Clobetasol propionate (CLO) is a potent glucocorticoid used to treat inflammation-based skin, scalp, and hair disorders. In such conditions, hair follicles (HF) are not only the target site but can also act as drug reservoirs when certain formulations are topically applied. Recently, we have demonstrated nanostructured lipid carriers (NLC) containing CLO presenting epidermal-targeting potential. Here, the focus was evaluating the HF uptake provided by such nanoparticles in comparison to a commercial cream and investigating the influence of different physical stimuli [i.e., infrared (IR) irradiation (with and without metallic nanoparticles-MNP), ultrasound (US) (with and without vibration) and mechanical massage] on their follicular targeting potential. Nanosystems presented sizes around 180 nm (PdI < 0.2) and negative zeta potential. The formulation did not alter skin water loss measurements and was stable for at least 30 days at 5 °C. Nanoparticles released the drug in a sustained fashion for more than 3 days and increased passively about 40 times CLO follicular uptake compared to the commercial cream. Confocal images confirmed the enhanced follicular delivery. On the one hand, NLC application followed by IR for heat generation showed no benefit in terms of HF targeting even at higher temperatures generated by metallic nanoparticle heating. On the other hand, upon US treatment, CLO retention was significantly increased in deeper skin layers. The addition of mechanical vibration to the US treatment led to higher follicular accumulation compared to passive exposure to NLC without stimuli. However, from all evaluated stimuli, manual massage presented the highest follicular targeting potential, driving more than double the amount of CLO into the HF than NLC passive application. In conclusion, NLC showed great potential for delivering CLO to HF, and a simple massage was capable of doubling follicular retention.Skin, hair, and scalp-related dermatological inflammatory pathologies have been treated for decades with oral and topical glucocorticoids. Among the topical drugs under study, clobetasol propionate (CLO) stands out as the most potent one 1 . Due to its vasoconstricting, anti-inflammatory, immunosuppressive and antiproliferative effects, the drug is useful in the treatment of conditions such as eczema, atopic dermatitis, alopecia areata, frontal fibrosing alopecia, psoriasis and lichen planopilaris 2-4 . Nevertheless, continuous use of typical CLO dermatological formulations may present local side effects as skin atrophy, pruritus, folliculitis, and telangiectasia 5-7 . Even though topical treatment results in fewer adverse effects when compared to oral or parenteral administration, formulations capable of controlling drug release while targeting and enhancing drug penetration to specific skin layers can provide additional therapeutic benefits.Previous studies from our group have shown CLO-loaded nanostructured lipid carriers (NLC), produced with 1/5 th of the drug dose used in commercial formulations, presented...
Introducing novel shapes to particulate carrier systems adds unique features to modern drug and gene delivery. Depending on the route of administration, particle geometry can influence deposition and fate within biological environments. In this work, a template-assisted engineering technique is applied, providing full control of size and shape in the preparation of aspherical, nanostructured microparticles. Based on the interconnection of nanoparticles, stabilized by a functional layer-by-layer (LbL) coating, the resulting cylindrical micrometer architecture is especially qualified for pulmonary delivery. Designed as gene delivery system, plasmid-DNA (pCMV-luciferase) and branched polyethylenimine are used to reach both structural integrity of the carrier system and delivery of genes into the cells of interest. Due to their size, particles are exclusively taken up by phagocytes, which also adds a targeting effect to the introduced system. The luciferase expression is demonstrated in macrophages showing increasing levels over a time period of at least 7 d. Furthermore, it is shown for the first time that the expression is depending on the LbL design. From in vivo experiments, corresponding luciferase expression is observed in mice alveolar macrophages. Combining site specific transport with the possibility of genetically engineering immunocompetent phagocytes, the presented system offers promising potential to improve applications for cell-based immunotherapy.
Nano-embedded microparticles represent promising carrier systems to tackle the challenges of nanoparticle delivery into the lungs by inhalation. While spray drying is widely used for the incorporation of nanoparticles into microparticles, the template-assisted technique is a novel method to prepare aspherical, cylindrical microparticles composed of nanoparticles. In this work, both techniques were applied to produce both spherical and cylindrical nanoembedded microparticles. For both geometries particles consisting of gelatin nanoparticles, mannitol and leucine were prepared in three different sizes each. Cylindrical microparticles could be prepared with defined dimensions and narrow size distributions, allowing to target a wide range of aerodynamic diameters. The size of spherical microparticles was influenced by the spraying feed concentration, yielding only small differences in geometric and aerodynamic diameters and broad particle size distributions. Regarding the redispersibility of the nano-embedded microparticles, spherical particles showed better disintegration behavior and higher nanoparticle release in comparison to cylindrical particles upon contact with water. The template-assisted technique yielded higher nanoparticle content in contrast to spray drying. In summary, cylindrical particles represent a promising drug delivery system with high potential for later application. However, further improvements in the preparation method are required to enable higher yields and a possible later scale-up.
Nanoparticles (NPs) are able to deliver a variety of substances into eukaryotic cells.However, their usage is often hampered by a lack of specificity, leading to the undesired uptake of NPs by virtually all cell types. In contrast to this, yeast is known to be specifically taken up into immune cells after entering the body. Therefore, we investigated the interaction of biodegradable surface-modified poly(lactic-co-glycolic acid) (PLGA) particles with yeast cells to overcome the unspecificity of the particulate carriers. Cells of different Saccharomyces cerevisiae strains were characterized regarding their interaction with PLGA-NPs under isotonic and hypotonic conditions. The particles were shown to efficiently interact with yeast cells leading to stable NP/ yeast-complexes allowing to associate or even internalize compounds. Notably, applying those complexes to a coculture model of HeLa cells and macrophages, the macrophages were specifically targeted. This novel nano-in-micro carrier system suggests itself as a promising tool for the delivery of biologically active agents into phagocytic cells combining specificity and efficiency.
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