Roudayna Diab

Ethanol injection method for hydrophilic and lipophilic drug-loaded liposome preparation

In this article, a hydrophobic (beclomethasone dipropionate; BDP) and a hydrophilic (cytarabine; Ara-C) drugs have been encapsulated in liposomes in order to be administered via the pulmonary route. For this aim, a liposome preparation method, which is easy to scale up, the ethanol injection method, has been selected. The effects of critical process and formulation parameters have been investigated. The drug-loaded liposomes were prepared and characterized in terms of size, zeta potential, encapsulation efficiency, release study, cell uptake, and aerodynamic behavior. Small multilamellar vesicles, with sizes ranging from about 80 to 170 nm, were successfully obtained. Results indicated a significant influence of phospholipid and cholesterol amounts on liposome size and encapsulation efficiency. The higher encapsulation efficiencies were about 100% for the hydrophobic drug (BDP) and about 16% for the hydrophilic one (Ara-C). The in vitro release study showed a prolonged release profile for BDP, in contrast with Ara-C, which was released more rapidly. The cell-uptake test revealed that fluorescent liposomes have been well internalized into the cytoplasm of SW-1573 human lung carcinoma cells, confirming the possibility to use liposomes for lung cell targeting. Nebulized Ara-C and BDP liposomes presented aerodynamic diameters compatible with deep lung deposition. In conclusion, the elaborated liposomes seem to be promising carriers for both Ara-C and BDP pulmonary delivery.

Engineered Nanoparticulate Drug Delivery Systems: The Next Frontier for Oral Administration?

For the past few decades, there has been a considerable research interest in the area of oral drug delivery using nanoparticle (NP) delivery systems as carriers. Oral NPs have been used as a physical approach to improve the solubility and the stability of active pharmaceutical ingredients (APIs) in the gastrointestinal juices, to enhance the intestinal permeability of drugs, to sustain and to control the release of encapsulated APIs allowing the dosing frequency to be reduced, and finally, to achieve both local and systemic drug targeting. Numerous materials have been used in the formulation of oral NPs leading to different nanoparticulate platforms. In this paper, we review various aspects of the formulation and the characterization of polymeric, lipid, and inorganic NPs. Special attention will be dedicated to their performance in the oral delivery of drug molecules and therapeutic genes.

Core-shell microcapsules of solid lipid nanoparticles and mesoporous silica for enhanced oral delivery of curcumin.

Newly designed microcapsules (MC) combining a core of solid lipid nanoparticle (SLN) and a mesoporous silica shell have been developed and explored as oral delivery system of curcumin (CU). CU-loaded MC (MC-CU) are 2 μm sized and have a mesoporous silica shell of 0.3 μm thickness with a wormlike structure as characterized by small angle X-ray scattering (SAXS), nitrogen adsorption/desorption and transmission electron microscopy (TEM) measurements. It was found that SLN acts as reservoir of curcumin while the mesoporous shell insures the protection and the controlled release of the drug. MC-CU displayed a pH-dependent in vitro release profile with marked drug retention at pH 2.8. Neutral red uptake assay together with confocal laser scanning microscopy (CLSM) showed a good cell tolerance to MC-CU at relatively high concentration of inert materials. Besides, the cell-uptake test revealed that fluorescent-MC were well internalized into Caco-2 cells, confirming the possibility to use MC for gut cells targeting. These findings suggest that organic core-silica shell microcapsules are promising drug delivery systems with enhanced bioavailability for poorly soluble drugs.

Paclitaxel-Loaded Microparticles for Intratumoral Administration via the TMT Technique: Preparation, Characterization, and Preliminary Antitumoral Evaluation

In our pursuit to develop suitable therapeutic particulate systems for intratumoral delivery by the targeted multi-therapy (TMT) technique, we describe the preparation of paclitaxel-loaded poly(d,l-lactic-co-glycolic) acid (PLGA) microparticles (MPs) (drug loading 35–38%, wt/wt; size 0.7–5 μm). Magnetite (15%, wt/wt) was also incorporated in some preparations for a future magnetic resonance imaging (MRI)-guided delivery. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) experiments showed that paclitaxel was not encapsulated in its initial crystalline form. The paclitaxel in vitro release pattern showed a biphasic tendency with a burst effect followed by a sustained release (28% released amount after 1 month), which was accompanied with MP erosion and degradation signs as confirmed by scanning electronic microscopy (SEM) micrographs. The paclitaxel-loaded MPs demonstrated a dose-dependent antitumor effect on human uterine cancer cells, with an IC50 value relatively close to that of commercial Taxol®. This paclitaxel delivery system represents a potent antiprofilerative and radiosensitizer agent for intratumoral administration via the TMT technique.

Time lasting S-nitrosoglutathione polymeric nanoparticles delay cellular protein S-nitrosation.

Physiological S-nitrosothiols (RSNO), such as S-nitrosoglutathione (GSNO), can be used as nitric oxide (NO) donor for the treatment of vascular diseases. However, despite a half-life measured in hours, the stability of RSNO, limited by enzymatic and non-enzymatic degradations, is too low for clinical application. So, to provide a long-lasting effect and to deliver appropriate NO concentrations to target tissues, RSNO have to be protected. RSNO encapsulation is an interesting response to overcome degradation and provide protection. However, RSNO such as GSNO raise difficulties for encapsulation due to its hydrophilic nature and the instability of the S-NO bound during the formulation process. To our knowledge, the present study is the first description of the direct encapsulation of GSNO within polymeric nanoparticles (NP). The GSNO-loaded NP (GSNO-NP) formulated by a double emulsion process, presented a mean diameter of 289 ± 7 nm. They were positively charged (+40 mV) due to the methacrylic acid and ethylacrylate polymer (Eudragit® RL) used and encapsulated GSNO with a satisfactory efficiency (i.e. 54% or 40 mM GSNO loaded in the NP). In phosphate buffer (37 °C; pH 7.4), GSNO-NP released 100% of encapsulated GSNO within 3h and remained stable still 6h. However, in contact with smooth muscle cells, maximum protein nitrosation (a marker of NO bioavailability) was delayed from 1h for free GSNO to 18h for GSNO-NP. Therefore, protection and sustained release of NO were achieved by the association of a NO donor with a drug delivery system (such as polymeric NP), providing opportunities for vascular diseases treatment.

Silica-based systems for oral delivery of drugs, macromolecules and cells

According to the US Food and Drug Administration and the European Food Safety Authority, amorphous forms of silica and silicates are generally recognized to be safe as oral delivery ingredients in amounts up to 1500mg per day. Silica is used in the formulation of solid dosage forms, e.g. tablets, as glidant or lubricant. The synthesis of silica-based materials depends on the payload nature, drug, macromolecule or cell, and on the target release (active or passive). In the literature, most of the examples deal with the encapsulation of drugs in mesoporous silica nanoparticles. Still to date limited reports concerning the delivery of encapsulated macromolecules and cells have been reported in the field of oral delivery, despite the multiple promising examples demonstrating the compatibility of the sol-gel route with biological entities, likewise the interest of silica as an oral carrier. Silica diatoms appear as an elegant, cost-effective and promising alternative to synthetic sol-gel-based materials. This review reports the latest advances silica-based systems and discusses the potential benefits and drawbacks of using silica for oral delivery of drugs, macromolecules or cells.

Microencapsulation of cytarabine using poly(ethylene glycol)–poly(ε-caprolactone) diblock copolymers as surfactant agents

Background: The high water solubility and the low molecular weight of cytarabine (Ara-C) are major obstacles against its particulate formulation as a result of its low affinity to the commonly used hydrophobic polymers. Methods: Biodegradable cytarabine loaded-microparticles (Ara-C MPs) were elaborated using poly(ϵ-caprolactone) (PCL) and monomethoxy polyethylene glycol (mPEG)–PCL diblock copolymer in order to increase the hydrophilicity of the polymeric matrix. For this purpose, a series of mPEG–PCL diblock copolymers with different PCL block lengths were synthesized. Compositions and molecular weights of obtained copolymers were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, size exclusion chromatography, and size exclusion chromatography–multi-angle laser light scattering. Ara-C MPs were prepared by double emulsion-solvent evaporation method. The effects of varying PCL block lengths on microparticle encapsulation efficiency, size, and zeta potential were evaluated. Results: Increasing the PCL block lengths of copolymers substantially increased the Ara-C encapsulation efficiency and the microparticle size but it decreased their zeta potential. Microparticles were spherical in shape, with a smooth surface and composed of homogenously distributed Ara-C-containing aqueous domains in the polymer matrix. The in vitro drug release kinetics of the optimized microparticles showed a hyperbolic profile with an initial burst release. Conclusion: These results showed the important role of the amphiphilic diblock copolymers as stabilizing agent in the encapsulation of Ara-C in PCL microparticles, suggesting their potential use for the microparticulate formulations of other small hydrophilic bioactive molecules.

Lipid nanocarriers as skin drug delivery systems: Properties, mechanisms of skin interactions and medical applications

During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology. Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers. In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well.

Human monocyte response to S-nitrosoglutathione-loaded nanoparticles: uptake, viability, and transcriptome.

S-Nitrosoglutathione (GSNO) is a good candidate for nitric oxide (NO(•)) delivery, and its nanoformulation improves NO(•) stability and bioavailability. We have compared the effect of empty Eudragit nanoparticles (eENP), GSNO-loaded ENP (gENP), and free GSNO on THP-1 human monocytic cell line. We investigated cellular viability and growth by WST-1 and trypan blue tests. ENP uptake was studied using transmission electron microscopy, confocal microscopy, and flow cytometry. Transcriptomic profiles were obtained using microarray. ENP entered cells by clathrin- and caveolae-mediated endocytosis. Exposure to either free GSNO or gENP induced an activation of genes from the same clusters, in favor of intracellular delivery of GSNO by ENP. GSNO nanoformulation might be a therapeutic option for NO(•) delivery.

Uptake of Eudragit Retard L (Eudragit ® RL) Nanoparticles by Human THP-1 Cell Line and Its Effects on Hematology and Erythrocyte Damage in Rats

The aim of this study was to prepare Eudragit Retard L (Eudragit RL) nanoparticles (ENPs) and to determine their properties, their uptake by the human THP-1 cell line in vitro and their effect on the hematological parameters and erythrocyte damage in rats. ENPs showed an average size of 329.0 ± 18.5 nm, a positive zeta potential value of +57.5 ± 5.47 mV and nearly spherical shape with a smooth surface. THP-1 cell lines could phagocyte ENPs after 2 h of incubation. In the in vivo study, male Sprague-Dawley rats were exposed orally or intraperitoneally (IP) with a single dose of ENP (50 mg/kg body weight). Blood samples were collected after 4 h, 48 h, one week and three weeks for hematological and erythrocytes analysis. ENPs induced significant hematological disturbances in platelets, red blood cell (RBC) total and differential counts of white blood cells (WBCs) after 4 h, 48 h and one week. ENP increased met-Hb and Co-Hb derivatives and decreased met-Hb reductase activity. These parameters were comparable to the control after three weeks when administrated orally. It could be concluded that the route of administration has a major effect on the induction of hematological disturbances and should be considered when ENPs are applied for drug delivery systems.