptake and the induction of apoptosis.

Peptic ulcer disease, a painful lesion of the gastric mucosa, is considered one of the most common gastrointestinal disorders. This study aims to investigate the formulation of pumpkin seed oil (PSO)-based nanostructured lipid carriers (NLCs) to utilize PSO as the liquid lipid component of NLCs and to achieve oil dispersion in the nano-range in the stomach.

Thymoquinone (TQ), a natural polyphenol, has been associated with various pharmacological responses; however, low bioavailability of TQ limits its clinical application. Thus, a novel phytosomal delivery system of TQ-Phospholipon® 90H complex (TQ-phytosome) was developed by refluxing combined with anti-solvent precipitation. This TQ delivery system was optimized by a three-factor, three-level Box-Behnken design. The optimized TQ-phytosome size was (45.59 ± 1.82 nm) and the vesicle size was confirmed by transmission electron microscopy. The in vitro release pattern of the formulation indicated a biphasic release pattern, where an initial burst release was observed within 2 h, followed by a prolonged release. A remarkable increase in dose-dependent cytotoxicity was evident from the significant decrease in IC50 value of TQ-phytosomes (4.31 ± 2.21 µM) against the A549 cell line. The differential effect of TQ-phytosomes in cell cycle analysis was observed, where cancer cells were accumulated on G2-M and pre-G1 phases. Furthermore, increased apoptotic induction and cell necrosis of TQ-phytosomes were revealed with the annexin V staining technique via activation of caspase-3. In reactive oxygen species (ROS) analysis, TQ-phytosomes acted to significantly increase ROS generation in A549 cells. In conclusion, the sustained release profile with significantly-improved anticancer potential could be obtained with TQ by this phytosomal nanocarrier platform.