Lipid extract from Black Soldier Fly larvae: A high value excipient for solid lipid nanoparticles tailored to tackle atopic dermatitis

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin condition, characterized by redness, dryness, and plaque formation. These symptoms arise from a complex interplay of environmental factors in genetically predisposed individuals (Weidinger et al., 2018). AD presents a significant threat among skin conditions, consistently contributing to patient disability, with its prevalence continuing to escalate (Langan et al., 2020, Yakupu et al., 2023). A hallmark of AD is the compromised epidermal barrier, primarily stemming from an aberrant lipid metabolism, leading to ceramide and fatty acid (FA) profile disturbances in the stratum corneum (Almeida et al., 2022a, Danso et al., 2017, Imokawa, 2021). This key alteration renders AD patients to be highly susceptible to irritants and allergens. The gold standard for AD management involves daily application of topical emollients coupled with either reactive or proactive topical use of glucocorticoids (GC) or calcineurin inhibitors (Wollenberg et al., 2022). Dexamethasone (DEX) is a widely used glucocorticoid to treat inflammatory skin dysfunctions, such as atopic dermatitis. Despite being considered a low potency glucocorticoid (Wiedersberg et al., 2008), there are some adverse effects associated with its topical application and limitations to its transcutaneous penetration.

Nanotechnology can provide sophisticated tools for developing high-performance drug delivery carriers, such as lipid nanoparticles. Solid lipid nanoparticles (SLNs) offer advantages like bio-vectorization and improved bioavailability, biocompatibility, and biodegradability (Almeida et al., 2022a, Souto et al., 2022). In this sense, these delivery systems can facilitate the permeation of drugs, as well as the protection of these compounds from possible physicochemical alterations or degradations (Souto et al., 2022). These characteristics can improve the safety and efficacy of topical formulations, providing an optimized release to the skin, as well as an improved delivery to the therapeutic target, thereby reducing the occurrence of adverse effects.

The epidermal stratum corneum (SC) provides an efficient barrier for many xenobiotics, including topical drugs. This layer is formed by corneocytes, mainly composed of keratin, immersed in an impermeable lipid matrix. Several skin diseases are related to alterations in this lipidic medium, causing dysfunctions in the cutaneous barrier, including atopic dermatitis and psoriasis (Almeida et al., 2022a, Danso et al., 2017). In addition to SC ceramides and cholesterol, free fatty acids (FA) perform a critical role in skin barrier function and in the regulation of water loss. The development of lipid nanoparticles made up of FA that are similar to those present in the epidermis may, thus, be a good strategy for topical formulations, since they can combine optimized delivery with an emollient protective effect.

Sustainable technological approaches in medicines development are pressing topics in Research, Development & Innovation and in current European Union and United Nations development policies. Moreover, the need has arisen in Europe to increase its resilience and explore locally sourced biomaterials as the foundation for innovative formulations. Hermetia illucens, commonly known as Black Soldier Fly, can be viewed as a source of compounds with high aggregated value and marketing potential due to the sustainable organic matter bioconversion process used as substrate for its development. Black Soldier Fly larvae (BSFL) biomass is rich in proteins, vitamins, minerals and, most importantly, lipids (Almeida et al., 2020). Previous work conducted by our group showed that the BSFL lipid extract is mainly composed of saturated FA, namely lauric acid (C12:0), followed by palmitic (C16:0), linoleic (C18:2), and oleic (C18:1n-9) acids (Almeida et al., 2022b). This blend of FA has a great potential in skin formulations, mainly as a conditioning and emollient ingredient (Almeida et al., 2020).

In this study, an innovative strategy for DEX nanodelivery for topical application was developed using the previously characterized BSFL lipid extract as a sustainable and versatile biomaterial. The SLNs based on the lipid extract were tailored for the management of AD, aiming to combine both controlled release and emollient properties. The optimized DEX-loaded SLNs were developed via a Box-Behnken Design (BBD) approach and physicochemically characterized in terms of storage stability and in vitro drug release. The impact of the nanoparticles on HaCaT cell viability was assessed by an MTT test and an internalization assay was performed to evaluate their capacity to permeate these cells. Overall, this proof-of-concept study aimed to establish BSFL lipid extract as a multipurpose ingredient for high-performance delivery systems, capable of improving glucocorticoid formulations to tackle AD.

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Materials

The Black Soldier Fly larvae (BSFL) were kindly supplied by Entogreen® company. The lipid extract was obtained from their biomass with a maceration technique using acetone as organic solvent, as described by Almeida et al. (Almeida et al., 2022b). DEX was obtained from AppliChem GmbH (Darmstadt, Germany), Tween® 80 from Sigma-Aldrich (Saint Louis, MO, USA) and Fluorescein isothiocyanate from Invitrogen (Waltham, MA, USA). Considering cell-based studies, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was obtained from Sigma-Aldrich (Saint Louis, MO, USA), DMEM low-glucose medium from Biowest (Nuaillé, France), Fetal Bovine Serum and Penicillin-streptomycin from Enzyfarma (Lisbon, Portugal), and trypsin-EDTA from ThermoFisher Scientific (Waltham, MA, USA).

Cíntia Almeida, Rossana Roque, João Vieira, Ana Júlio, Nuno Saraiva, Catarina Pereira-Leite, Catarina Rosado,
Lipid extract from Black Soldier Fly larvae: A high value excipient for solid lipid nanoparticles tailored to tackle atopic dermatitis, International Journal of Pharmaceutics, Volume 667, Part B, 2024, 124929, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124929.

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