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. 2023 Aug 13;15(8):2128.
doi: 10.3390/pharmaceutics15082128.

Cinnamyl-Modified Polyglycidol/Poly(ε-Caprolactone) Block Copolymer Nanocarriers for Enhanced Encapsulation and Prolonged Release of Cannabidiol

Natalia Toncheva-Moncheva  1 , Erik Dimitrov  1 , Georgi Grancharov  1 , Denitsa Momekova  2 , Petar Petrov  1 , Stanislav Rangelov  1
Affiliations

Cinnamyl-Modified Polyglycidol/Poly(ε-Caprolactone) Block Copolymer Nanocarriers for Enhanced Encapsulation and Prolonged Release of Cannabidiol

Natalia Toncheva-Moncheva et al. Pharmaceutics. .

Abstract

The present study describes the development of novel block copolymer nanocarriers of the phytocannabinoid cannabidiol (CBD), designed to enhance the solubility of the drug in water while achieving high encapsulation efficiency and prolonged drug release. Firstly, a well-defined amphiphilic block copolymer consisting of two outer hydrophilic polyglycidol (PG) blocks and a middle hydrophobic block of poly(ε-caprolactone) bearing pendant cinnamyl moieties (P(CyCL-co-CL)) were synthesized by the click coupling reaction of PG-monoalkyne and P(CyCL-co-CL)-diazide functional macroreagents. A non-modified polyglycidol/poly(ε-caprolactone) amphiphilic block copolymer was obtained as a referent system. Micellar carriers based on the two block copolymers were formed via the solvent evaporation method and loaded with CBD following two different protocols-loading during micelle formation and loading into preformed micelles. The key parameters/characteristics of blank and CBD-loaded micelles such as size, size distribution, zeta potential, molar mass, critical micelle concentration, morphology, and encapsulation efficiency were determined by using dynamic and static multiangle and electrophoretic light scattering, transmission electron microscopy, and atomic force microscopy. Embedding CBD into the micellar carriers affected their hydrodynamic radii to some extent, while the spherical morphology of particles was not changed. The nanoformulation based on the copolymer bearing cinnamyl moieties possessed significantly higher encapsulation efficiency and a slower rate of drug release than the non-modified copolymer. The comparative assessment of the antiproliferative effect of micellar CBD vs. the free drug against the acute myeloid leukemia-derived HL-60 cell line and Sezary Syndrome HUT-78 demonstrated that the newly developed systems have pronounced antitumor activity.

Keywords: cannabidiol; click reactions; functional nanomaterials; poly(ε-caprolactone); polyglycidol; self-assembly.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Preparation of CBD-loaded polymeric micelles according to protocol A (a) and protocol B (b).
Scheme 2
Scheme 2
Schematic representation of the synthesis of PEEGE50-b-PPO4-b-[P(CyCL)4-co-(CL)40]-b-PPO4-b-PEEGE50 copolymer by copper-catalyzed “click” coupling reaction and subsequent deprotection leading to the amphiphilic PG50-b-PPO4-b-[P(CyCL)4-co-(CL)40]-b-PPO4-b-PG50 block copolymer.
Figure 1
Figure 1
SEC traces of the polymer precursors tBu-PEEGE50-b-PPO4-C≡CH and N3-[P(CyCL)4-co-(CL)40]-N3), and the resulting copolymer PEEGE50-b-PPO4-b-[P(CyCL)4-co-(CL)40]-b-PPO4-b-PEEGE50. THF was used as the eluent at a flow rate of 1.0 mL·min−1, at a temperature of 40 °C.
Figure 2
Figure 2
Determination of the CMC of the PG50-b-PPO4-b-[P(CyCL)4-co-(CL)40]-b-PPO4-b-PG50 copolymer using 1,6-diphenyl-1,3,5-hexatriene absorbance at 356 nm in aqueous media at 25 °C.
Figure 3
Figure 3
(a) Representative relaxation time distribution (τ), measured at an angle of 90° for aqueous solution of the loaded micelles of the novel copolymer at a concentration of 1.0 mg·mL−1. (b) Relaxation rate (Γ) as a function of sin2(θ/2) for the loaded micelles of the novel copolymer at a concentration of 0.417 mg·mL−1. (c) Concentration dependence of diffusion coefficients for the loaded micelles of the novel copolymer. The lines through the data points in (b,c) represent the linear fit to the data. Measurements were performed at 25 °C.
Figure 4
Figure 4
Zimm plots of empty (a) and CBD-loaded (b) micelles of the novel copolymer in aqueous solution. Open symbols and closed symbols represent experimental points and extrapolated points of zero concentration and zero angle, respectively. Measurements were performed at 25 °C.
Figure 5
Figure 5
Transmission electron micrographs of blank (a) and loaded with CBD (b) PG50-b-PPO4-b-[P(CyCL)4-co-(CL)40]-b-PPO4-b-PG50 micelles. Samples were stained with uranyl acetate.
Figure 6
Figure 6
Representative AFM images, particle size (diameter), and size distributions of micelles deposited from their aqueous dispersion. Empty micelles (a) and micelles loaded with CBD (b) deposited from 1.0 mg·mL−1 dispersion.
Figure 7
Figure 7
In vitro release of CBD from block copolymer micelles in phosphate buffer (pH = 7.4). The copolymer/CBD weight ratio is 10:1.
Figure 8
Figure 8
Cytotoxicity of micellar vs. free CBD (as ethanol solution) against HUT-78 (a,b) and HL-60 (c,d) human tumor cell lines after 72 h continuous exposure at 37 °C. Loaded polymer micelles were prepared via protocols A and B. Each data point represents the arithmetic mean ± SD of six separate experiments. The copolymer: CBD-mass ratio is 10:1.
Figure 9
Figure 9
Cytotoxicity of empty micelles of the referent copolymer PG45-b-PCL35-b-PG45 (a) and novel copolymer PG50-b-PPO4-b-[P(CyCL)4-co-(CL)40]-b-PPO4-b-PG50 (b) against HUT-78 and HL-60 cell lines after 72 h continuous exposure at 37 °C.
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