Mohammad Najlah

Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier

The aim of this study was to investigate the ability of a third-generation (G3) polyamidoamine (PAMAM) dendrimer-based carrier to enhance the permeability of paclitaxel (pac) and to overcome cellular barriers. G3 dendrimers were surface modified with lauryl chains (L) and conjugated with paclitaxel (pac) via a glutaric anhydride (glu) linker, followed by labeling with FITC. Biological evaluation of the dendrimer and conjugates was conducted using the human colon adenocarcinoma cell line (Caco-2) and primary cultured porcine brain endothelial cells (PBECs). LDH assay was used to evaluate the cytotoxicity of the dendrimer and conjugates. Cytotoxicity studies showed that the conjugation of lauryl chains and paclitaxel on G3 dendrimer significantly (p<0.05) increased the cytotoxicity against both cell types. Permeability studies of dendrimer-drug conjugates demonstrated an increase in the apparent permeability coefficient (P(app)) in both apical to basolateral A→B and basolateral to apical B→A directions across both cell monolayers compared to unmodified G3 and free drug. The B→A P(app) of paclitaxel was significantly (p<0.05) higher than the A→B P(app), indicating active function of P-gp efflux transporter system in both cell models. L6-G3-glu-pac conjugate had approximately 12-fold greater permeability across both cell monolayers than that of paclitaxel alone.

A study of the effects of sodium halides on the performance of air-jet and vibrating-mesh nebulizers.

The influence of sodium halide electrolytes on aerosols generated from the Aeroneb Pro vibrating mesh nebulizer and the Sidestream air-jet nebulizer has been evaluated. Fluids with a range of concentrations of Na halides (i.e. NaF, NaCl, NaBr and NaI) were used as nebulizer solutions and their effect on aerosol properties such as total aerosol output, fine particle fraction (FPF), volume median diameter (VMD) and predicted regional airway deposition were investigated. For both nebulizers, the inclusion of electrolyte significantly enhanced the aerosol properties compared with HPLC grade (deionized) water. Aerosol output, FPF and aerosol fraction less than 2.15 μm were directly proportional to electrolyte concentration. Furthermore, the proportion of aerosols that are likely to deposit in the oropharyngeal region, and the VMD of the droplets were inversely related to the electrolyte concentration for both nebulizers. In general, the inclusion of electrolytes had a greater impact on the aerosol properties of the vibrating-mesh nebulizer. In the Aeroneb Pro, NaI 2.0% (w/v) was the optimum solution as it generated the highest aerosol output, FPF and output fraction below 2.15 μm with the lowest VMD and minimal predicted oropharyngeal deposition. This was attributed to the polarizing ability of iodide ions present in the largest quantity at the air-water interface. This study has shown that the Aeroneb Pro vibrating-mesh device demonstrated greatly enhanced aerosol properties when halides were included in the nebulizer solutions.

The effects of suspension particle size on the performance of air-jet, ultrasonic and vibrating-mesh nebulisers

Using latex microspheres as model suspensions, the influence of suspension particle size (1, 4.5 and 10 μm) on the properties of aerosols produced using Pari LC Sprint (air-jet), Polygreen (ultrasonic), Aeroneb Pro (actively vibrating-mesh) and Omron MicroAir NE-U22 (passively vibrating-mesh) nebulisers was investigated. The performance of the Pari nebuliser was independent of latex spheres particle size. For both Polygreen and Aeroneb Pro nebulizers, total aerosol output increased when the size of latex spheres increased, with highest fine particle fraction (FPF) values being recorded. However, following nebulisation of 1 or 4.5 μm suspensions with the Polygreen device, no particles were detected in the aerosols deposited in a two-stage impinger, suggesting that the aerosols generated from this device consisted mainly of the continuous phase while the dispersed microspheres were excluded and remained in the nebuliser. The Omron nebuliser efficiently nebulised the 1 μm latex spheres, with high output rate and no particle aggregation. However, this device functioned inefficiently when delivering 4.5 or 10 μm suspensions, which was attributed to the mild vibrations of its mesh and/or the blockage of the mesh apertures by the microspheres. The Aeroneb Pro fragmented latex spheres into smaller particles, but uncontrolled aggregation occurred upon nebulisation. This study has shown that the design of the nebuliser influenced the aerosol properties using latex spheres as model suspensions. Moreover, for the recently marketed mesh nebulisers, the performance of the Aeroneb Pro device was less dependent on particle size of the suspension compared with the Omron MicroAir nebuliser.

Liposome Delivery Systems for Inhalation: A Critical Review Highlighting Formulation Issues and Anticancer Applications

This is a critical review on research conducted in the field of pulmonary delivery of liposomes. Issues relating to the mechanism of nebulisation and liposome composition were appraised and correlated with literature reports of liposome formulations used in clinical trials to understand the role of liposome size and composition on therapeutic outcome. A major highlight was liposome inhalation for the treatment of lung cancers. Many in vivo studies that explored the potential of liposomes as anticancer carrier systems were evaluated, including animal studies and clinical trials. Liposomes can entrap anticancer drugs and localise their action in the lung following pulmonary delivery. The safety of inhaled liposomes incorporating anticancer drugs depends on the anticancer agent used and the amount of drug delivered to the target cancer in the lung. The difficulty of efficient targeting of liposomal anticancer aerosols to the cancerous tissues within the lung may result in low doses reaching the target site. Overall, following the success of liposomes as inhalable carriers in the treatment of lung infections, it is expected that more focus from research and development will be given to designing inhalable liposome carriers for the treatment of other lung diseases, including pulmonary cancers. The successful development of anticancer liposomes for inhalation may depend on the future development of effective aerosolisation devices and better targeted liposomes to maximise the benefit of therapy and reduce the potential for local and systemic adverse effects.

Novel paclitaxel formulations solubilized by parenteral nutrition nanoemulsions for application against glioma cell lines.

The aim of this study is to investigate using nanoemulsion formulations as drug-delivery vehicles of paclitaxel (PX), a poor water-soluble anticancer drug. Two commercially available nanoemulsion fat formulations (Clinoleic 20% and Intralipid 20%) were loaded with PX and characterised based on their size, zeta potential, pH and loading efficiency. The effect of formulation on the cytotoxicity of PX was also evaluated using MTT assay. The droplet size of the Clinoleic emulsion increased from 254.1nm to 264.7nm when paclitaxel (6mg/ml) was loaded into the formulation, compared to the drug-free formulation. Similarly, the droplet size of Intralipid increased from 283.3 to 294.6nm on inclusion of 6mg/ml paclitaxel. The Polydispersity Indexes (PDIs) of all the nanoemulsion formulations (Clinoleic and Intralipid) were less than 0.2 irrespective of paclitaxel concentration indicating that all nanoemulsion formulations used were homogeneously sized. The pH range for the Clinoleic formulations (7.1-7.5) was slightly higher than that of the Intralipid formulations (6.5-6.9). The zeta potential of linoleic had a greater negative value than that of Intralipid. Loading efficiencies for paclitaxel were 70.4-80.2% and 44.2-57.4% for Clinoleic and Intralipid formulations, respectively. Clinoleic loaded with paclitaxel decreased the viability of U87-MG cell to 6.4±2.3%, compared to Intralipid loaded with paclitaxel (21.29±3.82%). Both nanoemulsions were less toxic to the normal glial cells (SVG-P12), decreasing the cell viability to 25-35%. This study suggests that nanoemulsions are useful and potentially applicable vehicles of paclitaxel for treatment of glioma.

The cytotoxic mechanisms of disulfiram and copper(II) in cancer cells

The anticancer activity of disulfiram (DS) is copper(ii) (Cu)-dependent.

Development and characterisation of disulfiram-loaded PLGA nanoparticles for the treatment of non-small cell lung cancer

Graphical abstract Figure. No caption available. Abstract Non‐Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer in both men and women. A recent phase IIb study demonstrated that disulfiram (DSF) in combination with cisplatin and vinorelbine was well tolerated and prolonged the survival of patients with newly diagnosed NSCLC. However, DSF is rapidly (4 min) metabolised in the bloodstream and it is this issue which is limiting its anticancer application in the clinic. We have recently demonstrated that a low dose of DSF‐loaded poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles supplemented with oral Cu inhibited tumour growth and reduced metastasis in a xenograft mouse lung cancer model. Here we demonstrate the influence of PLGA polymer, stabilizer loading and molecular weight as well as sonication time on the characteristics, including DSF release and the cytotoxicity of 10% w/w DSF‐loaded PLGA nanoparticles. The paper demonstrates that the choice of PLGA as no significance on the characteristics of the nanoparticles apart from their DSF release, which is due to the differing degradation rates of the polymers. However, increasing the loading and molecular weight of the stabilizer as well as the sonication time reduced the size of the nanoparticles, reduced their ability to protect the DSF from reacting with Cu and degrading in serum, while increasing their DSF release rate and cytotoxicity. Additionally, increasing the sonication time resulted in the premature degradation of the PLGA, which increased the permeability of the nanoparticles further decreasing their ability to protect DSF from reacting with Cu and degrading in serum, while increasing their DSF release rate and cytotoxicity.

Effect of non-cross-linked calcium on characteristics, swelling behaviour, drug release and mucoadhesiveness of calcium alginate beads

In this study, ibuprofen-loaded calcium alginate beads (CABs) with varying amounts of non-cross-linked calcium (NCL-Ca) were prepared using different washing methods. The influence of NCL-Ca on beads properties was investigated. Increasing the number or duration of washes led to significant decreases in the amount of NCL-Ca whereas the impact of the volume of washes was not significant. Approximately 70% of the initial amount of Ca(2+) was NCL-Ca which was removable by washing while only 30% was cross-linked (CL-Ca). Ca(2+) release from the CABs was bimodal; NCL-Ca was burst-released followed by a slower release of CL-Ca. Washing methods and the amount of NCL-Ca had significant influences on the encapsulation efficiency, beads weight, beads swelling, drug release profile and the mucoadhesiveness of CABs. This study highlighted the importance of washing methods and the amount of NCL-Ca to establish CABs properties and understand their behaviour in the simulated intestinal fluids (SIFs).

Stability of parenteral nanoemulsions loaded with paclitaxel: the influence of lipid phase composition, drug concentration and storage temperature

Abstract Paclitaxel was loaded into licensed parenteral nutrition nanoemulsions (Clinoleic® and Intralipid®) using bath sonication, and the stability of the formulations was investigated following storage for two weeks at room temperature or at 4 °C. In general, Clinoleic droplets were smaller than Intralipid droplets, being around 255 and 285 nm, respectively, for blank and freshly loaded emulsions. Regardless of storage temperature, the Clinoleic exhibited a very slight or no increase in droplet size upon storage, whilst the droplet size of the Intralipid emulsion increased significantly. The droplet size of both emulsions was minimally affected by paclitaxel concentration within the range of 0, 1, 3 and 6 mg/ml. The pH of both emulsions markedly decreased upon storage at room temperature, which was possibly attributed to the production of fatty acids resulting from phospholipid hydrolysis. However, at 4 °C, the pH of Clinoleic emulsion was unaffected by storage or paclitaxel concentration while the Intralipid emulsion demonstrated a trend for pH reduction. Both nanoemulsions had a negative zeta potential, with the Clinoleic formulations having the highest charge, possibly explaining the better size stability of this emulsion. Overall, this study has shown that paclitaxel was successfully loaded into clinically licensed parenteral emulsions and that Clinoleic showed greater stability than the Intralipid.

Efficient approach to enhance drug solubility by particle engineering of bovine serum albumin

The aim of this study was to investigate the use of bovine serum albumin (BSA) as a solubility enhancer for indometacin (IND) as a model drug. IND-BSA solid dispersions were prepared by both spray drying and freeze drying techniques using IND:BSA solution (20:1 Molar Ratio (MR)) and IND:BSA suspension (100:1 MR). The solid state of IND in solid dispersions was characterised by SEM, DSC and XRD. The aqueous solubility of IND in the presence of increased amounts of BSA was evaluated. Additionally, IND dissolution and release profiles were evaluated. IND in solid dispersions with BSA showed significantly higher solubility in water than that of the physical mixture of both. Enhancement factors of 24,000 and 100,000 were obtained for the solid dispersion formulated in 20:1 MR and 100:1 MR, respectively. Dissolution studies in-vitro indicated a significant increase in the dissolution rate of IND from solid dispersions compared to that of the free drug, with almost 95% of the drug dissolved in the first 5min. Furthermore, an immediate release of IND from BSA solid dispersions was shown. The potential use of albumin as solubility enhancer for poorly soluble drugs, particularly, for immediate release volume-limited dosage forms is reported.