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. 2019 Dec 12;11(12):675.
doi: 10.3390/pharmaceutics11120675.

Hyaluronan Graft Copolymers Bearing Fatty-Acid Residues as Self-Assembling Nanoparticles for Olanzapine Delivery

Marco Paolino  1 , Mariano Licciardi  2 , Cristina Savoca  2 , Gaetano Giammona  2 , Laura Modica De Mohac  3 , Annalisa Reale  1 , Germano Giuliani  1 , Hartmut Komber  4 , Alessandro Donati  1 , Gemma Leone  1 , Agnese Magnani  1 , Maurizio Anzini  1 , Andrea Cappelli  1
Affiliations

Hyaluronan Graft Copolymers Bearing Fatty-Acid Residues as Self-Assembling Nanoparticles for Olanzapine Delivery

Marco Paolino et al. Pharmaceutics. .

Abstract

In order to evaluate the potential of a technology platform based on hyaluronan copolymers grafted with propargylated ferulate fluorophores (HA-FA-Pg) in the development of drug delivery systems, the propargyl groups of HA-FA-Pg derivatives were employed with oleic acid (OA) or stearic acid (SA) residues across a biocompatible hexa(ethylene glycol) (HEG) spacer. The designed materials (i.e., HA-FA-HEG-OA or HA-FA-HEG-SA) showed clear-cut aggregation features in an aqueous environment, as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), generating nanoaggregate systems. In fact, HA-FA-HEG-OA and HA-FA-HEG-SA derivatives showed the property to create self-assembled cytocompatible nanostructured aggregates in water, thanks to the simultaneous presence of hydrophilic portions in the polymeric backbone, such as hyaluronic acid, and hydrophobic portions in the side chains. Furthermore, the designed materials interact with living cells showing a high degree of cytocompatibility. The potential ability of nanosystems to load pharmacologically active molecules was assessed by the physical entrapment of olanzapine into both polymeric systems. The drug loading evaluation demonstrated that the nanoparticles are able to incorporate a good quantity of olanzapine, as well as improve drug solubility, release profile, and cytocompatibility.

Keywords: drug delivery systems; ferulic acid; hyaluronic acid; olanzapine; oleic acid; self-assembling nanocarriers; stearic acid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Design and development of the technology platform based on hyaluronan copolymers grafted with propargylated ferulate fluorophores (HA-FA-Pg).
Figure 2
Figure 2
1H- and 13C-NMR spectra of model compound FA-HEG-OA in CDCl3.
Scheme 1
Scheme 1
Synthesis of HA-FA-HEG-OA and HA-FA-HEG-SA materials. Reagents: (i) CDI, THF; (ii) TEA, THF; (iii) CuSO4, sodium ascorbate, tert-BuOH, H2O. Substituents: R = H or C2H5; R’ = C17H33 (1a, 2a, 4a, HA-FA-HEG-OA) or C17H35 (1b, 2b, 4b, HA-FA-HEG-SA).
Scheme 2
Scheme 2
Synthesis of hexa(ethylene glycol) derivative 3. Reagents: (i) MesCl, TEA, CH2Cl2; (ii) NaN3, Bu4N+Br−, DMF; (iii) PPh3, toluene, HCl 3 N.
Scheme 3
Scheme 3
Synthesis of model compounds 8 and FA-HEG-OA. Reagents: (i) CuSO4, sodium ascorbate, tert-BuOH, H2O; (ii) NaOH, H2O, C2H5OH.
Figure 3
Figure 3
Comparison of 1H-NMR spectra obtained from HA-FA-HEG-OA (c) and HA-FA-HEG-SA (d) derivatives measured in D2O and FE-HEG-OA (e) measured in CDCl3 with those obtained from the starting HA-FA-Pg (b) and HA (a) samples (solvent: D2O; (a) and (b) were recorded with water suppression). In the spectrum of HA, “Et” labels indicate the signals of ethyl groups of the monomeric units with R = C2H5.
Figure 4
Figure 4
Comparison of 13C-NMR spectra of HA-FA-HEG-SA (c) and HA-FA-HEG-OA (d) derivatives measured in D2O and FE-HEG-OA (e) measured in CDCl3 with those obtained from starting HA-FA-Pg (b) and HA (a) samples in D2O. In the spectrum of HA, “Et” labels indicate the signals of ethyl groups of the monomeric units with R = C2H5.
Figure 5
Figure 5
DLS size distribution histograms of HA-FA-HEG-OA (A) and HA-FA-HEG-SA (B) in Milli-Q water.
Figure 6
Figure 6
I1(373)/I3(384) intensity ratios obtained from pyrene emission spectra (blue curve) and I338/I332 intensity ratios obtained from pyrene excitation spectra (orange curve) for HA-FA-HEG-OA derivative water dispersions (A) or HA-FA-HEG-SA derivative water dispersions (C) at 25 °C, in the concentration range of 0.0001–10 mg/mL; size distribution values of HA-FA-HEG-OA (B) or HA-FA-HEG-SA (D) in the same conditions.
Figure 7
Figure 7
Representative transmission electron micrograph of HA-FA-HEG-OA (A,B) and HA-FA-HEG-SA (C,D) nanoparticles.
Figure 8
Figure 8
Viscosity curve of 2% w/v aqueous solution of HA (■) and HA-FA-HEG-SA (●) as a function of shear rate (range 1–100 s−1).
Figure 9
Figure 9
In vitro OZ release profiles in PBS solution pH 7.4 at 37 °C. The amount of released OZ is reported as the percentage ratio between the weight of the drug released from the nano-aggregates and the drug loading.
Figure 10
Figure 10
Cell viability evaluated by MTS on 16-HBE cells, after 24 h of incubation with HA-FA-HEG-OA, HA-FA-HEG-SA, HA-FA-HEG-OA-OZ, HA-FA-HEG-SA-OZ, and olanzapine alone.
Figure 11
Figure 11
Representation of hyaluronan graft copolymer HA-FA-HEG-OA bearing fatty acid residues as self-assembling nanoparticles for olanzapine delivery.
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