Slavomira Doktorovova

Nanotoxicology applied to solid lipid nanoparticles and nanostructured lipid carriers - a systematic review of in vitro data.

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were developed as alternative to other colloidal carriers. They were designed to overcome lipid nanoemulsions and liposomes in stability and ability to control the release of an encapsulated substance, and at the same time to be better tolerated than polymeric nanoparticles. Since the patenting of SLN discovery, large amount of data became available on the behaviour of these systems in vitro. SLN/NLC have many prerequisites to be a well tolerated carrier - the currently available data seem to confirm it, but there are also some contradictory results. In this review, we collected the available data from cytotoxicity, oxidative stress and hemocompatibility studies in vitro and analysed their outcomes. We also provide a summary of the available data in a form of reference table.

Formulating fluticasone propionate in novel PEG-containing nanostructured lipid carriers (PEG-NLC)

The aim of this study was to develop nanostructured lipid carriers (NLC) for topical delivery of fluticasone propionate (FP) with the aim to further improve the safety profile and decrease the adverse-side effects commonly reported in topical corticotherapy. NLC are colloidal drug-carriers consisting of a blend of a solid lipid and a small amount of liquid lipid since these carriers have proved to be effective in epidermal targeting in particular of glucocorticoids. NLC consisting of glyceryl palmito-stearate, and PEG-containing medium chain triglycerides mixture, stabilised by polysorbate 80 and soybean phosphatidylcholine were prepared. A mean particle size between 380 and 408 nm and entrapment efficacy of 95% were obtained for FP-loaded NLC. The crystallinity and polymorphic phase behaviour of FP-free and FP-loaded NLC were examined by differential scanning calorimetry and wide angle X-ray diffraction. Results revealed a low-crystalline structure and confirmed the incorporation of FP into the particles. The suitability of PEG-containing liquid lipids to form the lipid matrix of NLC was also confirmed.

Feasibility of Lipid Nanoparticles for Ocular Delivery of Anti-Inflammatory Drugs

Due to the multiple barriers imposed by the eye against the penetration of drugs, the ocular delivery and targeting are considered difficult to achieve. A major challenge in ocular drug therapy is to improve the poor bioavailability of topically applied ophthalmic drugs by overcoming the severe constraints imposed by the eye on drug absorption. One of the promising strategies nowadays is the use of colloidal carrier systems characterized by a submicron-meter size. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) represent promising alternatives to conventional and very popular ocular carrier systems, such as the nanoemulsions, liposomes, and polymeric nanoparticles. Nevertheless, taking into account the characteristics of the eye, morphometrical properties of the colloidal systems (e.g., average particle size and polydispersion) may represent a limiting factor for topical application without induced corneal irritation, being responsible for the selected system. This review article focuses on the application of lipid nanoparticles (SLN, NLC) as carriers for both non-steroidal and steroidal anti-inflammatory drugs for the treatment of ocular inflammatory disorders. Major benefits, as well as shortcomings, of ocular inflammation conditions are described, in particular upon management of inflammation induced by ocular surgery (e.g., cataracts, refractive surgery). Particular emphasis is given to the clinical choices currently available, while examining the most recent drugs that have been approved.

Nanostructured lipid carrier-based hydrogel formulations for drug delivery: A comprehensive review

The scientific literature today provides several systems that can deliver active pharmaceutical ingredients (APIs) across the skin. These include reservoir matrices, matrix diffusion-controlled devices, multiple polymer devices and multilayer matrix assemblies. Among these, nanostructured lipid carriers (NLC) have emerged as novel systems composed of physiological lipid materials suitable for topical, dermal and transdermal administration. This review focuses on the design characteristics, production and composition of semi-solid formulations containing NLC as API carriers. One of the useful semi-solid systems are hydrogels, which can be used as vehicles to provide appropriate consistency for NLC formulations to be applied onto the skin. In the present review recent developments in the field are highlighted, including examples of APIs successfully entrapped within NLC now amenable for delivery via the skin. Further innovations in NLC composition and formulation, as well as in semi-solid hydrogel assemblies, are likely to expand the number of APIs available for topical, dermal and transdermal delivery.

Solid Lipid Nanoparticle Formulations: Pharmacokinetic and Biopharmaceutical Aspects in Drug Delivery

Solid lipid nanoparticles (SLNs) have emerged as important tools to modify the release profile for a large number of drugs including protein and peptide molecules. SLNs are produced from biocompatible and biodegradable lipid materials, making them a promising therapeutic strategy for drug targeting and delivery, and surmounting the inherent limitations of regulation acceptance. Due to their versatility in loading both lipophilic and hydrophilic molecules in the solid lipid matrix, SLNs depict the ability to prolong, extend or sustain the release profile of the loaded molecules, therefore reducing the repeated administration, and increasing the therapeutic value of a certain treatment. Additional advantages include reduction of drug toxicity and increase of drug bioavailability. To develop SLN formulations for drug targeting and delivery, a basic pharmacokinetic understanding of drug distribution is of major relevance, as well as the biopharmaceutical aspects of the administration route. This chapter provides a fundamental understanding of the pharmacokinetic properties of SLNs, which influence both biopharmaceutical and clinical profiles of the loaded molecules.

Cationic solid lipid nanoparticles (cSLN): Structure, stability and DNA binding capacity correlation studies

Cationic solid lipid nanoparticles (cSLN) are promising lipid nanocarriers for intracellular gene delivery based on well-known and widely accepted materials. cSLN containing single-chained cationic lipid cetyltrimethylammonium bromide were produced by high pressure homogenization and characterized in terms of (a) particle size distribution by photon correlation spectroscopy (PCS) and laser diffractometry (LD), (b) thermal behaviour using differential scanning calorimetry (DSC) and (c) the presence of various polymorphic phases was confirmed by X-ray diffraction (WAXD). SLN composed of Imwitor 900P (IMW) showed different pDNA stability and binding capacity in comparison to those of Compritol 888 ATO (COM). IMW-SLN, having z-ave=138-157 nm and d(0.5)=0.15-0.158 μm could maintain this size for 14 days at room temperature. COM-SLN had z-ave=334 nm and d(0.5)=0.42 μm on the day of production and could maintain similar size during 90 days. IMW-SLN revealed improved pDNA binding capacity. We attempted to explain these differences by different interactions between the solid lipid and the tested cationic lipid.

Preclinical safety of solid lipid nanoparticles and nanostructured lipid carriers: Current evidence from in vitro and in vivo evaluation

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were designed as exceptionally safe colloidal carriers for the delivery of poorly soluble drugs. SLN/NLC have the particularity of being composed of excipientsalready approved for use in medicines for human use, which offers a great advantage over any other nanoparticulate system developed from novel materials. Despite this fact, any use of excipients in new route of administration or in new dosage form requires evidence of safety. After 25 years of research on SLN and NLC, enough evidence on their preclinical safety has been published. In the present work, published data on in vitro and in vivo compatibility of SLN/NLC have been surveyed, in order to provide evidence of high biocompatibility distinguished by intended administration route. We also identified critical factors and possible weak points in SLN/NLC formulations, such as the effect of surfactants on the cell viability in vitro, which should be considered for further development.

Lipid-based colloidal systems (nanoparticles, microemulsions) for drug delivery to the skin: materials and end-product formulations

Drug delivery to or via the skin presents both unique opportunities and obstacles due to skin structure, physiology, and barrier properties. The skin, the largest organ of the body, may be viewed either as a natural protective barrier against penetration of toxic exogenous compounds, excessive loss of water and other essential compounds, or as a promising portal of entry for drugs for local and/or systemic action. Many novel lipid nanocarriers have been designed for topical application of drugs since they allow these molecules to overcome the skin barrier and improve cutaneous bioavailability. The increased drug absorption is often a consequence of a reversibly disrupted barrier function of the skin by the vehicle itself or by specific ingredients figuring in the topical formulation that act as penetration enhancer. Micro/nanoemulsions and lipid nanoparticles are known to provide several advantages over conventional formulations in terms of stability and skin penetration enhancement. However, their characteristics in the original form are low viscous liquids and colloidal dispersions. Therefore, their topical application may be limited in some cases. This review describes recent works in formulating lipid nanocarriers, especially in the semi-solids and hydrogels forms, and reports their special features for biomedical and dermocosmetic applications.

Cationic solid lipid nanoparticles interfere with the activity of antioxidant enzymes in hepatocellular carcinoma cells.

Solid lipid nanoparticles (SLN) are colloidal drug and/or gene carriers developed from solid lipids and surfactants that are considered safe. Cationic SLN, usually used for formulating poorly water-soluble drugs and for gene delivery purposes, as positively charged particles may attach to cellular surfaces and be internalized more easily than negatively charged SLN, but they can also cause damage. The main aim of this work was to test a set of cationic SLN and investigate its influence on the amount of reactive oxygen species (ROS), on antioxidant enzymes activities and on possible oxidative damage to membrane lipids in HepG2 cells. The Dichlorofluorescein assay revealed great increase in ROS presence after cell exposure to SLN. While the exposure to SLN increased the activities of superoxide dismutase and glutathione peroxidase it decreased glutathione reductase activity. Although no significant increase in thiobarbituric reactive species was found, a decrease in sulfhydryl groups was detected. These results indicate that cationic SLN caused oxidative stress in HepG2 cells, but under reported exposure conditions HepG2 cells could attenuate the stress and thus the damage to cellular components was minimal.

Modified Rose Bengal assay for surface hydrophobicity evaluation of cationic solid lipid nanoparticles (cSLN)

Surface hydrophobicity of nanocarriers influences protein binding and subsequently fate of nanoparticles in blood circulation. Therefore, characterization of surface hydrophobicity of nanocarriers provides important preclinical information. Here, a modified classical adsorption method for the needs of characterization of cationic solid lipid nanoparticles (cSLN) was developed. We have identified possible method limitations that should be considered when performing the analysis, i.e. the problems associated with particle separation from the dispersion and their own absorbance in visible spectrum. We propose two modified methods for performing the assay overcoming the stated limitations. We also discuss here evaluation by different approaches (calculation of binding constants or partitioning quotient) and their suitability for the prepared cSLN formulation. Overall, we confirmed that our modified adsorption method can provide useful information about surface properties of (cationic) SLN, however, performing and evaluation of the assay need special attention in order to obtain the desired results.