Investigating the superiority of chitosan/D-alpha-tocopheryl polyethylene glycol succinate binary coated bilosomes in promoting the cellular uptake and anti-SARS-CoV-2 activity of polyphenolic herbal drug candidate.

The evolution of a safe and effective therapeutic system to conquer SAR-CoV-2 infection deemed to be a crucial worldwide demand. Curcumin (CUR) is a phytomedicinal polyphenolic drug that exhibited a well-reported anti-SAR-CoV-2. However, the therapeutic activity of CUR is hindered by its poor intestinal permeability and diminished aqueous solubility. Therefore, this study strived to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) bilosomes (TPGS-Bs) adopting 23 full factorial designs to improve solubility and intestinal permeability of CUR, hence boosting its anti-SARS-CoV-2 activity. Eight experimental runs were attained considering three independent variables: soybean phosphatidylcholine amount (mg) (SPC amount), bile salt amount (mg) (BS amount), and TPGS amount (mg). The optimum formula (F4) exhibited EE % (88.5 ± 2.4 %), PS (181.5 ± 21.6 nm), and ZP (-34.5 ± 3.7 mV) with desirability value = 0.739 was picked as an optimum formula. Furthermore, the optimum formula (F4) was extra coated with chitosan (CS) to improve permeability and anti-SAR-CoV-2 activity. Caco-2 cell uptake after 2 hr revealed the superiority of CS-F4 and F4 by 6 and 5 folds relative to CUR dispersion, respectively. Furthermore, CS-F4 exhibited a significantly higher anti-SARS-CoV-2 activity with IC50 (0.24 µg/ml) by 8.3 times than F4 (1.99 µg/ml). Besides, the mechanistic study demonstrated that the two formulae imparted antiviral activity by inhibiting the spike protein by virucidal potentialities. In addition, the conducted molecular docking and MD simulations towards the SARS-CoV-2 Mpro enzyme confirmed the interaction of CUR with key residues of the virus enzymes. Based on the preceded, CS-F4 could be assumed to be used to effectively eradicate SARS-CoV-2 infection.

Experimental design of D-α-tocopherol polyethylene glycol 1000 succinate stabilized bile salt based Nano-vesicles for improved cytotoxicity and bioavailability of colchicine binding site inhibitor Candidates: In Vitro, in silico, and pharmacokinetic studies.

Nowadays, conventional anticancer therapy suffers many pitfalls, including drastic side effects and limited therapeutic efficacy resulting from diminished oral bioavailability. So, in an attempt to enhance their poor solubility and oral bioavailability along with the cytotoxic activity, the developed lead compounds (C1 and C2) were loaded in D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) modified vesicles adopting thin film hydration technique. The formulations of the aforementioned candidates (F1 and F2, respectively) were elected as the optimum formula with desirability values of 0.701 and 0.618, respectively. Furthermore, an outstanding enhancement in the drug's cytotoxic activity against different cancer cell lines (MCF-7, HepG-2, MDA-MB-321, A375, and MGC-803) after being included in the nano-TPGS-modified optimum formula was noticed relative to the unformulated compounds. The formula F1 showed the best cytotoxic activities against HepG-2 with an IC50 = 3 µM. Furthermore, regarding MCF-7, F1 was shown to be the most potent and protective among all the tested formulations with an IC50 = 6 µM. Besides, F1 exerted the best caspase 3/7 activity stimulation (around a 5-folds increase) compared to control in the MCF-7 cell line. Notably, it was disclosedthat both C1 and C2 induced cell cycle arrest at the resting S growth phase. Moreover, C1 and C2 decreased tubulin concentrations by approximately 2-folds and 6-folds, respectively. Meanwhile, the conducted molecular docking studies ensure the eligible binding affinities of the assessed compounds. Besides, MD simulations were performed for 1000 ns to confirm the docking results and study the exact behavior of the target candidates (C1 and C2) toward the CBS.

Chitosan Surface-Modified PLGA Nanoparticles Loaded with Cranberry Powder Extract as a Potential Oral Delivery Platform for Targeting Colon Cancer Cells.

Nutraceutical cranberry powder extract (CBPE) has distinct polyphenols inhibiting colon cancer growth and proliferation. However, its oral therapeutic efficacy is hindered because of its low permeability. This study aims to formulate chitosan surface-modified PLGA nanoparticles (CS-PLGA NPs) for encapsulating CBPE and modulating its release rate, permeation, cell targeting, and, therefore, its cytotoxicity. A full 23 factorial design is employed to scrutinize the effect of lactide/glycolide ratio, PLGA weight, and stabilizer concentrations on entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimum formula (F4) shows spherical particles with a relatively high EE% (72.30 ± 2.86%), an appropriate size of 370.10 ± 10.31 nm, PDI; 0.398 ± 0.001, and ZP; -5.40 ± 0.21 mV. Alongside the ATR-FTIR outcomes, the chitosan surface-modified formula (CS-F4) demonstrates a significant increase in particle size (417.67 ± 6.77 nm) and a shift from negative to positive zeta potential (+21.63 ± 2.46 mV), confirming the efficiency of surface modification with chitosan. The intestinal permeability of F4 and CS-F4 is significantly increased by 2.19- and 3.10-fold, respectively, compared to the CBPE solution, with the permeability coefficient (Papp) being 2.05 × 10-4 cm/min and 2.91 × 10-4 cm/min, for F4 and CS-F4, respectively, compared to the CBPE solution, 9.36 × 10-5 cm/min. Moreover, CS-F4 evidences significant caspase-3 protein level expression stimulation and significant inhibition of vascular endothelial growth factor (VEGF) and signal transducer and activator of transcription-3 (STAT-3) protein expression levels, confirming the superiority of CS-F4 for targeting HT-29 cells. Briefly, CS-PLGA NPs could be regarded as a prosperous delivery system of CBPE with enhanced permeation, cell targeting, and antitumor efficacy.

'Poly phenolic phytoceutical loaded nano-bilosomes for enhanced caco-2 cell permeability and SARS-CoV 2 antiviral activity': in-vitro and insilico studies.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) predisposed to the emergence of worldwide catastrophe that impels the evolution of safe and effective therapeutic system. Polyphenols as resveratrol (RSV) exhibit a well evidenced antiviral activity. Unfortunately, like most phenolic nutraceuticals, RSV suffers from restrained solubility and massive degradation in GIT and liver which in turn prohibit its clinical use. Herein, PEGylated bilosomes (PBs) contain PEGylated edge activator along with the traditional components as (Span 60, cholesterol and bile salts) were proposed to boost both permeability and bioavailability of RSV. The investigation of the prominent effect of the diverse variables on the characteristics of the vesicles and picking of the optimum formula were conducted via construction of 23 factorial experiment. The appraisal of the formulae was conducted on the basis of entrapment efficiency percent (EE%), particle size (PS) and zeta potential (ZP). In addition, the spherical shaped optimal formula (F5) exhibited EE% of 86.1 ± 2.9%, PS of 228.9 ± 8.5 nm, and ZP of -39.8 ± 1.3 mV. The sorted optimum formula (F5) exhibited superior dissolution behaviors, and boosted Caco-2 cells cellular uptake by a round 4.7 folds relative to RSV dispersion. In addition, F5 demonstrated a complete in vitro suppression of SARS-CoV-2 at a concentration 0.48 µg/ml with 6.6 times enhancement in antiviral activity relative to RSV dispersion. The accomplished molecular modeling heavily provided proof for the possible interactions of resveratrol with the key residues of the SARS-CoV2 Mpro enzyme. Finally, F5 could be proposed as a promising oral panel of RSV for curation from SARS-CoV-2 infection.

Adjunctive proximal aortic and aortodistal prosthetic wrapping of vascular anastomoses for Adamantiadis-Behçet's aortic/aortoiliac aneurysms: A revisit.

BACKGROUND: We described our local experiences with a single-layer wrapping technique for the vascular anastomoses in patients with Adamantiadis-Behçet's aortic/aortoiliac aneurysms using InterGard Silver-impregnated Dacron® patch prosthesis. METHODS: Between January 2013 to December 2019, we retrospectively reviewed 20 patients presented with Adamantiadis-Behçet's aortic/aortoiliac aneurysms. All patients presented with Adamantiadis-Behçet's aortic/aortoiliac aneurysms. Two groups were analyzed, Group I, considered as a control group (n = 20). While group II (n = 20), of which prosthetic wrapping was performed. Follow up took place for a maximum of 24 months. RESULTS: during a six-year retrospective study period, 20 patients were recruited. They included 15 males and five females (ratio 3:1). The median age was 30.5 ± 4.2 years. Anastomotic pseudoaneurysms were reported in group I (control, [non-wrapping group]). While group II doesn't (wrapping group). Paired samples t test revealed a significant difference between those underwent wrapping and those with non-wrapping (p = .019 and .038). False aneurysms were reported in 80% of the non-wrapping group as estimated by the Kaplan-Meier curves. While Log-rank test results revealed a significant difference between both the studied groups (p < .008). Primary graft patency was 90% at 24 months as reported by the Kaplan-Meier survival method. CONCLUSIONS: adjunctive wrapping for vascular anastomoses using Intergard Silver-impregnated Dacron® patch in patients with Adamantiadis-Behçet's aortic/aortoiliac aneurysms is an applicable, simple, and reliable technique. It was associated with low morbidity and mortality rates. Moreover, we discussed a relatively old technique aiming to explore its success and safety in treating arterial aneurysms in Adamantiadis-Behçet's disease patients.

Boosting the anti MERS-CoV activity and oral bioavailability of resveratrol via PEG-stabilized emulsomal nano-carrier: Factorial design, in-vitro and in-vivo assessments.

Resveratrol (RSV) is a phytoceutical polyphenolic compound exhibiting a well evidenced wide range of therapeutic activities. Unfortunately, its diminished aqueous solubility and extensive metabolism in gastro intestinal tract (GIT) and liver prohibit its biological activity and systemic availability. Herein the conducted study PEG stabilized emulsomes (PEMLs) were customized to enclose RSV aiming to boost its biological availability and antiviral activity. PEGylating the vesicles not only grant the promoted steric stability of the system but also being beneficial in exaggerating the intestinal permeability and extending the period of circulation of the drug, hence its targeted clinical use. The Investigation of the influence of predetermined variables on the physical characterization of formulae (entrapment efficiency EE%, particle size PS and zeta potential ZP) was implemented utilizing Design Expert® software. (F4) with desirability value (0.772), picked to be the optimal formula, which is fabricated utilizing 35 mg compritol as the lipidic core and 60 mg 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-Mpeg-2000). The dominance of the F4 relative to RSV dispersion was affirmed by the data acquired from ex-vivo and pharmacokinetic studies. In addition, F4 exhibited significant lower EC50 value (0.0127 µg/mL) relative to that of RSV dispersion(0.338 µg/mL) by around 26 times denoting the capability of the formulation to boost the antiviral activity. To a great extent, F4 was able to significantly suppress the inflammatory response and oxidative stress resulted from MERS-CoV infection on comparison with RSV dispersion. Finally, the potentiality of PEMLs as nano-panel with boosted both antiviral and oral bioavailability for RSV could be deduced based on the outcomes mentioned herein.

Design and synthesis of new trimethoxylphenyl-linked combretastatin analogues loaded on diamond nanoparticles as a panel for ameliorated solubility and antiproliferative activity.

A new series of vinyl amide-, imidazolone-, and triazinone-linked combretastatin A-4 analogues have been designed and synthesised. These compounds have been evaluated for their cytotoxic activity against MDA-MB-231 breast cancer cells. The triazinone-linked combretastatin analogues (6 and 12) exhibited the most potent cytotoxic activity, in sub-micromolar concentration compared with combretastatin A-4 as a reference standard. The results of ß-tubulin polymerisation inhibition assay appear to correlate well with the ability to inhibit ß-tubulin polymerisation. Additionally, these compounds were subjected to biological assays relating to cell cycle aspects and apoptosis induction. In addition, the most potent compound 6 was loaded on PEG-PCL modified diamond nanoparticles (PEG-PCL-NDs) and F4 was picked as the optimum formula. F4 exhibited enhanced solubility and release over the drug suspension. In the comparative cytotoxic activity, PEG-PCL modified F4 was capable of diminishing the IC50 by around 2.89 times for nude F4, while by 3.48 times relative to non-formulated compound 6.

Design, Synthesis, In Vitro Biological Activity Evaluation and Stabilized Nanostructured Lipid Carrier Formulation of Newly Synthesized Schiff Bases-Based TMP Moieties.

A series of novel Schiff bases-based TMP moieties have been designed and synthesized as potential anticancer agents. The target Schiff bases were screened for their cytotoxic activity against the MDA-MB-231 breast cancer cell line. Most of the tested molecules revealed good cytotoxic activity, especially compounds 4h, 4j and 5d. Being the most potent, compound 4h showed good tubulin polymerization inhibition activity as revealed by immunofluorescence analysis and ELISA assay. Additionally, compound 4h was screened for cell cycle disturbance and apoptosis induction. Pre-G1 apoptosis and cell growth halt at the G2/M phase were discovered to be caused by it. Moreover, compound 4h induced apoptosis via p53 and Bax activation, as well as reduced the level of Bcl-2. Additionally, the most potent compound 4h was lodged on nanostructured lipid carriers (NLCs). 23 full factorial design was involved to govern the influence of the fabrication variables on the in vitro characters of the casted NLCs. F3 was picked as the optimum formula exhibiting dominant desirability value 0.805, EE% 95.6 ± 2.4, PS 222.4 ±18.7, PDI 0.23 ± 0.05 and ZP −39.2 ± 3.9 Mv. Furthermore, F3 affirmed improved solubility and release over the drug suspension. In the comparative cytotoxic activity, F3 was capable of diminishing the IC50 by around 2.15 times for pure 4h, while nearly close to the IC50 of the reference drug. Thus, NLCs could be a potential platform for boosted antitumor activity.

"TPGS surface modified bilosomes as boosting cytotoxic oral delivery systems of curcumin against doxorubicin resistant MCF-7 breast cancer cells".

The goal of this work was to design nude bilosomes (Bil) and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) surface coated bilosomes as an oral delivery platform for improving the antitumor activity and poor oral permeability of Curcumin (CUR). Twelve different formulae were acquired from 31.22 factorial analysis considering different independent variables: bile salt type; Sodium taurocholate (STC) or Sodium cholate (SC) and weight percent; 1% or 5 % W/W, both at 2 levels respectively, while Span 60:Cholesterol ratio at 3 levels (1:1, 5:1, 9:1). Following optimization, the selected optimum formula was picked up based on the favorable minimum particle size (187.2 ± 2.2 nm), maximum zeta potential value (-41.3 ± 2.2 mV) and maximum entrapment efficiency (93.4 ± 5.1%) which was further coated with TPGS. The mean fluorescence intensity (MFI) of CUR permeated from the optimum TPGS-F7 and CUR-Bil (F7) formulae exhibited 6.6 and 3.4 folds increase respectively adopting ex-vivo duodenal permeation assay relative to that of CUR suspension. Moreover, the cellular uptake efficiency via the established Caco-2 cells revealed that the uptake of CUR was 61.9 ± 5.3% and 34.76 ± 0.61% from TPGS-F7 and CUR-Bil (F7) relative to the uptake efficiency of CUR suspension (7.4 ± 2.12%). Coherently, TPGS-CUR-Bil showed excellent response expressed in dominant reduction in IC50 value (2.8 ± 0.07 µg/ml) against multidrug resistant (MDR) tumors following 48 h incubation of Doxorubicin Resistant Breast Cancer (MCF-7/ADR) cell lines.

Design, Green Synthesis and Tailoring of Vitamin E TPGS Augmented Niosomal Nano-Carrier of Pyrazolopyrimidines as Potential Anti-Liver and Breast Cancer Agents with Accentuated Oral Bioavailability.

VEGF plays a crucial role in cancer development, angiogenesis and progression, principally liver and breast cancer. It is vital to uncover novel chemical candidates of VEGFR inhibitors to develop more potent anti-breast and anti-liver cancer agents than the currently available candidates, sorafenib and regorafenib, that face resistance obstacles and severe side effects. Herein, nine pyrazolopyrimidine derivatives were designed, synthesized as sorafenib and regorafenib analogues and screened for their in vitro cytotoxic and growth inhibition activities against four human cancer cell lines, namely breast cancer (Michigan Cancer Foundation-7 (MCF-7), hepatocellular carcinoma (HCC) type (HepG2), lung carcinoma (A-549) and human colorectal carcinoma-116 (HCT-116)). Among the tested compounds, compounds 1, 2a, 4b and 7 showed the uppermost cytotoxic activities against all aforementioned cell lines with IC50 estimates varying from 6 to 50 µM, among which compound 7 showed the best inhibitory activity on all tested compounds. Stunningly, compound 7 showed the best significant inhibition of the VEGFR-2 protein expression level (72.3%) as compared to the control and even higher than that produced with sorafenib and regorafenib (70.4% and 55.6%, respectively). Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the ATP binding sites on the hinge region and the "DFG out" motif of VEGFR-2 kinase. Collectively, our present study suggests that pyrazolopyrimidine derivatives are a novel class of anti-cancer drug candidates to inhibit VEGF-VEGFR function. Aspiring to promote constrained aqueous solubility, hence poor oral bioavailability of the developed lead molecule, 7 and 2a-charged D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) surface-coated niosomes were successfully constructed, adopting a thin film hydration technique striving to overcome these pitfalls. A 23 full factorial design was involved in order to investigate the influence of formulation variables: type of surfactant, either Span 60 or Span 40; surfactant:cholesterol ratio (8:2 or 5:5) along with the amount of TPGS (25 mg or 50 mg) on the characteristics of the nanosystem. F2 and S2 were picked as the optimum formula for compounds 2a and 7 with desirability values of 0.907 and 0.903, respectively. In addition, a distinguished improvement was observed in the compound's oral bioavailability and cytotoxic activity after being included in the nano-TPGS-coated niosomal system relative to the unformulated compound. The nano-TPGS-coated niosomal system increased the hepatocellular inhibitory activity four times fold of compound 7a (1.6 µM) and two-fold of 2a (3 µM) relative to the unformulated compounds (6 µM and 6.2 µM, respectively).

Design and Synthesis of Newly Synthesized Acrylamide Derivatives as Potential Chemotherapeutic Agents against MCF-7 Breast Cancer Cell Line Lodged on PEGylated Bilosomal Nano-Vesicles for Improving Cytotoxic Activity.

Cancer is a multifaceted disease. With the development of multi drug resistance, the need for the arousal of novel targets in order to avoid these drawbacks increased. A new series of acrylamide derivatives was synthesized from starting material 4-(furan-2-ylmethylene)-2-(3,4,5-trimethoxyphenyl)oxazol-5(4H)-one (1), and they are evaluated for their inhibitory activity against ß-tubulin polymerization. The target molecules 2-5 d were screened for their cytotoxic activity against breast cancer MCF-7 cell line. The results of cytotoxicity screening revealed that compounds 4e and 5d showed good cytotoxic profile against MCF-7 cells. Compounds 4e produced significant reduction in cellular tubulin with excellent ß-tubulin polymerization inhibition activity. In addition, compound 4e exhibited cytotoxic activity against MCF-7 cells by cell cycle arrest at pre-G1 and G2/M phases, as shown by DNA flow cytometry assay. Aiming to enhance the limited aqueous solubility and, hence, poor oral bioavailability of the prepared lead acrylamide molecule, 4e-charged PEGylated bilosomes were successfully fabricated via thin film hydration techniques as an attempt to improve these pitfalls. 23 full factorial designs were manipulated to examine the influence of formulation variables: types of bile salt including either sodium deoxy cholate (SDC) or sodium tauro cholate (STC), amount of bile salt (15 mg or 30 mg) and amount of DSPE-mPEG-2000 amount (25 mg or 50 mg) on the characteristics of the nanosystem. The F7 formula of entrapment efficiency (E.E% = 100 ± 5.6%), particle size (PS = 280.3 ± 15.4 nm) and zeta potential (ZP = -22.5 ± 3.4 mv) was picked as an optimum formula with a desirability value of 0.868. Moreover, prominent enhancement was observed at the compound's cytotoxic activity (IC50 = 0.75 ± 0.03 µM) instead of (IC50 = 2.11 ± 0.19 µM) for the unformulated 4e after being included in the nano-PEGylated bilosomal system.

Management of Extremity Venous Thrombosis in Neonates and Infants: An Experience From a Resource Challenged Setting.

We aimed to evaluate the outcome of different treatment modalities for extremity venous thrombosis (VT) in neonates and infants, highlighting the current debate on their best tool of management. This retrospective study took place over a 9-year period from January 2009 to December 2017. All treated patients were referred to the vascular and pediatric surgery departments from the neonatal intensive care unit. All patients underwent a thorough history-taking as well as general clinical and local examination of the affected limb. Patients were divided into 2 groups: group I included those who underwent a conservative treated with the sole administration of unfractionated heparin (UFH), whereas group II included those who were treated with UFH plus warfarin. Sixty-three patients were included in this study. They were 36 males and 27 females. Their age ranged from 3 to 302 days. Forty-one (65%) patients had VT in the upper limb, whereas the remaining 22 (35%) had lower extremity VT. The success rate of the nonsurgical treatment was accomplished in 81% of patients. The remaining 19% underwent limb severing, due to established gangrene. The Kaplan-Meier survival method revealed a highly significant increase in both mean and median survival times in those groups treated with heparin and warfarin compared to heparin-only group ( P < .001). Nonoperative treatment with anticoagulation or observation (ie, wait-and-see policy) alone may be an easily applicable, effective, and a safe modality for management of VT in neonates and infants, especially in developing countries with poor or highly challenged resource settings.

Operative management of non-iatrogenic pediatric and adolescence peripheral arterial trauma: An experience from a resource challenged setting.

OBJECTIVES: To evaluates the management and outcome of non-iatrogenic pediatric and adolescence extremity arterial injuries in a resource-challenged setting. METHODS: A retrospective study of the surgical management for non-iatrogenic extremity arterial trauma in pediatric and adolescence during the period from January 2008 to December 2015. This study was performed in two different countries at tertiary referral university and teaching hospitals having a specialized emergency and trauma centers. A thorough study of each patient record was collected from these centers including, the original demographic data and their clinical presentations. Operative data of each patient was also reported. RESULTS: During the 8-year period of the study, 149 pediatric and adolescent extremity arterial trauma patients were treated. They were 93.3% male, and 6.7% female, respectively. The age ranged from 2 to 18 years with a mean of 10.25 ± 4.05 years. Lower extremity arterial trauma was recorded in 51%, while 49% were having upper extremity injuries. Primary repair with end-to-end vascular anastomosis was performed in 51.7%, while an interposition reversed saphenous vein graft was performed in 48.3%. The operative procedures were performed by an experienced vascular surgeon and well-trained pediatric surgeons and general surgeons. Pseudoaneurysms was recorded in 9% of cases. Fasciotomy was performed in 15% of cases. CONCLUSION: Treatment of pediatric and adolescent extremity arterial injuries with primary end-to-end vascular anastomoses or with the use of an interposition reversed saphenous vein graft is a reliable, feasible, and more cost-effectiveness technique with good results. Moreover, it should be adopted for all vascular trauma patients, whenever possible.