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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.

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.

Abdel-Kawy, M. A., C. G. Michel, F. A. R. I. D. N. KIROLLOS, R. A. A. Hussien, A. M. Al-mahallawi, and M. S. Sedeek, "Chemical composition and potentiation of insecticidal and fungicidal activities of L. fruits essential oil against , and nano-cubosomes.", Natural product research, vol. 35, issue 14, pp. 2438-2443, 2021. Abstract

Development of natural nano-based plant-protection formulations represents an emerging phenomenon that has been widely improved for crops protection and for enhancing the efficiency and safety of pesticides. In the present study we isolated the essential oil from the fruits of L. and investigated it using gas chromatography-mass spectrometry analysis. Limonene (78.46%) was the major component followed by β-Myrcene (7.94%) and Caryophyllene (4.20%). essential oil (CTEO) loaded nano-cubosomes were successfully prepared by the emulsification technique. The insecticidal and fungicidal activities of formulated CTEO nano-cubosomes and unformulated CTEO were tested. While both of them exhibited substantial activities, CTEO nano-cubosomes were more effective than unformulated oil. It is the first time to formulate CTEO in nano-cubosomes and examine their insecticidal and fungicidal activities. In light of the current study, CTEO as it is or as nano-cubosomes is recommended as a promising candidate for pest and fungal pathogens control.Supplemental data for this article can be accessed at

rofida albash, A. M. Al-mahallawi, M. Hassan, and A. A. Alaa-Eldin, "Development and Optimization of Terpene-Enriched Vesicles (Terpesomes) for Effective Ocular Delivery of Fenticonazole Nitrate: In vitro Characterization and in vivo Assessment.", International journal of nanomedicine, vol. 16, pp. 609-621, 2021. Abstract

OBJECTIVE: The aim of the current study was to load fenticonazole nitrate, a slightly water-soluble antifungal agent, into terpene-enriched phospholipid vesicles (terpesomes) as a potential delivery system for the management of ocular fungal infection.

METHODS: Thin film hydration method was used to prepare terpesomes according to a 3 full factorial design to inspect the effect of several variables on vesicles' features. The investigated factors were terpenes type (X) and terpenes amount (X) while the dependent responses were encapsulation efficiency percent (Y), particle size (Y) and polydispersity index (Y). Design Expert program was used to chose the best achieved formula. The selected terpesomes were further optimized via incorporation of a positive charge inducer (stearylamine) to enhance adhesion to the negatively charged mucus covering the eye surface. The in vivo performance of the optimized fenticonazole nitrate-loaded terpesomes relative to drug suspension was evaluated by measuring the antifungal activity (against ) retained in the tear's fluid at different time intervals after ocular application in albino rabbits.

RESULTS: The optimized terpesomes showed spherical vesicles with entrapment efficiency of 79.02±2.35%, particle size of 287.25±9.55 nm, polydispersity index of 0.46±0.01 and zeta potential of 36.15±1.06 mV. The in vivo study demonstrated significantly higher ocular retention of the optimized fenticonazole nitrate-loaded terpesomes relative to the drug suspension. Moreover, the histopathological studies proved the safety and biocompatibility of the prepared terpesomes.

CONCLUSION: The obtained results verified the potential of the terpesomes for safe and effective ocular delivery of fenticonazole nitrate.

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.

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.

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.

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

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.

Fahmy, A. M., M. Hassan, D. A. El-Setouhy, S. A. Tayel, and A. M. Al-mahallawi, "Statistical optimization of hyaluronic acid enriched ultradeformable elastosomes for ocular delivery of voriconazole via Box-Behnken design: characterization and evaluation.", Drug delivery, vol. 28, issue 1, pp. 77-86, 2021. Abstract

Voriconazole (VCZ) is a well-known broad spectrum triazole antifungal, mainly used orally and intravenously. The study aimed to formulate VCZ into ultradeformable elastosomes for the topical treatment of ocular fungal keratitis. Different formulae were prepared using a modified ethanol injection method, employing a 3 Box-Behnken design. They were characterized by measuring their entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP). The optimized formula was subjected to further investigations and evaluation studies. The prepared vesicles had satisfactory EE%, PS, PDI and ZP values. The numerical optimization process suggested an optimal elastosomal formula (OE) composed of phosphatidyl choline and brij S100 at the weight ratio of 3.62: 1, 0.25%w/v hyaluronic acid and 5% (percentage from phosphatidyl choline/brij mixture) polyvinyl alcohol. It had high EE (72.6%), acceptable PS and PDI (362.4 nm and 0.25, respectively) and highly negative ZP of -41.7 mV. OE exhibited higher elasticity than conventional liposomes, with acceptable stability for three months. Transmission electron microscopy demonstrated the spherical morphology of vesicles with an external transparent coat of Hyaluronic acid. OE was expected to cause no ocular irritation or blurring in vision as reflected by pH and refractive index measurements. The histopathological study revealed the safety of OE for ocular use. The fungal susceptibility testing using demonstrated the superiority of OE to VCZ suspension, with greater and more durable growth inhibition. Therefore, OE can be regarded as a promising formula, achieving both safety and efficacy.

rofida albash, C. Yousry, A. M. Al-mahallawi, and A. A. Alaa-Eldin, "Utilization of PEGylated cerosomes for effective topical delivery of fenticonazole nitrate: characterization, statistical optimization, and assessment.", Drug delivery, vol. 28, issue 1, pp. 1-9, 2021. Abstract

In this investigation, we focused on ceramide IIIB, a skin component whose depletion tends to augment multiple skin disorders and fungal infections. Ceramide IIIB was included into PEGylated surfactant-based vesicular phospholipid system to formulate 'PEGylated cerosomes' (PCs) loaded with fenticonazole nitrate (FTN). FTN is a potent antifungal agent adopted in the treatment of mixed mycotic and bacterial infections. The ceramide content of the vesicles may provide protective and regenerative skin activity whereas Brij; the PEGylated surfactant, can enhance drug deposition and skin hydration. Both components are expected to augment the topical effect of FTN. PCs were prepared by thin-film hydration technique. A 2 full-factorial design was applied to study the effect of ceramide amount (X), Brij type (X) and Brij amount (X) on the physicochemical properties of the formulated PCs namely; entrapment efficiency (EE%;Y), particle size (PS;Y), polydispersity index (PDI;Y) and zeta potential (ZP;Y). The optimal formula was selected for further dermatokinetic and histopathological study. The optimal FTN-loaded PC (PC6) showed nanosized cerosomes (551.60 nm) with high EE% (83.00%w/w), and an acceptable ZP value of 20.90 mV. Transmission electron micrographs of the optimal formula illustrated intertwined tubulation form deviated from the conventional spherical vesicles. Finally, the dermatokinetic study of PC6 showed higher drug concentration and localization of FTN in skin layers when compared with FTN suspension and the histopathological study confirmed its safety for topical application. The overall findings of our study verified the effectiveness of utilizing PEGylated cerosomes to augment the activity of FTN as a topical antifungal agent.

Fahmy, A. M., M. Hassan, D. A. El-Setouhy, S. A. Tayel, and A. M. Al-mahallawi, "Voriconazole Ternary Micellar Systems for the Treatment of Ocular Mycosis: Statistical Optimization and In Vivo Evaluation.", Journal of pharmaceutical sciences, vol. 110, issue 5, pp. 2130-2138, 2021. Abstract

Voriconazole (VRC) is a broad spectrum, second generation triazole antifungal. The main use of VRC is via the oral and intravenous route. The study aimed to formulate VRC into ternary micellar systems (TMSs) for the topical treatment of ocular mycosis. TMSs were successfully prepared by water addition/solvent evaporation method, applying a 3-factor D-optimal design. The numerical optimization process suggested an optimal formula (OTMS) composed of total Pluronics to drug weight ratio of 22.89: 1, 1:1 weight ratio of Pluronic® P123 and F68, and 2% w/v of Labrasol. OTMS had high solubilization efficiency of 98.0%, small micellar size of 21.8 nm and suitable zeta potential and polydispersity index values of -9.0 mV and 0.261, respectively. OTMS exhibited acceptable stability for 3 months. Transmission electron microscopy demonstrated the spherical morphology of micelles. OTMS was expected to cause no ocular irritation or blurring in vision as reflected by pH and refractive index measurements. The histopathological study revealed the safety of OTMS for ocular use. The fungal susceptibility testing using Candida albicans demonstrated the superiority of OTMS to VRC suspension, with greater and more durable growth inhibition. Therefore, ocular application of optimized VRC-loaded TMSs can be a promising treatment for ocular mycosis.

Mohamed, M. I., A. M. Al-mahallawi, and S. M. Awadalla, "Development and optimization of osmotically controlled drug delivery system for poorly aqueous soluble diacerein to improve its bioavailability.", Drug development and industrial pharmacy, vol. 46, issue 5, pp. 814-825, 2020. Abstract

In an attempt to improve the low oral bioavailability of Diacerein (DCN), the combination of a ternary solid dispersion and an asymmetric osmotic pump system had been designed to enhance solubility and to control DCN delivery. Ternary DCN solid dispersion was prepared by melting fusion method using surfactant polymers, and carrier (Pluronic PF127, Solutol HS15, and PEG 35 K) and this DCN solid dispersion powder with the proper amount of excipients were compressed and coated with OpadryCA to develop a Semi-Permeable and Asymmetric Osmotic Pump tablets. The ternary DCN solid dispersion by using surfactant polymers (Pluronic F127 and Solutol HS 15) with a ratio of 1:1 was displayed market significant improvement in saturated solubility (70.2 ± 4.14 µg/ml) and fast dissolution rate (Q = 79.28 ± 3.1% and IDR = 5.25 ± 0.19 ml/min) in comparison to pure DCN. Moreover, the optimized asymmetric osmotic pump tablet with following parameters; 3% w/v Opadry CA coat concentration, 1% w/w HPMC E15 gelling polymer and 35.8%w/w NaCl Osmogen concentration, was displayed control release of DCN at zero-order kinetic (R = 0.977) for up to 24 h(s). The study conducted on rabbits was revealed a significant enhancement in the bioavailability of the optimized osmotic pump (28.84 ± 3.32 compared to DCN dispersion (10.39 ± 1.45 In conclusion, the approach of enhancing solubility and wet-ability in accompany with optimized asymmetric osmotic pump system could serve as a promising delivery system and a way to improve the bioavailability of poorly aqueous soluble drugs.

Sayed, M. M., H. A. El-Sabagh, A. M. Al-mahallawi, E. - S. Abd El-Halim, A. M. Amin, and A. A. El-bary, "Enhancing Tumor Targeting Efficiency of Radiolabeled Uridine (via) Incorporation into Nanocubosomal Dispersions.", Cancer biotherapy & radiopharmaceuticals, vol. 35, issue 3, pp. 167-176, 2020. Abstract

Several nanosystems are currently being utilized to enhance the targeting efficiency of several cancer chemotherapeutic agents. This study was designed to improve tumor accumulation of iodine-125 (I)-uridine incorporation into a nanocubosomal preparation. Nanocubosomes were prepared with the aid of Glycerol mono-oleate and Pluronic F127. Each prepared nanocubosomal preparation was adequately characterized by testing their particle size, polydispersity index (PDI), ζ potential (ZP), and transmission electron microscopy. The radiolabeling of uridine with I was attempted using several oxidizing agents to achieve a high radiochemical yield, and the factors affecting the reaction yield were studied in detail. A comparative biodistribution study of free I-uridine and I-uridine loaded nanocubosomes was performed in normal and tumor bearing mice. The biodistribution was evaluated by intravenous injection of the sterile test solution, and animals were anesthetized and dissected at different time intervals postinjection (p.i.). I-uridine was obtained in a high radiochemical yield (92.5% ± 0.8%). Afterward, I uridine was incorporated in a selected nanocubosome formulation, which showed nanosized cubic particles (178.6 ± 0.90 nm) with PDI (0.301 ± 0.04) and a ZP (34.35 ± 0.4). The biodistribution studies revealed that I-uridine nanocubosomes showed higher tumor localization (3.1 ± 0.4%IA/g at 2 h p.i. and a tumor/muscle ratio of 6.2) compared with the free I-uridine (2.7% ± 0.4%IA/g at 2 h p.i. and a tumor/muscle ratio of 3.3). The results of this study confirmed that I-uridine loaded nanocubosome had better efficiency in targeting the tumor site, which makes it an adequate targeting agent for tumor imaging.

Abdel-Bar, H. M., S. E. Khater, D. M. Ghorab, and A. M. Al-mahallawi, "Hexosomes as Efficient Platforms for Possible Fluoxetine Hydrochloride Repurposing with Improved Cytotoxicity against HepG2 Cells.", ACS omega, vol. 5, issue 41, pp. 26697-26709, 2020. Abstract

The aim of this study was to investigate the feasibility of hexosomes (HEXs) as competent platforms for fluoxetine hydrochloride (FH) repurposing against HepG2 hepatocellular carcinoma. Different FH-loaded HEX formulations were prepared and optimized by the hot emulsification method. The HEX features such as particle size, ζ potential, and drug entrapment efficiency (EE%) can be tailored by tuning HEX components and fabrication conditions. The composition of the optimized FH hexosome (OFH-HEX) was composed of 3.1, 1.4, 0.5, 0.2, and 94.8% for glyceryl monooleate, oleic acid, pluronic F127, FH, and deionized water, respectively. The anionic OFH-HEX with a particle size of 145.5 ± 2.5 nm and drug EE% of 45.4 ± 1.2% was able to prolong the FH release, where only 19.5 ± 2.3% released in phosphate-buffered saline (PBS) pH 7.4 after 24 h. Contrarily, HEX rapidly released FH in acetate buffer pH 5.5 and achieved a 90.5 ± 4.7% release after 24 h. The obtained HEX showed an improved cellular internalization in a time-dependent manner and enhanced the cytotoxicity (2-fold higher than FH solution). The current study suggests the potential of FH-HEX as a possible anticancer agent against hepatocellular carcinoma.

Farrah, A. Y., A. M. Al-mahallawi, E. B. Basalious, and D. I. Nesseem, "Investigating the Potential of Phosphatidylcholine-Based Nano-Sized Carriers in Boosting the Oto-Topical Delivery of Caroverine: in vitro Characterization, Stability Assessment and ex vivo Transport Studies.", International journal of nanomedicine, vol. 15, pp. 8921-8931, 2020. Abstract

Purpose: Drug delivery into the inner ear across the intact tympanic membrane (TM) has been a challenge in the treatment of inner ear disorders. In this study, nano-sized carriers were formulated for improving the non- invasive oto-topical delivery of caroverine for the treatment of tinnitus.

Methods: Caroverine was loaded into two types of phospholipid-containing systems, namely, nano elastic vesicles (EVs) and phosphatidylcholine-based liquid crystalline nano-particles (PC-LCNPs). The prepared formulations were characterized for their drug loading, particle size, polydispersity index, zeta potential, morphological features by transmission electron microscopy (TEM), and physicochemical stability. In addition, comparative ex vivo transport study was carried out using rabbits' TM for both types of formulations.

Results: The findings show a significant superiority of PC-LCNPs over the EVs formulations in the drug payload (1% and 0.25%, respectively), physical stability and the efficiency of permeation across rabbits' TM. The results showed a more than twofold increase in the cumulative drug flux values of PC-LCNPs (699.58 ± 100 µg/cm) compared to the EVs (250 ± 45 µg/cm) across the TM.

Conclusion: The current study revealed the smart physicochemical properties of PC-LCNPs demonstrating the potential of this carrier as a new attractive candidate for improving the non-invasive oto-topical delivery of caroverine.

Abdelbary, A. A., W. H. Abd-Elsalam, and A. M. Al-mahallawi, "Fabrication of levofloxacin polyethylene glycol decorated nanoliposomes for enhanced management of acute otitis media: Statistical optimization, trans-tympanic permeation and in vivo evaluation.", International journal of pharmaceutics, vol. 559, pp. 201-209, 2019 Jan 23. Abstract

Acute otitis media (AOM), an infection in the middle ear, is usually treated through systemic administration of antibiotics because the stratum corneum of the intact tympanic-membrane (TM) possesses low permeability that holds against the ototopical antibiotics use. Therefore, the objective of this work was to encapsulate levofloxacin (LFX) into polyethylene glycol 400 (PEG 400) decorated nanoliposomes (PNLs) as an approach for drug delivery through the intact tympanic-membrane. LFX loaded-PNLs were primed by ethanol injection technique. A 2 full factorial design, using Design-Expert® software, was developed to optimize formulation variables. Particle size, polydispersity index, zeta potential and entrapment efficiency percent of the formulae were determined. The optimal formulation (F7, prepared using 30:1 phospholipid to drug weight ratio, 30 mg cholesterol and 125 mg PEG 400) exhibited improved ex vivo trans-tympanic permeation compared to nanoliposomes lacking PEG 400 and drug solution. In addition, F7 showed greater extent of in vivo deposition of LFX in the intact TM compared to drug solution. Furthermore, in vivo histopathological examination proved the tolerability of the PNLs after ototopical application. Overall, the obtained results revealed that PNLs could be promising for LFX delivery through intact TM providing means for the ototopical drug application for treatment of acute middle ear infections.

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.

Al-mahallawi, A. M., A. R. Fares, and W. H. Abd-Elsalam, "Enhanced Permeation of Methotrexate via Loading into Ultra-permeable Niosomal Vesicles: Fabrication, Statistical Optimization, Ex Vivo Studies, and In Vivo Skin Deposition and Tolerability.", AAPS PharmSciTech, vol. 20, issue 5, pp. 171, 2019. Abstract

The aim of this study was to incorporate methotrexate (MTX) into ultra-permeable niosomal vesicles, containing cremophor RH40 as an edge activator (EA) and polyvinyl alcohol (PVA) as a stabilizer to enhance the drug permeation. Formulae were prepared by ethanol injection method following a Box-Behnken design in order to optimize the formulation variables (EA%, stabilizer %, and sonication time). To investigate the role of both cremophor RH40 and PVA, conventional MTX niosomes and MTX niosomes containing PVA only were fabricated. Drug entrapment efficiency percent (EE%), particle size (PS) analysis, zeta potential (ZP) measurements, and transmission electron microscopy (TEM) were conducted to characterize the vesicles. Cell viability studies and ex vivo permeation experiments of the optimized formula were conducted. Lastly, in vivo skin deposition of MTX from both the optimized formula and MTX solution was performed in rats. Besides, histopathological changes in rat skin were assessed. The optimized MTX ultra-permeable niosomal formula demonstrated spherical morphology, with an EE% of 65.16% and a PS of 453.6 nm. The optimized formula showed better physical stability in comparison with that of the same composition but lacking PVA. The cell viability studies verified the superior cytotoxicity of the optimized formula, and the ex vivo permeation studies revealed its ability to improve the drug permeation. The optimized formula demonstrated a significant deposition of MTX in rat dorsal skin, and histopathological evaluation confirmed the tolerability of the optimized formula in rats upon topical application. Accordingly, ultra-permeable noisomes, as a stable nanosystem, could be promising for effective delivery of MTX.

Abd-Elsalam, W. H., S. N. El-helaly, M. A. Ahmed, and A. M. Al-mahallawi, "Preparation of novel phospholipid-based sonocomplexes for improved intestinal permeability of rosuvastatin: In vitro characterization, dynamic simulation, Caco-2 cell line permeation and in vivo assessment studies.", International journal of pharmaceutics, vol. 548, issue 1, pp. 375-384, 2018 Sep 05. Abstract

The study aimed to fabricate innovative drug-phospholipid complexes termed "sonocomplexes" adopting ultrasound irradiation to increase the liposolubility and to enhance the intestinal absorption of rosuvastatin as a model drug for BCS class III active pharmaceutical ingredients (APIs). A 2 full factorial design was fashioned to investigate the influence of phosphatidylcholine content in the phospholipid (∼30 and 60%) and molar ratio of phospholipid to rosuvastatin (1:1 and 2:1) on physicochemical properties of sonocomplexes. In comparison to pure drug, sonocomplexes showed a minimum of about 2 folds and a maximum of about 15 folds increase in lipophilicity (expressed in terms of partition coefficient, P). Results of molecular docking, dynamic simulations, Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) confirmed the strong interactions between rosuvastatin and the phospholipid via hydrogen bonding interaction, van der Waals forces and hydrophobic interaction. The complexation efficiency reached around 99% and transmission electron microscopy (TEM) of the aqueous dispersion of the optimal sonocomplex showed spherical nanosized vesicles. The optimal sonocomplex showed significantly superior Caco-2 cells permeability and markedly better oral bioavailability compared to the pure drug. In summary, sonocomplexes can be considered as effective approach for enhancing the liposolubility and consequently the intestinal permeability of BCS class III drugs.

Abd-Elsalam, W. H., S. A. El-Zahaby, and A. M. Al-mahallawi, "Formulation and in vivo assessment of terconazole-loaded polymeric mixed micelles enriched with Cremophor EL as dual functioning mediator for augmenting physical stability and skin delivery.", Drug delivery, vol. 25, issue 1, pp. 484-492, 2018 Nov. Abstract

The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 2 full factorial design was performed using Design-Expert® software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98 ± 0.40%) and a very small micellar size (33.23 ± 8.00 nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ.

Saber, M. M., A. M. Al-mahallawi, N. N. Nassar, B. Stork, and S. A. Shouman, "Targeting colorectal cancer cell metabolism through development of cisplatin and metformin nano-cubosomes.", BMC cancer, vol. 18, issue 1, pp. 822, 2018 Aug 15. Abstract

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of death worldwide. Utilizing cisplatin in CRC is correlated with severe adverse effects and drug-resistance. Combined anticancer drug-treatment, along with, their enhanced delivery, can effectively kill cancer through multiple pathways. Nano-cubosomes are emerging as nanocarriers for anticancer therapies, hence, we constructed nano-cubosomes bearing cisplatin and cisplatin-metformin combination for investigation on HCT-116 cells.

METHODS: Nano-cubosomes bearing either cisplatin alone or cisplatin-metformin combination were formulated using emulsification technique. The loaded nano-cubosomes were characterized in vitro and the optimized formulation was selected. Their cytotoxic effects were investigated by Sulphorhodamine-B (SRB) assay. The AMPK/mTOR metabolic pathway as well as the Akt/mTOR pathway were analyzed using ELISA technique. Colorimetry was used in NADPH oxidase, LDH and caspase-3 activity determination.

RESULTS: nano-cubosomal formulations exhibited superior cytotoxic effect compared to unformulated cisplatin. This cytotoxic effect was profound upon incorporation of metformin, an indirect mTOR inhibitor, in cisplatin nano-cubosomes. The induced CRC cell apoptosis was through inhibition of several metabolic pathways, namely, AMPK/mTOR and Akt/mTOR. Drug-loaded nano-cubosomes ensued depletion in glucose and energy levels that led to AMPK activation and thus mTOR inhibition. mTOR was additionally inhibited via suppression of p-Akt (Ser473) levels after nano-cubosomal treatment. Moreover, drug-loaded nano-cubosomes produced a notable escalation in ROS levels, evident as an increase in NADPH oxidase, inhibition of LDH and a consequential upsurge in caspase-3.

CONCLUSION: These results demonstrated the influence exerted by cisplatin-loaded nano-cubosomes on CRC cell survival and enhancement of their cytotoxicity upon metformin addition.

Farrag, N. S., H. A. El-Sabagh, A. M. Al-mahallawi, A. M. Amin, A. A. El-bary, and W. Mamdouh, "Comparative study on radiolabeling and biodistribution of core-shell silver/polymeric nanoparticles-based theranostics for tumor targeting.", International journal of pharmaceutics, vol. 529, issue 1-2, pp. 123-133, 2017 Aug 30. Abstract

A simple and rapid method for radiolabeling of three types of Ag NPs has been performed using (125)I isotope, with high labeling yields, >90% without disturbing the optical properties. All the factors affecting labeling yield were studied. In order to monitor the in-vivo tissue uptake of radiolabeled Ag NPs using γ-rays, Ag-based radioiodo-NPs with a maximum labeling yield were intravenously injected in normal and solid tumor bearing mice. The preliminary biodistribution study revealed that this new radioiodo-NPs have a high affinity to be localized in the tumor site for a long period of time. The reported highly efficient method provides new radiolabeled Ag-based NPs as tumor-specific agents for both diagnostic and therapeutic applications.