Solid lipid nanoparticle-based calix[n]arenes and calix-resorcinarenes as building blocks: synthesis, formulation and characterization

Abstract

Solid lipid nanoparticles (SLNs) have attracted increasing attention during recent years. This paper presents an overview about the use of calix[n]arenes and calix-resorcinarenes in the formulation of SLNs. Because of their specific inclusion capability both in the intraparticle spaces and in the host cavities as well as their capacity for functionalization, these colloidal nanostructures represent excellent tools for the encapsulation of different active pharmaceutical ingredients (APIs) in the area of drug targeting, cosmetic additives, contrast agents, etc. Various synthetic routes to the supramolecular structures will be given. These various routes lead to the formulation of the corresponding SLNs. Characterization, properties, toxicological considerations as well as numerous corresponding experimental studies and analytical methods will be also exposed and discussed.

Figure 1

Proposed structure of solid lipid nanoparticles (SLNs), the interior structure varies from amorphous to crystalline.

Figure 2

Synthetic route to different amphiphilic structures based on calix[4]arene. Alk = CH₃(CH₂)_n, n = 4 (a), 6 (b), 8 (c), 10 (d).

Figure 3

Non-contact mode atomic force microscopy (AFM) images of 2d-based SLNs reconstituted after freeze-drying in a solution of glucose (2%) at 5 mm scan range.

Figure 4

Formulae of 2d, 5d and 6d.

Figure 5

General formulae of the amphiphilic calix-arenes used in the haemolysis experiment.

Figure 6

Chemical structures of amphiphilic calixarenes.

Figure 7

(a) Static ¹²⁹Xe NMR spectra recorded under continuous flow of hyperpolarized xenon at an effective Xe pressure of 7 Torr and T 293 K; (b) Plot of the chemical shift of Xe in the host cavity versus the chain length of the amphiphilic calixarenes [68].

Figure 8

In situ transformation of 2a SLNs (bottom) after a pulse of methylene chloride (next to bottom) as monitored by continuous flow hyperpolarized ¹²⁹Xe MAS NMR. Consecutive spectra were recorded every 4.5 min at room temperature. Sharp signals at ±40 ppm are spinning sidebands [68].

Figure 9

Differential scanning calorimetry traces for para-hexanoyl calix-[4]arene 2a[68].

Figure 10

Top view to the cavity of para-hexanoylcalix[4]arene 2a (left) and para-hexylcalix[4]arene (right) [70].

Figure 11

Structures of para-Hexanoyl Calix[4]arene (2a) and t-EHMC.

Figure 12

Capsular structure of inclusion complex of para-hexanoyl calix[4]-arene with t-EHMC (2*2a. t-EHMC). Disorder and H-atoms are omitted for clarity [71].

Figure 13

Powder XRD patterns of 2a SLNs: unloaded SLN (a); SLNEHMC-1.2 (b); and crystalline inclusion complex 2*2a.1t-EHMC (c) [71].

Figure 14

Structures of para-hexanoyl calix[4]arene (2a) and MT.

Figure 15

Electron spin resonance (ESR) spectra of SLN of 2a loaded with MT upon treatment by the solution of sodium ascorbate at room temperature in buffer solution of pH 7.4. Insets: integrated spectra. The asterisk denotes the ascorbate anion-radical [75].

Figure 16

Synthetic route to the amphiphilic para-acyl-calix[9]arenes, 9a–e.

Figure 17

Synthetic route to the compounds 14 and 15.

Figure 18

Noncontact mode AFM image of the solid lipid nanoparticles formed by 14 on mica at 5 × 5 μm scan size, z axis is 94 nm. A 20 μL portion of a suspension of the SLNs was deposited, and imaging was performed after drying for 24 h at 25 °C [86].

Figure 19

Non-contact mode AFM image of the solid lipid nanoparticles formed by 15 on mica at 5 × 5 μm scan size, z axis is 140 nm. A 20 μL portion of a suspension of the SLNs was deposited, and imaging was performed after drying for 24 h at 25 °C [86].

Figure 20

Variation of the diameter of solid lipid nanoparticles formed by 14 in the presence of varying concentrations of Na⁺ (♦); K⁺ (•); Mg²⁺ (▪); and Ca²⁺ (▴) [86].

Figure 21

Variation of the diameter of solid lipid nanoparticles formed by 15 in the presence of varying concentrations of Na⁺ (♦); K⁺ (•); Mg²⁺ (▪); and Ca²⁺ (▴) [86].

Figure 22

Noncontact mode AFM image of the solid lipid nanoparticles of 15 in the presence of 3 mM CaCl₂ on mica at10 μm scan size [86].

Figure 23

Synthetic route to 17.

Figure 24

Atomic force micrsocope image of 17-based SLNs spread on mica and imaged in air in noncontact mode [92].

Figure 25

Agarose gel electrophoresis of 17-based SLNs incubated with increasing concentrations of plasmid DNA (values are expressed in mg mL⁻¹) [98].

Figure 26

ζ-potential values for 17-based SLNs incubated with an increasing amount of DNA [98].

Figure 27

ζ-potential values during the LbL formation; +D: DNA addition; +C: chitosan addition [98].

Figure 28

Transfection rates of MDCK cells, normalized with the values obtained for lipofection experiments, using SLNs coated with DNA (a); DNA + chitosan: DC (b); D–C–D (c); D–C–D–C (d); D–C–D–C–D (e); D–C–D–C–D–C (f); D–C–D–C–D–C–D (g); and D–C–D–C–D–C–D–C (h); black bars represent the SLNs having the chitosan as the last layer [98].

Figure 29

Confocal micrograph of a transfected cell that has expressed green fluorescent protein (GFP). The red color representing the labeled-chitosan appeared to be in the cytoplasmic compartment of the cell [98].

Figure 30

Chemical formula of 5,11,17,23-tetracarboxy-25,26,27,28-tetradodecyloxycalix[4]arene.

Figure 31

AFM images of a suspension of 18 spread on a mica surface (top) at scan ranges of 15 (left) and 2 mm (right) and SEM images of 18-based SLNs [104].

Figure 32

Molecular formula of para-H-tetra-O-dodecyl-calix[4]arene 19.

Figure 33

Non-contact mode AFM image of 19-based nanoparticles ([107]).

Figure 34

Formula of c-2, c-8, c-14, c-20-tetraundecylclix[4]resorcinarene 20.

Figure 35

Non-contact mode AFM images of 20-based SLNs on glass (a) and on mica (b) at 10 μm scan ranges [109].

Figure 36

Non-contact mode AFM images of SLNs based on mixtures of 20 and pluronic^® F68 acid (10%) at 10 × 10 μm scan range [109].

Figure 37

Synthetic route to l-RA-Pro 21.

Figure 38

Scanning electron miroscopy image of l-RA-Pro-based SLNs spread on a glass surface (scale bar 200 nm) [120].

Figure 39

Non-contact mode AFM image of l-RA-Pro-based SLNs spread on a freshly cleaned glass slide [120].

Figure 40

Schematic representation of the proposed interaction mechanism. The lateral chain of Phe is represented by a dashed line for the l-enantiomer (For clarity, only the prolyl moiety of l-RA-Pro is represented) [121].

Figure 41

Synthetic route to proteo-SLNs 23[120].

Figure 42

Non-contact mode AFM of proteo-SLNs immobilized on a gold surface via antibody-antigen interactions and schematic representation of the strategy used to attach the SLNs on the surface (1: activated ester; 2: deactivated amide functions, 3: antibody anti-BSA) [120].

Figure 43

Scanning electron microscopy image of proteo-SLNs spread on a glass substrate (scale bars 1 μm and 200 nm (inset)) [120].

Figure 44

Structure of the resorcinarene bis-crowns CNBC5 24, R = C_nH_2n+1 where n = 2, 3, 4, 5, 7, 9, 10, 11 with selected crystallographic numbering. cw and ccw enantiomers are shown; the A/C plane runs through the upright aryl rings (A and C) and the B/D plane through parallel aryl rings (B and D) respective to the methine plane C7–C14–C21–C28 [124].

Figure 45

SEM image of C11BC5 SLN on SiO_x; spherical particles with a mean diameter of 300 nm are shown [124].

Figure 46

SLN diameters for all CNBC5 24 (mean of the size distribution from DLS showing standard deviation). SLNs with a constant 0.1 mM concentration (black) and with a constant mass 100 mg L⁻¹ (grey) show increasing diameter for longer alkyl chains [124].