Abdelbary Elhissi

Carbon Nanotubes in Cancer Therapy and Drug Delivery

Carbon nanotubes (CNTs) have been introduced recently as a novel carrier system for both small and large therapeutic molecules. CNTs can be functionalized (i.e., surface engineered) with certain functional groups in order to manipulate their physical or biological properties. In addition to the ability of CNTs to act as carriers for a wide range of therapeutic molecules, their large surface area and possibility to manipulate their surfaces and physical dimensions have been exploited for use in the photothermal destruction of cancer cells. This paper paper will discuss the therapeutic applications of CNTs with a major focus on their applications for the treatment of cancer.

Amphotericin B lipid nanoemulsion aerosols for targeting peripheral respiratory airways via nebulization.

Amphotericin B (AmB) lipid nanoemulsions were prepared and characterized and their suitability for pulmonary delivery via nebulization was evaluated. AmB nanoemulsions were prepared by sonicating and vortexing the drug with two commercially available lipid nanoemulsions: the Intralipid(®) or Clinoleic(®). Loading the nanoemulsions with the drug slightly increased the size of the lipid droplets and did not affect the zeta potential of the nanoemulsions. The loading efficiency of AmB was found to be 87.46±2.21% in the Intralipid(®) nanoemulsions and 80.7±0.70% in the Clinoleic(®) formulation. This respectively corresponded to 21.86 mg and 20.19 mg of AmB being successfully loaded in the nanoemulsions. On aerosolization using a Pari Sprint jet nebulizer, both nanoemulsions produced very high drug output which was approximately 90% for both formulations. Using the two-stage impinger, the Clinoleic(®) emulsion had higher fine particle fraction (FPF) than the Intralipid(®), since the Clinoleic(®) displayed higher deposition of AmB in the lower impinger stage (exceeding 80%), compared to 57% for the Intralipid(®). Overall, the ease of preparation of the AmB lipid nanoemulsions, along with their in vitro nebulization performance suggest that lipid nanoemulsions could be successful nanocarriers for delivery of AmB to the peripheral respiratory airways.

Vibrating-mesh nebulization of liposomes generated using an ethanol-based proliposome technology

This is the first study that evaluates the influence of the compartmental design of the micropump Aeroneb Go nebulizer and the viscosity of a proliposome hydration medium on vibrating-mesh aerosolization of liposomes. Ethanol-based proliposomes comprising soya phosphatidylcholine and cholesterol (1:1 mole ratio) were hydrated by using isotonic NaCl (0.9%) or sucrose (9.25%) solutions to generate liposomes that entrapped approximately 61% of the hydrophilic drug, salbutamol sulphate. Liposomes were aerosolized by the nebulizer to a two-stage impinger. For both formulations, the aerosol mass output was higher than the phospholipid output, indicating some accumulation of large liposomes or liposome aggregate within the nebulizer. Using NaCl (0.9%) solution as the dispersion medium, aerosol droplet size was much smaller and aerosol mass and phospholipid outputs were higher. This was attributed to the lower viscosity of the NaCl solution, resulting in a reduced retention of the aerosols in the “trap” of the nebulizer. For the entrapped salbutamol sulphate, although the “fine particle fraction” was relatively high (57.44%), size reduction of the liposomes during nebulization caused marked losses of the drug originally entrapped. Overall, liposomes generated from proliposomes when using this nebulizer showed high nebulization output and small droplet size. However, further work is required to reduce the losses of the originally entrapped drug from liposomes.

Targeted paclitaxel delivery to tumors using cleavable PEG-conjugated solid lipid nanoparticles.

AbstractPurposeTo develop a tumor-targeted drug delivery system based on solid lipid nanoparticles (SLNs) conjugated with the enzymatically cleavable polyethylene glycol (PEG).MethodsSLNs loaded with paclitaxel (PTX) were prepared using the film ultrasonication method, followed by conjugation with a PEGylated peptide (Pp) that can specifically interact with matrix metalloproteinases (MMPs) that is over-expressed by tumor cells. The physicochemical characteristics of the Pp-PTX-SLNs were studied and the in vitro drug release, cytotoxicity and cell uptake of the formulations were investigated. Furthermore, using an animal model, the pharmacokinetic properties, biodistribution and anti-tumor activity of this system were evaluated.ResultsThe resulting Pp-PTX-SLNs penetrated through tumor cells via facilitated uptake mediated by MMPs. The uncleavable Pp’-PTX-SLNs showed a lower cell uptake efficiency, compared with the Pp-PTX-SLNs. In a tumor-bearing mice model, Pp-PTX-SLNs accumulated to a greater extent at the tumor location, persisted longer in blood circulation, and showed lower toxicity than did PTX-SLNs or Taxol®. Most importantly, the mice treated with Pp-PTX-SLNs survived longer than the groups treated with Pp’-PTX-SLNs, PTX-SLNs or Taxol®.ConclusionsThese results suggest that Pp-PTX-SLNs hold promise as a new strategy for paclitaxel chemotherapy, and that Pp-SLNs can be a useful nanocarrier for other chemotherapeutic drugs. FigureShielding the SLN with PEG2000-Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln-Cys prolongs its circulation time in blood. Cleavage of the PEG chain by tumor-secreted MMPs leads to paclitaxel uptake by target tumor cells. This SLN modification offers a new strategy for paclitaxel chemotherapy.

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.

Glycoside-based niosomal nanocarrier for enhanced in-vivo performance of Cefixime

This study aimed to evaluate the potential of a novel glycoside non-ionic surfactant synthesized and characterized in our laboratory for increased oral bioavailability of Cefixime. The surfactant was synthesized by simple etherification of bergenin with bromoundecane and characterized by (1)H NMR and mass spectroscopy (MS). Biocompatibility of the surfactant (BRM-BG) was assessed by in-vitro cytotoxicity against NIH/3T3 cells and human blood hemolysis. In-vivo acute toxicity was evaluated in mices. Cefixime loaded BRM-BG niosomes were investigated for drug entrapment efficiency using HPLC and surface morphology and vesicle size by atomic force microscopy (AFM) and dynamic light scattering (DLS). The in-vivo oral bioavailability and pharmacokinetics studies were carried out using rabbits. Cefixime loaded BRM-BG vesicles were spherical in the size range of 178.66±8.17nm with a polydipersity index (PDI) of 0.20±0.01, offering an entrapment efficiency as high as 78.4±0.83%. When the surfactant was applied on NIH 3T3 tissue culture, as high as 90.77±3.15% and 86.86±3.02%, cell viability at 1000μg/mL concentration after 24 and 48h respectively were observed. The surfactant also caused 5.49±1.62% haemolysis and was found to be safe at a dose up to 2000mg/kg. In-vivo drug plasma concentration (Cmax) was found to be 9.69±1.22μg/mL, much higher than that resulting from the intake of commercial suspension and capsules. BRM-BG demonstrated to be safe and effective as carrier of Cefixime following oral dosing in rabbits. The BRM-BG surfactant delivery nano-system is relatively safe and in animal models it is an appropriate carrier for Cefixime, offering enhanced bioavailability compared to commercially available formulations of the drug.

Extraction and RP-HPLC determination of taxol in rat plasma, cell culture and quality control samples

A rapid, sensitive, selective and validated reverse phase high-performance liquid chromatography (RP-HPLC) method for the estimation of paclitaxel in micro-sample of rat plasma and in culture of cancer cells was performed in this study. The mobile phase consisted of an optimized mixture of methanol:water: trifluroacetic acid (80: 20: 0.1, v/v/v). Column elution at a flow rate of 1 mL/minute with UV detection at 225 nm at room temperature was used. The RP-HPLC method was successfully applied for the determination of paclitaxel in plasma samples and in culture of cancer cells with nano-quantity of estimation. The validation studies were performed in accordance with the International Conference on Harmonization (ICH) guidelines. The intra- and inter-day precision showed that the coefficients of variation ranged from 1.07% to 4.27% at different levels of concentrations. To the best of our knowledge, this study also reported for the first time the optimization of different solvents for effective extraction of paclitaxel wherein tert.-butyl methyl ether (TBME): diethyl ether (DEE) in 50: 50 v/v composition was found most efficient with extraction efficiency ranging between 77.99% and 91.74% and between 76.14 and 93.66% in the plasma and cell culture, respectively. This proposed method was successfully applied to study the pharmacokinetics of paclitaxel and the influence of verapamil and all-trans retinoic acid (atRA) on paclitaxel pharmacokinetics in rat models. This proposed method might emerge as a valuable aid in the laboratory monitoring of paclitaxel in a variety of in vitro as well as in vivo scenarios.

Thymopentin Nanoparticles Engineered with High Loading Efficiency, Improved Pharmacokinetic Properties, and Enhanced Immunostimulating Effect Using Soybean Phospholipid and PHBHHx Polymer

Formulation of protein and peptide drugs with sustained release properties is crucial to enhance their therapeutic effect and minimize administration frequency. In this study, immunomodulating polymeric systems were designed by manufacturing PHBHHx nanoparticles (NPs) containing thymopentin (TP5). The release profile of the drug was studied over a period of 7 days. The PHBHHx NPs containing TP5-phospholipid (PLC) complex (TP5-PLC) displayed a spherical shape with a mean size, zeta potential, and encapsulation efficiency of 238.9 nm, -32.0 mV, and 72.81%, respectively. The cytotoxicity results showed the PHBHHx NPs had a relatively low toxicity in vitro. TP5 entrapped in the NPs could hardly release in vitro, while the NPs had longer than 7 days release duration after a single subcutaneous injection in Wistar rats. The immunodepression rat model was built to evaluate the immunomodulating effects of TP5-PLC-NPs in vivo. The results of T-lymphocyte subsets (CD3(+), CD4(+), CD8(+), and CD4(+)/CD8(+) ratio) analysis and superoxide dismutase (SOD) values suggested that TP5-PLC-NPs had stronger immunoregulation effects than TP5 solution. In conclusion, an applicable approach to markedly enhancing the loading of a water-soluble peptide into a hydrophobic polymer matrix has been introduced. Thus, TP5-PLC-NPs are promising nanomedicine systems for sustained release effects of TP5.