A Stepwise Framework for the Systematic Development of Lipid Nanoparticles

A properly designed nanosystem aims to deliver an optimized concentration of the active pharmaceutical ingredient (API) at the site of action, resulting in a therapeutic response with reduced adverse effects. Due to the vast availability of lipids and surfactants, producing stable lipid dispersions is a double-edged sword: on the one hand, the versatility of composition allows for a refined design and tuning of properties; on the other hand, the complexity of the materials and their physical interactions often result in laborious and time-consuming pre-formulation studies. However, how can they be tailored, and which premises are required for a “right at first time” development?

Here, a stepwise framework encompassing the sequential stages of nanoparticle production for disulfiram delivery is presented. Drug in lipid solubility analysis leads to the selection of the most suitable liquid lipids. As for the solid lipid, drug partitioning studies point out the lipids with increased capacity for solubilizing and entrapping disulfiram. The microscopical evaluation of the physical compatibility between liquid and solid lipids further indicates the most promising core compositions. The impact of the outer surfactant layer on the colloidal properties of the nanosystems is evaluated recurring to machine learning algorithms, in particular, hierarchical clustering, principal component analysis, and partial least squares regression. Overall, this work represents a comprehensive systematic approach to nanoparticle formulation studies that serves as a basis for selecting the most suitable excipients that comprise solid lipid nanoparticles and nanostructured lipid carriers.

Introduction

Disulfiram (DSF) is a dithiocarbamate derivative that has long been used in the clinic to treat alcohol addiction. As an inhibitor of hepatic aldehyde dehydrogenase 1 and 2, it increases blood acetaldehyde levels upon alcohol consumption, leading to nausea, sweating, respiratory distress, hypotension, and other alcohol intoxication symptoms [1]. Recently, it has shown promising results in reducing the cell viability of different types of cancer, with a possible effect on at least nineteen different targets or pathways. Nonetheless, clinical trials have failed to support the in vitro/in vivo findings, which is most likely due to DSF’s low half-time (extensive hepatic metabolism and serum degradation) and aqueous solubility (0.2 g/L) [2]. Several anticancer drugs are also hydrophobic. Consequently, they are usually poorly absorbed, have low oral bioavailability, and cannot be administered parenterally.

The use of nanotechnology may circumvent this issue by providing a strategy to improve drug bioavailability in tumor tissues and ensure an appropriate therapeutic effect. Solid lipid-based nanoparticles are prominent drug delivery systems composed of a solid lipid core, either in amorphous or crystalline state, stabilized by one or more surfactants, which are usually non-ionic and/or cationic (Figure 1a). Lipid nanoparticles stem from oil-in-water emulsions in which the introduction of a solid lipid at room and body temperature leads to the formation of a solid core. Similar to polymeric systems, this solid matrix is responsible for the controlled release of active substances as well as chemical and physical protection against degradation [4].

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About this article: Basso, J.; Mendes, M.; Cova, T.; Sousa, J.; Pais, A.; Fortuna, A.; Vitorino, R.; Vitorino, C. A Stepwise Framework for the Systematic Development of Lipid Nanoparticles. Biomolecules 2022, 12, 223. https://doi.org/10.3390/biom12020223

Materials

Disulfiram (CAS number 97-77-8), Kolliphor RH40, Myrj 52, oleic acid, Tween 20, and Tween 80 were purchased from Sigma-Aldrich (Saint Louis, WI, USA). Apifil, Capryol 90, Capryol PGMC, cetylpalmitate, Compritol 888 ATO, Labrafac Lipophile WL 1349, Labrafac PG, Lauroglicol 90, Geleol FPF, Geleol mono/dyglicerides NF, Geloil SC, Labrafil M 2125 CS, Labrafil 1944 CS, Labrasol, Labrasol ALF, Monosteol, Precirol Ato 5, Softisan 601, Suppocire CM, Suppocire DM, Suppocire NB, Suppocire CS2X, and Transcutol HP were kindly gifted by Gatefossé (Lyon, France). Capmul MCM and Mygliol 812 N were provided by Abitec (Columbus, OH, USA). Dynasan 116, Dynasan 118, Inwitor 900 F, Witepsol E76, and Witepsol E85 were donated by IOI Oleochemical (Hamburg, Germany). Lipoid S75 was gifted by Lipoid GmbH (Ludwigshafen, Germany). Kolliwax CA, Kolliwax CSA, Kolliwax GMS II, Kolliwax S, Kolliphor P188, Kolliphor ELP, Kolliphor HS15, and Tween 60 were provided by BASF (Ludwigshafen, Germany). Squalene and Squalane were acquired from EFP Biotek (Figueira da Foz, Portugal). Tween 40, Span 20, Span 40, Span 60, and Span 80 were gifted by SEPPIC SA (Paris, France). Water (Ω = 18.2 MΩ.cm, TOC < 1.5 µg/L) was ultrapurified (Sartorius®, Gottingen, Germany) and filtered through a 0.22 µm nylon filter prior to use. All the other reagents were analytical or High Performance Liquid Chromatography (HPLC) grade.