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

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.

Click-Chemistry Cross-Linking of Hyaluronan Graft Copolymers

“…Compounds 3 and 4 and their respective ethyl ester precursors 6 and 7 were synthesized from the intermediate ferulate 5 bearing a propargyl group [ 28 ] and an hexa(ethylene glycol) derivative terminated with azide groups at both ends (compound 1 , azido- HEG- azido) [ 20 ]. In particular, a copper(I)-catalyzed azide alkyne 1,3-dipolar cycloaddition (CuAAC) reaction was performed using copper(I) bromide as a catalyst in the presence of N , N -diisopropylethylamine (DIPEA) as the base in THF.…”

“…An Agilent 1100 LC/MSD running with an electrospray source was used in mass spectrometry measurements. The intermediate α,ω-diazido-hexa(ethylene glycol) 1 was synthesized as previously reported in [ 20 ].…”

“…The procedure of coating a polybenzofulvene cylindrical brush surface with HA by means of HA-FA-Pg graft copolymers was gradually transformed into a technology platform which was applied to the coating of the surfaces of different nanostructures such as liposomes [ 19 ], self-assembling micelles [ 20 ], and magnetic nanoparticles [ 21 ].…”

Hyaluronan‐coated poly(propylene imine) dendrimers as biomimetic nanocarriers of doxorubicin

“…The synthesis started with the activation of hexa(ethylene glycol) derivative 1 59 bearing an azide group at one end and an amino group at the other extremity by reaction with bis(4‐nitrophenyl) carbonate to obtain reactive intermediate 2 (yield 80%) as depicted in Scheme 1.…”

Polymer-Based Nanosystems—A Versatile Delivery Approach

“…Furthermore, HA structure benefits from ease of chemical modification, extending its application possibilities in drug delivery by conjugating and functionalizing with other molecules [78]. Particularly, their covalent conjugation with lipophilic molecules (e.g., propargylated ferulate fluorophores linked to fatty-acid residues through hexa(ethylene glycol) spacers) represents a promising path for creating self-assembled drug delivery colloidal nanosystems [81].…”