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.

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.

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 ng.hr/ml) compared to DCN dispersion (10.39 ± 1.45 ng.hr/ml). 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.

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.

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.

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.

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.

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.

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