Ahmed, M. A., A. M. Al-mahallawi, S. N. El-helaly, and W. H. Abd-Elsalam, "The effect of the saturation degree of phospholipid on the formation of a novel self-assembled nano-micellar complex carrier with enhanced intestinal permeability.", International journal of pharmaceutics, vol. 569, pp. 118567, 2019. Abstract

The aim of this research was to formulate a novel nano-micellar complex carrier with intrinsically enhanced intestinal permeability for rosuvastatin calcium (RSV); as a model of BCS class III active pharmaceutical ingredients (APIs). The model drug is used primarily for treating hypercholesterolemia. Three phospholipid types with different degrees of saturation were chosen for the study. The saturation degree of the phospholipids was calculated accurately by proton NMR. A D-optimal statistical design was utilized to correlate the saturation degree of the phospholipids with the physico-chemical characteristics of the prepared nano-micellar carrier. The nature of the interaction between the phospholipids and the model drug was studied by proton NMR, photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM). Molecular docking and molecular dynamics simulations were performed to understand the formation mechanism of the complex micelles on a molecular level. The results demonstrated that the interaction of the hydrophilic drug molecule with the polar head of a saturated phospholipid induces an intramolecular self-coiling of phospholipid saturated acyl chain leading to a structural transformation from a two-tailed cylindrical configuration into a one-tailed, surfactant-like configuration owing to the flexibility of the saturated chains. This transformation leads to the construction of a novel nano-micellar structure in which the drug has lower water solubility but higher lipophilicity than in traditional micelles. Permeability studies conducted on Caco-2 cells demonstrated that the novel nano-micellar carrier had superior permeability to that of the un-complexed hydrophilic drug. The optimized nano-micellar formulation showed significantly (P < 0.5) superior bioavailability in rats to that of the aqueous drug solution in terms of both the rate and extent of drug absorption. Overall, the results confirmed that the formation of the phospholipid nano-micellar complex increased the permeability of the hydrophilic BCS class III drug and converted it to a class BCS I drug by a simple and effective formulation technique.

Farag, D. B. E., C. Yousry, A. M. Al-mahallawi, H. I. El-Askary, M. R. Meselhy, and N. AbuBakr, "The efficacy of nanocubosomal systems in ameliorating submandibular salivary gland alterations in streptozotocin-induced diabetic rats.", Drug delivery, vol. 29, issue 1, pp. 62-74, 2022. Abstract

Diabetes mellitus is a challenging health problem. Salivary gland dysfunction is one of its complications. Current treatments possess numerous adverse effects. Therefore, herbal extracts have emerged as a promising approach for safe and effective treatment. However, they are required in large doses to achieve the desired effect. Accordingly, extract (OE) was incorporated into nano-sized systems to enhance its biological effects at lower dosages. OE was standardized against rosmarinic acid (RA) and then loaded into nano-cubosomal (NC) systems via a 2 full-factorial design. Two optimum nano-systems at different drug loads (2.08 or 1.04 mg-RA/mL) were selected and assessed to compare their effects in streptozotocin-induced diabetic rats against conventional OE (2.08 mg-RA/mL). Blood glucose was evaluated weekly. Submandibular salivary glands were processed for histopathological examination and nuclear factor-erythroid 2-related factor 2 (), Kelch-like ECH-associated protein 1 (), and gene expression analysis. NC systems were successfully prepared and optimized where the optimum systems showed nano-sized vesicles (210.4-368.3 nm) and high zeta potential values. results showed a significant lower blood glucose in all treated groups, with an exceptional reduction with NC formulations. Marked histopathological improvement was observed in all OEtreated groups, with OE-NC4 (2.08 mg-RA/mL) demonstrating the best features. This was supported by RT-PCR; where the OE-NC4 group recorded the highest mean value of and the least mean values of and , followed by OE-NC3 and OE groups. In conclusion, OE-loaded NC enhanced the anti-hyperglycemic effect of OE and ameliorated diabetic gland alterations compared to conventional OE. Thus, cubosomal nano-systems could be anticipated as potential carriers for the best outcome with OE.

Saber, M. M., A. M. Al-mahallawi, and B. Stork, "Metformin dampens cisplatin cytotoxicity on leukemia cells after incorporation into cubosomal nanoformulation.", Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, vol. 143, pp. 112140, 2021. Abstract

Acute lymphoblastic leukemia (ALL) is one of the most common type of leukemia in children. It is caused by abnormal cell division of the lymphoid progenitor cells in the bone marrow. In the past decade, metformin has gained increased attention for its anti-leukemic potential. Moreover, other chemotherapeutic agents were investigated for the possible superior efficacy over the existing treatments in treating ALL. Several studies examined the effect of cisplatin as a potential candidate for therapy. Here, we investigate the anti-leukemic effect of metformin and cisplatin on 697 cells. Both compounds revealed significant cytotoxic effects. Specifically designed lipid-based cubosomal nanoformulations were used as drug carriers to facilitate compound entry in low doses. Our results indicate that the use of the carrier did not affect cytotoxicity significantly. In addition, combining the drugs in different carriers demonstrated an antagonistic effect through damping the efficacy of both drugs. This was evident from experiments investigating cellular viability, annexin V/PI staining, mitochondrial membrane potential and caspase-3 activity. Taken together, it appears that metformin does not represent a suitable option for sensitizing leukemia cells to cisplatin.

Ghareeb, D. A., S. R. Saleh, M. G. Seadawy, M. S. Nofal, S. A. Abdulmalek, S. F. Hassan, S. M. Khedr, M. G. AbdElwahab, A. A. Sobhy, A. S. A. Abdel-Hamid, et al., "Nanoparticles of ZnO/Berberine complex contract COVID-19 and respiratory co-bacterial infection in addition to elimination of hydroxychloroquine toxicity.", Journal of pharmaceutical investigation, pp. 1-23, 2021. Abstract

PURPOSE: A novel coronavirus (COVID-19) that has not been previously identified in humans and has no specific treatment has recently spread. Treatment trials using antiviral and immune-modulating drugs such as hydroxychloroquine (HCQ) were used to control this viral outbreak however several side effects have emerged. Berberine (BER) is an alkaloid that has been reported to reveal some pharmacological properties including antioxidant and antimicrobial activities. Additionally, Zinc oxide nanoparticles (ZnO-NPs) possess potent antioxidant and anti-inflammatory properties. Therefore, this study was undertaken to estimate the efficiency of both BER and synthetic ZnO/BER complex as an anti-COVID-19 therapy.

METHODS: First, the ZnO/BER complex was prepared by the facile mixing method. Then in vitro studies on the two compounds were conducted including VeroE6 toxicity, anti-COVID-19 activity, determination of inhibitory activity towards papain-like proteinase (PL pro) and spike protein- and receptor- binding domain (RBD) as well as assessment of drug toxicity on RBCs.

RESULTS: The results showed that ZnO/BER complex acts as an anti-COVID-19 by inhibiting spike protein binding with angiotensin-converting enzyme II (ACE II), PL pro activity, spike protein and E protein levels, and expression of both E-gene and RNA dependent RNA polymerase (RdRp) at a concentration lower than that of BER or ZnO-NPs alone. Furthermore, ZnO/BER complex had antioxidant and antimicrobial properties where it prevents the auto oxidation of 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and the culture of lower respiratory system bacteria that affected Covid 19 patients. The ZnO/BER complex prevented as well the HCQ cytotoxic effect on both RBC and WBC (in vitro) and hepatotoxicity, nephrotoxicity and anemia that occurred after HCQ long administration in vivo.

CONCLUSION: The ZnO/BER complex can be accounted as promising anti-COVID 19 candidate because it inhibited the virus entry, replication, and assembly. Furthermore, it could be used to treat a second bacterial infection that took place in hospitalized COVID 19 patients. Moreover, ZnO/BER complex was found to eliminate the toxicity of long-term administration of HCQ in vivo

Sedeek, M. S., A. M. Al-mahallawi, R. A. A. Hussien, A. A. M. Ali, I. A. Naguib, and M. K. Mansour, "Hexosomal Dispersion: A Nano-Based Approach to Boost the Antifungal Potential of Citrus Essential Oils against Plant Fungal Pathogens.", Molecules (Basel, Switzerland), vol. 26, issue 20, 2021. Abstract

The demand for natural fungicides to replace synthetic ones has surged since toxic residues persist in soils, causing environmental contamination and posing a serious threat to worldwide public health. In the context of crop protection and enhancing the efficiency and safety of fungicides, nanotechnology is an eco-friendly strategy in managing fungal pathogens. In the present study, essential oils were isolated from the peels of four citrus fruits (, , , and ) and were investigated using gas chromatography-mass spectrometric analysis. Monoterpene hydrocarbon was the most predominant group and limonene was the most abundant in the four oils. The antifungal potential of the oils was investigated, and the most active oil () was loaded into hexosomal dispersion, and its antifungal potential was retested against the same fungi. The structurally unique nano-based formulation showed great potency for fungal control. To the best of our knowledge, it is the first time the oil of in nano-hexosomes has been formulated and its fungicidal activity examined. The data collected suggest that citrus essential oils (CEOs), especially when nano-formulated, could be successfully used in integrated fungus management programs.

Khater, S. E., A. El-Khouly, H. M. Abdel-Bar, A. M. Al-mahallawi, and D. M. Ghorab, "Fluoxetine hydrochloride loaded lipid polymer hybrid nanoparticles showed possible efficiency against SARS-CoV-2 infection.", International journal of pharmaceutics, vol. 607, pp. 121023, 2021. Abstract

Up to date, there were no approved drugs against coronavirus (COVID-19) disease that dangerously affects global health and the economy. Repurposing the existing drugs would be a promising approach for COVID-19 management. The antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs) class, have antiviral, anti-inflammatory, and anticoagulant effects, which makes them auspicious drugs for COVID 19 treatment. Therefore, this study aimed to predict the possible therapeutic activity of SSRIs against COVID-19. Firstly, molecular docking studies were performed to hypothesize the possible interaction of SSRIs to the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-COV-2) main protease. Secondly, the candidate drug was loaded in lipid polymer hybrid (LPH) nanoparticles to enhance its activity. The studied SSRIs were Fluoxetine hydrochloride (FH), Atomoxteine, Paroxetine, Nisoxteine, Repoxteine RR, and Repoxteine SS. Interestingly, FH could effectively bind with SARS-COV-2 main protease via hydrogen bond formation with low binding energy (-6.7 kcal/mol). Moreover, the optimization of FH-LPH formulation achieved 65.1 ± 2.7% encapsulation efficiency, 10.3 ± 0.4% loading efficiency, 98.5 ± 3.5 nm particle size, and -10.5 ± 0.45 mV zeta potential. Additionally, it improved cellular internalization in a time-dependent manner with good biocompatibility on Human lung fibroblast (CCD-19Lu) cells. Therefore, the study suggested the potential activity of FH-LPH nanoparticles against the COVID-19 pandemic.

Al-mahallawi, A. M., D. Ahmed, M. Hassan, and D. A. El-Setouhy, Enhanced ocular delivery of clotrimazole via loading into mucoadhesive microemulsion system: In vitro characterization and in vivo assessment, , vol. 64, pp. 102561, 2021. AbstractWebsite

This work aimed to formulate clotrimazole (CLZ), a water-insoluble antifungal drug, into a chitosan-coated microemulsion system for achieving enhanced ocular delivery. In this study, CLZ loaded microemulsions were firstly prepared according to 22 × 31 full factorial design in order to investigate the influence of different formulation variables on microemulsion properties. The selected microemulsion formulation (F4: oleic acid, Cremophor EL: Transcutol HP (1:1) and water (20, 70 and 10%, w/w, respectively)) showed nanosized spherical globules with a droplet size of 229.1 ± 0.989 nm, polydispersity index of 0.5085 ± 0.0095, and zeta potential of −33.3 ± 0.98 mV. The selected microemulsion was then coated with low molecular weight chitosan to increase the contact time with the eye surface. In vivo studies in albino rabbits demonstrated the superiority of chitosan-coated microemulsion over the uncoated microemulsion and drug suspension formulation concerning sustainment of antifungal activity over the eye surface. Moreover, the in vivo, ocular tolerance and histopathological studies conducted using male albino rabbits proved the safety of the prepared microemulsions after topical ocular application. Generally, the obtained results confirmed that CLZ chitosan-coated microemulsion could be promising for ocular CLZ delivery.

Elsherif, N. I., A. M. Al-mahallawi, A. A. Abdelkhalek, and R. N. Shamma, "Investigation of the Potential of Nebivolol Hydrochloride-Loaded Chitosomal Systems for Tissue Regeneration: In Vitro Characterization and In Vivo Assessment.", Pharmaceutics, vol. 13, issue 5, 2021. Abstract

In this study, we evaluated the synergistic effect of nebivolol hydrochloride (NVH), a third-generation beta-blocker and NO donor drug, and chitosan on the tissue regeneration. Ionic gelation method was selected for the preparation of NVH-loaded chitosomes using chitosan lactate and sodium tripolyphosphate. The effect of different formulation variables was studied using a full factorial design, and NVH entrapment efficiency percentages and particle size were selected as the responses. The chosen system demonstrated high entrapment efficiency (73.68 ± 3.61%), small particle size (404.05 ± 11.2 nm), and good zeta potential value (35.6 ± 0.25 mV). The best-achieved formula demonstrated spherical morphology in transmission electron microscopy and amorphization of the crystalline drug in differential scanning calorimetry and X-ray diffraction. Cell culture studies revealed a significantly higher proliferation of the fibroblasts in comparison with the drug suspensions and the blank formula. An in vivo study was conducted to compare the efficacy of the proposed formula on wound healing. The histopathological examination showed the superiority of NVH-loaded chitosomes on the wound proliferation and the non-significant difference in the collagen deposition after 15 days of the injury to that of intact skin. In conclusion, NVH-loaded chitosomes exhibited promising results in enhancing skin healing and tissue regeneration.

Al-mahallawi, A. M., A. A. Abdelbary, and S. A. El-Zahaby, "Norfloxacin loaded nano-cubosomes for enhanced management of otitis externa: In vitro and in vivo evaluation.", International journal of pharmaceutics, vol. 600, pp. 120490, 2021. Abstract

The research's goal is to design and formulate nano-structured cubosomes loaded with norfloxacin (NFX)formanagement of otitis externa. In this study, glyceryl monooleate (GMO) as lipid phase, Cremophor EL as surfactant and either Pluronic F108 or Pluronic F127 as stabilizer were the used ingredients. The nano-cubosomal formulation "CUB 1" (its dispersed phase is composed of GMO (95%), Cremophor EL (2.5%) and Pluronic F108 (2.5%)) was the best achieved one. It had small particles size (216.75 ± 2.47 nm), good polydispersity index (0.339 ± 0.012) and acceptable zeta potential (-41.2 ± 2.262 mV). Images obtained after transmission electron microscopy examination ensured nearly cubic shape of formed nanoparticles with excellent dispersibility. Moreover, micrographs of rabbit ear skin specimens examined by confocal laser microscopy ensured good permeation capability of nano-structured cubosomes.In addition, in vivoskin deposition results revealed that higher amount of NFX was deposited in the rabbit ear skin throughout the study period (10 h) compared to drug suspension. Additionally, histopathological results proved that NFX loaded cubosomes can be safely applied topically on ear skin without any signs of inflammation nor skin irritation. Accordingly, these results anticipated the nano-structured cubosomal capabilities as a favorable nano-carrier for dermal NFX delivery to external ear skin for enhancing the management of otitis externa.

Ghareeb, D. A., S. R. Saleh, M. S. Nofal, M. M. Y. Kaddah, S. F. Hassan, I. K. Seif, S. A. El-Zahaby, S. M. Khedr, M. Y. Kenawy, A. A. Masoud, et al., "Potential therapeutic and pharmacological strategies for SARS-CoV2.", Journal of pharmaceutical investigation, vol. 51, issue 3, pp. 281-296, 2021. Abstract

BACKGROUND: At the end of 2019, the new Coronavirus disease 2019 (COVID-19) strain causing severe acute respiratory syndrome swept the world. From November 2019 till February 2021, this virus infected nearly 104 million, with more than two million deaths and about 25 million active cases. This has prompted scientists to discover effective drugs to combat this pandemic.

AREA COVERED: Drug repurposing is the magic bullet for treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Therefore, several drugs have been investigated in silico, in vitro, as well as through human trials such as anti-SARS-CoV2 agents, or to prevent the complications resulting from the virus. In this review, the mechanisms of action of different therapeutic strategies are summarized. According to the WHO, different classes of drugs can be used, including anti-malarial, antiviral, anti-inflammatory, and anti-coagulant drugs, as well as angiotensin-converting enzyme inhibitors, antibiotics, vitamins, zinc, neutralizing antibodies, and convalescent plasma therapy. Recently, there are some vaccines which are approved against SARS-CoV2.

EXPERT OPINION: A complete understanding of the structure and function of all viral proteins that play a fundamental role in viral infection, which contribute to the therapeutic intervention and the development of vaccine in order to reduce the mortality rate.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40005-021-00520-4.