Publications by authors named "Eman Alaaeldin"

12 Publications

  • Page 1 of 1

Cytotoxic Potential, Metabolic Profiling, and Liposomes of sp. Crude Extract Supported by in silico Analysis.

Int J Nanomedicine 2021 4;16:3861-3874. Epub 2021 Jun 4.

Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.

Introduction: Sponge- sp. (Family: Spongiidae) is a coastal sponge that possesses a broad variety of natural-products. However, the exact chemical constituents and cytotoxic activity of the extract are still undefinable.

Methodology: In the present study, the metabolomic profiling of sp. dereplicated 20 compounds, utilizing liquid chromatography coupled with high-resolution mass spectrometry (LC-HRESIMS). derived crude extract, before and after encapsulation within nanosized liposomes, was in vitro screened against hepatic, breast, and colorectal carcinoma human cell lines (HepG2, MCF-7, and Caco-2, respectively).

Results: The identified metabolites were fit to diverse chemical classes, covering diterpenes, an indole alkaloid, sesterterpenoid, sterol, and methylherbipoline salt. Comprehensive in silico experiments predicted several compounds in the sponge-derived extract (eg, compounds -) to have an anticancer potential via targeting multiple targets. The crude extract showed moderate antiproliferative activities towards studied cell lines with IC values range from 10.7 to 12.4 µg/mL. The formulated extract-containing liposomes (size 141±12.3nm, PDI 0.222, zeta potential 20.8 ± 2.3), significantly enhanced the in vitro anticancer activity of the entrapped extract (IC values ranged from 1.7 to 4.1 µg/mL).

Discussion: Encapsulation of both the hydrophilic and the lipophilic components of the extract within the lipid-based nanovesicles enhanced the cellular uptake and accessibility of the entrapped cargo. This study introduces liposomal nano-vesicles as a promising approach to improve the therapeutic potential of sponge-derived extracts.
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http://dx.doi.org/10.2147/IJN.S310720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187037PMC
June 2021

Correction to: A New Approach for Dry Eye Management by Mucoadhesive In situ Gel of Vitamin B12: Formulation, In vitro and In vivo Assessment.

AAPS PharmSciTech 2021 Apr 6;22(3):124. Epub 2021 Apr 6.

Department of Pharmaceutics, Faculty of Pharmacy, Minia University, P.O. Box: 61111, Minia, Egypt.

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http://dx.doi.org/10.1208/s12249-021-01991-2DOI Listing
April 2021

A New Approach for Dry Eye Management By Mucoadhesive In situ Gel of Vitamin B12: Formulation, In vitro and In vivo Assessment.

AAPS PharmSciTech 2021 Mar 4;22(3):87. Epub 2021 Mar 4.

Department of Pharmaceutics, Faculty of Pharmacy, Minia University, P.O. Box: 61111, Minia, Egypt.

The commitment of the existent study was to develop a mucoadhesive in situ gel systems of vitamin B12 for the management of dry eye disease. The gels were prepared using pluronic F-127 and either of chitosan, carbapol 971P, sodium alginate, or hydroxy propyl methyl cellulose. Drug-excipients compatibility was investigated by means of differential scanning calorimetry and Fourier transform infrared spectroscopy. The gels were characterized for pH, clarity, gelling capacity, viscosity, and adhesion. In vitro release of vitamin B12 from the selected gels was investigated. In vivo effectiveness of the selected gel was determined in rabbit models using Schirmer's and fluorescein tests. The compatibility studies revealed the possibility of incidence of drug/polymer interaction in some formulations. F2-containing pluronic F127 and hydroxypropyl methyl cellulose showed the most appropriate physical characterization and in vitro release profile. The prepared gels showed prolonged drug release with drug release mechanism of combined diffusion and erosion. The in vivo study revealed good effectiveness of the prepared mucoadhesive in situ gel system of vitamin B12 in the treatment of dry eye disease that was comparable to that of the marketed drops.
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http://dx.doi.org/10.1208/s12249-021-01957-4DOI Listing
March 2021

Topical Nano-Vesicular Spanlastics of Celecoxib: Enhanced Anti-Inflammatory Effect and Down-Regulation of TNF-α, NF-кB and COX-2 in Complete Freund's Adjuvant-Induced Arthritis Model in Rats.

Int J Nanomedicine 2021 8;16:133-145. Epub 2021 Jan 8.

Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt.

Background: Rheumatoid arthritis (RA) is an autoimmune disease that underlies chronic inflammation of the synovial membrane. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat RA. However, a long list of adverse events associated with long-term treatment regimens with NSAIDs negatively influences patient compliance and therapeutic outcomes.

Aim: The aim of this work was to achieve site-specific delivery of celecoxib-loaded spanlastic nano-vesicle-based delivery system to the inflamed joints, avoiding systemic administration of large doses.

Methodology: To develop spanlastic nanovesicles for transdermal delivery of celecoxib, modified injection method was adopted using Tween 80 or Brij as edge activators. Entrapment efficiency, vesicle size, ex vivo permeation, and morphology of the prepared nano-vesicles were characterized. Carbopol-based gels containing the selected formulations were prepared, and their clarity, pH, rheological performance, and ex vivo permeation were characterized. Celecoxib-loaded niosomes and noisome-containing gels were developed for comparison. The in vivo efficacy of the selected formulations was evaluated in a rat model of Freund's complete adjuvant-induced arthritis. Different inflammatory markers including TNF-α, NF-кB and COX-2 were assessed in paw tissue before and after treatment.

Results: The size and entrapment efficiency of the selected spanlastic nano-vesicle formulation were 112.5 ± 3.6 nm, and 83.6 ± 2.3%, respectively. This formulation has shown the highest transdermal flux and permeability coefficient compared to the other investigated formulations. The spanlastics-containing gel of celecoxib has shown transdermal flux of 6.9 ± 0.25 µg/cm/hr while the celecoxib niosomes-containing gel and unprocessed celecoxib-loaded gel have shown 5.2 ± 0.12 µg/cm/hr and 0.64 ± 0.09 µg/cm/hr, respectively. In the animal model of RA, the celecoxib-loaded spanlastics-containing gel significantly reduced edema circumference and significantly suppressed TNF-α, NF-кB and COX-2 levels compared to the niosomes-containing gel, the marketed diclofenac sodium gel, and unprocessed celecoxib-loaded gel.

Conclusion: The spanlastic nano-vesicle-containing gel represents a more efficient site-specific treatment for topical treatment of chronic inflammation like RA, compared to commercial and other conventional alternatives.
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http://dx.doi.org/10.2147/IJN.S289828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802787PMC
January 2021

Optimization and evaluation of propolis liposomes as a promising therapeutic approach for COVID-19.

Int J Pharm 2021 Jan 7;592:120028. Epub 2020 Nov 7.

Department of Pharmaceutics, Faculty of Pharmacy, Deraya University, Minia, Egypt; Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt. Electronic address:

The present work aimed to develop an optimized liposomal formulation for enhancing the anti-viral activity of propolis against COVID-19. Docking studies were performed for certain components of Egyptian Propolis using Avigan, Hydroxychloroquine and Remdesivir as standard antivirals against both COVID-19 3CL-protease and S1 spike protein. Response surface methodology and modified injection method were implemented to maximize the entrapment efficiency and release of the liposomal formulation. The optimized formulation parameters were as follow: LMC of 60 mM, CH% of 20% and DL of 5 mg/ml. At those values the E.E% and released % were 70.112% and 81.801%, respectively with nanosized particles (117 ± 11 nm). Docking studies revealed that Rutin and Caffeic acid phenethyl ester showed the highest affinity to both targets. Results showed a significant inhibitory effect of the optimized liposomal formula of Propolis against COVID-3CL protease (IC50 = 1.183 ± 0.06) compared with the Egyptian propolis extract (IC50 = 2.452 ± 0.11), P < 0.001. Interestingly, the inhibition of viral replication of COVID-19 determined by RT_PCR has been significantly enhanced via encapsulation of propolis extract within the liposomal formulation (P < 0.0001) and was comparable to the viral inhibitory effect of the potent antiviral (remdesivir). These findings identified the potential of propolis liposomes as a promising treatment approach against COVID-19.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647905PMC
January 2021

Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon.

J Control Release 2020 07 9;323:102-109. Epub 2020 Apr 9.

Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, Japan. Electronic address:

The accelerated blood clearance (ABC) phenomenon, caused in large degree via in vivo anti-PEG IgM production, is one of obstacles for development of PEGylated liposome and protein formulations, due to decreased efficiency and/or side effects such as anaphylaxis upon repeat administrations. We have shown in murine ABC models that splenectomy suppressed the level of anti-PEG IgM production induced by PEGylated liposomes, indicating that murine splenic B cells play an important role in its production. However, splenectomy did not completely inhibit production of anti-PEG IgM, suggesting that other cells may contribute to its production in the ABC phenomenon. In this study, we examined the contribution of hepatosplenic phagocytic cells to anti-PEG IgM production and clearance of PEGylated liposomes during the ABC phenomenon. Depletion of hepatosplenic phagocytic cells by pretreatment of mice with clodronate-containing non-PEGylated liposomes suppressed anti-PEG IgM production to a considerable degree, without a change in the number of splenic B cells, and attenuated the enhanced clearance of second dose of PEGylated liposomes. These results suggest that hepatosplenic phagocytic cells, in addition to splenic B cells, contribute to the production of anti-PEG IgM and the ABC phenomenon against PEGylated liposomes. The mechanism whereby splenic B cells interact with hepatosplenic phagocytic cells to produce anti-PEG IgM, upon administration of an initial dose of PEGylated liposomes remains to be elucidated.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.011DOI Listing
July 2020

Design And Characterisation Of Novel Sorafenib-Loaded Carbon Nanotubes With Distinct Tumour-Suppressive Activity In Hepatocellular Carcinoma.

Int J Nanomedicine 2019 29;14:8445-8467. Epub 2019 Oct 29.

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt.

Purpose: Over the past 30 years, no consistent survival benefits have been recorded for anticancer agents of advanced hepatocellular carcinoma (HCC), except for the multikinase inhibitor sorafenib (Nexavar), which clinically achieves only ~3 months overall survival benefit. This modest benefit is attributed to limited aqueous solubility, slow dissolution rate and, consequently, limited absorption from the gastrointestinal tract. Thus, novel formulation modalities are in demand to improve the bioavailability of the drug to attack HCC in a more efficient manner. In the current study, we aimed to design a novel sorafenib-loaded carbon nanotubes (CNTs) formula that is able to improve the therapeutic efficacy of carried cargo against HCC and subsequently investigate the antitumour activity of this formula.

Materials And Methods: Sorafenib was loaded on functionalized CNTs through physical adsorption, and an alginate-based method was subsequently applied to microcapsulate the drug-loaded CNTs (CNTs-SFN). The therapeutic efficacy of the new formula was estimated and compared to that of conventional sorafenib, both in vitro (against HepG2 cells) and in vivo (in a DENA-induced HCC rat model).

Results: The in vitro MTT anti-proliferative assay revealed that the drug-loaded CNTs formula was at least two-fold more cytotoxic towards HepG2 cells than was sorafenib itself. Moreover, the in vivo animal experiments proved that our innovative formula was superior to conventional sorafenib at all assessed end points. Circulating AFP-L3% was significantly decreased in the CNTs-SFN-MCs-treated group (14.0%) in comparison to that of the DENA (40.3%) and sorafenib (38.8%) groups. This superiority was further confirmed by Western blot analysis and immunofluorescence assessment of some HCC-relevant biomarkers.

Conclusion: Our results firmly suggest the distinctive cancer-suppressive nature of CNTs-SFN-MCs, both against HepG2 cells in vitro and in a DENA-induced HCC rat model in vivo, with a preferential superiority over conventional sorafenib.
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http://dx.doi.org/10.2147/IJN.S223920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825507PMC
January 2020

Modified Spraying Technique and Response Surface Methodology for the Preparation and Optimization of Propolis Liposomes of Enhanced Anti-Proliferative Activity against Human Melanoma Cell Line A375.

Pharmaceutics 2019 Oct 28;11(11). Epub 2019 Oct 28.

Department of Pharmaceutics, faculty of Pharmacy, Minia University, Minia 61519, Egypt.

Propolis is a honeybee product that contains a mixture of natural substances with a broad spectrum of biological activities. However, the clinical application of propolis is limited due to the presence of a myriad of constituents with different physicochemical properties, low bioavailability and lack of appropriate formulations. In this study, a modified injection technique (spraying technique) has been developed for the encapsulation of the Egyptian propolis within liposomal formulation. The effects of three variables (lipid molar concentration, drug loading and cholesterol percentage) on the particle size and poly dispersity index (PDI) were studied using response surface methodology and the Box-Behnken design. Response surface diagrams were used to develop an optimized liposomal formulation of the Egyptian propolis. A comparative study between the optimized liposomal formulation prepared either by the typical ethanol injection method (TEIM) or the spraying method in terms of particle size, PDI and the in-vitro anti-proliferative effect against human melanoma cell line A375 was carried out. The spraying method resulted in the formation of smaller propolis-loaded liposomes compared to TEIM (particle sizes of 90 ± 6.2 nm, and 170 ± 14.7 nm, respectively). Furthermore, the IC50 values against A375 cells were found to be 3.04 ± 0.14, 4.5 ± 0.09, and 18.06 ± 0.75 for spray-prepared propolis liposomes (PP-Lip), TEIM PP-Lip, and propolis extract (PE), respectively. The encapsulation of PE into liposomes is expected to improve its cellular uptake by endocytosis. Moreover, smaller and more uniform liposomes obtained by spraying can be expected to achieve higher cellular uptake, as the ratio of liposomes or liposomal aggregates that fall above the capacity of cell membrane to "wrap" them will be minimized.
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http://dx.doi.org/10.3390/pharmaceutics11110558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921042PMC
October 2019

PEGylated liposomes: immunological responses.

Sci Technol Adv Mater 2019 26;20(1):710-724. Epub 2019 Jun 26.

Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan.

A commonly held view is that nanocarriers conjugated to polyethylene glycol (PEG) are non-immunogenic. However, many studies have reported that unexpected immune responses have occurred against PEG-conjugated nanocarriers. One unanticipated response is the rapid clearance of PEGylated nanocarriers upon repeat administration, called the accelerated blood clearance (ABC) phenomenon. ABC involves the production of antibodies toward nanocarrier components, including PEG, which reduces the safety and effectiveness of encapsulated therapeutic agents. Another immune response is the hypersensitivity or infusion reaction referred to as complement (C) activation-related pseudoallergy (CARPA). Such immunogenicity and adverse reactivities of PEGylated nanocarriers may be of potential concern for the clinical use of PEGylated therapeutics. Accordingly, screening of the immunogenicity and CARPA reactogenicity of nanocarrier-based therapeutics should be a prerequisite before they can proceed into clinical studies. This review presents PEGylated liposomes, immunogenicity of PEG, the ABC phenomenon, C activation and lipid-induced CARPA from a toxicological point of view, and also addresses the factors that influence these adverse interactions with the immune system.
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http://dx.doi.org/10.1080/14686996.2019.1627174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598536PMC
June 2019

Optimization and Characterization of Thymoquinone-Loaded Liposomes with Enhanced Topical Anti-inflammatory Activity.

AAPS PharmSciTech 2018 Nov 14;19(8):3490-3500. Epub 2018 Sep 14.

Department of Pharmaceutics, The University of Minia, Main Road, Minia, 19623, Egypt.

Thymoquinone, the major constituent of Nigella sativa oil has been found to have a promising topical anti-inflammatory activity; however, exaggerated heat and photo-sensitivity and lipophilicity prevent the best use of this promising product. The present work aimed to formulate an ideal thymoquinone liposomal system for topical delivery. Different liposomal systems were developed using thin film hydration method by applying different cholesterol molar concentrations, different total lipid molar concentrations, and different drug-to-lipid ratios. Morphological characterization of the prepared formulae was performed using polarized light, scanning electron microscope, and transmission electron microscope. The optimized formula (F12) was selected on the basis of enhanced permeation through the skin and was incorporated into chitosan gel for topical application. The gel formulation was clear with suitable skin permeation and exhibited acceptable rheological properties. Using carrageenan-induced paw edema in rats, the developed chitosan gel (F12) showed significant superior in vivo anti-inflammatory activity over the chitosan gel of the TQ (p < 0.05) and comparable effect to the marketed indomethacin gel. As a conclusion, results revealed the potential of formulating thymoquinone as liposomal formulation in enhancing the anti-inflammatory effect compared to the TQ solution.
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http://dx.doi.org/10.1208/s12249-018-1166-1DOI Listing
November 2018

Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules.

J Control Release 2017 06 28;255:210-217. Epub 2017 Apr 28.

Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences,Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan. Electronic address:

Many therapeutic strategies have been applied in efforts to conquer the development and/or progression of cancer. The combination of chemotherapy and an RNAi-based approach has proven to be an efficient anticancer therapy. However, the feasibility of such a therapeutic strategy has been substantially restricted either by the failure to achieve the efficient delivery of RNAi molecules to tumor tissue or by the immunostimulatory response triggered by RNAi molecules. In this study, therefore, we intended to investigate the efficacy of using liposomal oxaliplatin (liposomal l-OHP) to guarantee the efficient delivery of RNAi molecules, namely shRNA against thymidylate synthase (TS shRNA) complexed with cationic liposome (TS shRNA-lipoplex), to solid tumors, and to suppress the immunostimulatory effect of RNAi molecules, TS shRNA, following intravenous administration. Herein, we describe how liposomal l-OHP enhanced the intra-tumor accumulation of TS shRNA-lipoplex and significantly reduced the immunostimulatory response triggered by TS shRNA. Consequently, such enhanced accumulation of TS shRNA-lipoplex along with the cytotoxic effect of liposomal l-OHP led to a remarkable tumor growth suppression (compared to mono-therapy) following systemic administration. Our results, therefore, may have important implications for the provision of a safer and more applicable combination therapy of RNAi molecules and anti-cancer agents that can produce a more reliable anti-tumor effect.
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http://dx.doi.org/10.1016/j.jconrel.2017.04.040DOI Listing
June 2017

The co-delivery of oxaliplatin abrogates the immunogenic response to PEGylated siRNA-lipoplex.

Pharm Res 2013 Sep 15;30(9):2344-54. Epub 2013 May 15.

Department of Pharmacokinetics and Biopharmaceutics Institute of Health bioscience, The University of Tokushima, 1-78-1 Sho-machi, Tokushima, Japan.

Purpose: In vivo application of siRNA/PEGylated cationic liposome complex (lipoplex) is impeded by two main obstacles: cytokine responses and anti-PEG IgM responses to PEGylated siRNA-lipoplex. Here, we investigated whether co-administration of oxaliplatin (l-OHP) abrogates the cytokine release and anti-PEG IgM production by PEGylated siRNA-lipoplex.

Methods: Free l-OHP was administered either simultaneously or 30 min prior to PEGylated siRNA-lipoplex administration, and cytokine response and anti-PEG IgM production were evaluated. In addition, the effect of the liposomal encapsulation of l-OHP on the immunogenic response of PEGylated siRNA-lipoplex was investigated.

Results: Simultaneous co-administration of free l-OHP with PEGylated siRNA-lipoplex caused a significant reduction in anti-PEG IgM production, along with an increase in the cytokine response. Free l-OHP injected prior to the lipoplex injection, however, successfully reduced cytokine release and anti-PEG IgM response. Platination of siRNA by simultaneously administered free l-OHP might facilitate the dissociation of double-stranded siRNA to single-stranded siRNA, resulting in the inducement of a potent immuno-stimulation of siRNA via endosomal toll-like receptors (TLRs). On the other hand, encapsulation of l-OHP into the siRNA-lipoplex resulted in a reduction of both anti-PEG IgM production and cytokine responses.

Conclusions: Our results suggest that, besides the expected therapeutic efficacy of co-administration, encapsulation of l-OHP into the PEGylated siRNA-lipoplex has great potential for minimizing the immunostimulation of PEGylated siRNA-lipoplex, resulting in a safe, applicable, and compliant treatment regimen for sequential clinical administration.
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http://dx.doi.org/10.1007/s11095-013-1078-4DOI Listing
September 2013
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