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. 2024 Feb 15:651:123723.
doi: 10.1016/j.ijpharm.2023.123723. Epub 2023 Dec 17.

Development of nanoparticles based on amphiphilic cyclodextrins for the delivery of active substances

Luc Augis  1 , Ingeborg Nerbø Reiten  2 , Jan-Lukas Førde  3 , Juan M Casas-Solvas  4 , Christina Sizun  5 , Thomas Bizien  6 , Ivan Rajkovic  7 , Eric Larquet  8 , Alexandre Michelet  9 , Mayeul Collot  10 , Sylviane Lesieur  1 , Lars Herfindal  2 , François-Xavier Legrand  11
Affiliations

Development of nanoparticles based on amphiphilic cyclodextrins for the delivery of active substances

Luc Augis et al. Int J Pharm. .

Abstract

Although amphiphilic cyclodextrin derivatives (ACDs) serve as valuable building blocks for nanomedicine formulations, their widespread production still encounters various challenges, limiting large-scale manufacturing. This work focuses on a robust alternative pathway using mineral base catalysis to transesterify β-cyclodextrin with long-chain vinyl esters, yielding ACD with modular and controlled hydrocarbon chain grafting. ACDs with a wide range of degrees of substitution (DS) were reliably synthesized, as indicated by extensive physicochemical characterization, including MALDI-TOF mass spectrometry. The influence of various factors, including the type of catalyst and the length of the hydrocarbon moiety of the vinyl ester, was studied in detail. ACDs were assessed for their ability to form colloidal suspensions by nanoprecipitation, with or without PEGylated phospholipid. Small-angle X-ray scattering and cryo-electron microscopy revealed the formation of nanoparticles with distinct ultrastructures depending on the DS: an onion-like structure for low and very high DS, and reversed hexagonal organization for DS between 4.5 and 6.1. We confirmed the furtivity of the PEGylated versions of the nanoparticles through complement activation experiments and that they were well tolerated in-vivo on a zebrafish larvae model after intravenous injection. Furthermore, a biodistribution experiment showed that the nanoparticles left the bloodstream within 10 h after injection and were phagocytosed by macrophages.

Keywords: Amphiphilic cyclodextrin; Complement activation; Nanoparticles; PEGylation; Zebrafish larvae.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
MALDI-MS Spectrum of β-CD-C10-DS10.5 derivative. The gray area represents the distribution of the derivative-related peaks. An increasing cumulative frequency curve was established from the intensity of each peak, represented by the dotted curve. A median molecular weight of 2756.5 g.mol−1 was measured, with a standard deviation of 379.0 g.mol−1, corresponding to the width at half height calculated by the m/z difference between 75% and 25% frequencies. This leads to a median degree of substitution (DS) of 10.52, with a standard deviation of 2.46.
Figure 2.
Figure 2.
Transesterification reaction of β-CD using vinyl decanoate reagent (A). DS dependence of β-CD-C10 derivatives on sodium-based catalyst pKa (B) and on the cationic counter ion radius of carbonate-based catalyst (C). The pKa values were determined based on the relative acid forms (Parsons, 1967) and the atomic radii values were sourced from (Slater, 1964). Exponential (B) and sigmoid (C) fits were applied.
Figure 3.
Figure 3.
SAXS profiles of β-CD-C10 derivatives NPs in aqueous medium from DS 3.7 to 14.6.
Figure 4.
Figure 4.
Cryo-EM images of non-PEGylated (left column) and PEGylated (right column) β-CD-C10-NPs in aqueous medium with DS ranging from 3.7 to 14.6 (bottom to top). The inserts display Fourier Transform patterns and provide the corresponding range distance related to the first order.
Figure 5.
Figure 5.
Estimated molecular shapes and critical packing parameter (CPP) values for each derivative according to their degree of substitution. CPP values are assumptions and were not quantified.
Figure 6.
Figure 6.
Survival rate (A) and heart rate percentage of control group (B, C) over 3 days post injections of PEGylated β-CD-C10 NPs (N = 12/13 for B and N = 22 for C). The first, second and third bars for each group correspond to 24, 48 and 72 HPI. Values from each day are compared with each other. MEA values are shown between Glu 5 % and all the ACD-NPs (p-values keys: * = 0.01 ≤ p < 0.05, ** = 0.001 ≤ p < 0.01, *** = 0.0001 ≤ p < 0.001, and **** = p < 0.0001). Complement activation (D) of β-CD-C10 NPs non-PEGylated (in grey) and PEGylated (in yellow), both using VBS2+ as buffer. VBS-EGTA-Mg2+ buffer was also used on non-PEGylated NPs (in blue). Displayed values are averages of triplicates.
Figure 7.
Figure 7.
Confocal images focused on the tail portion of mpeg1:mCherry embryos with red fluorescent macrophages injected with PEGylated NPs (green fluorescence). Columns represent DS 3.7, 6.1 and 14.6 NPs, while rows represent the post-injection time, ranging from 3 to 48 hours.
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