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Functional block copolymers bearing pendant cinnamyl groups for enhanced solubilization of caffeic acid phenethyl ester

Abstract

The natural bioactive compound caffeic acid phenethyl ester (CAPE) possesses antioxidant, antiinflammatory and anticancer activity. However, the in vivo application of CAPE is limited due to its poor solubility in aqueous media. In this contribution, we report a strategy for enhancing the solubility of CAPE in water by novel micellar carriers comprising segments structurally similar to the CAPE molecule. A series of amphiphilic poly(ethylene oxide)-b-poly(α-cinnamyl-ε-caprolactone-co-ε-caprolactone)-b-poly(ethylene oxide) (PEO-b-P(CyCL-co-CL)-b-PEO) triblock copolymers were synthesized by combining ring-opening copolymerization and “click” reactions. Calculations of the Flory–Huggins parameter suggested that P(CyCL-co-CL) copolymers have a higher affinity for CAPE than do PCL polymer. Micellar carriers based on PEO-b-P(CyCL-co-CL)-b-PEO were formed via the solvent evaporation method and then loaded with CAPE. Dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM) revealed the formation of nanosized spherical micelles that maintained their structural integrity upon dilution to 0.055–0.06 g L−1. The main characteristics of the PEO-b-P(CyCL-co-CL)-b-PEO systems were compared to those of the PEO-b-PCL-b-PEO system. The attachment of pendant cinnamyl moieties to the hydrophobic PCL block enhanced the encapsulation efficiency of the micelles and reduced their burst release behavior.

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Scheme 1
Fig. 1: 1H-NMR spectra of the precursors and hydrophobic macroreagent in CDCl3.
Fig. 2: 1H-NMR spectrum of the amphiphilic triblock copolymer in CDCl3.
Fig. 3: GPC chromatograms of the two macroreagents and the amphiphilic triblock copolymer.
Fig. 4: Preparation of CAPE-loaded polymeric micelles.
Fig. 5: Hydrodynamic diameter distribution of blank block copolmer micelles.
Fig. 6: Cryo-TEM micrographs and the corresponding histograms of block copolymer micelles in water.
Fig. 7: In vitro release of CAPE from block copolymer micelles in phosphate buffer (pH = 7.4).
Fig. 8: In vitro toxicity evaluation of blank micelles, pure drug and drug-loaded micelles.

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Acknowledgements

This work was supported by the Bulgarian National Science Fund [Grant number DN 09-1/2016]. The authors thank Mrs R. Radeva and Dr Ch. Novakov for GPC measurements.

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Correspondence to Petar D. Petrov.

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Grancharov, G., Atanasova, MD., Aluani, D. et al. Functional block copolymers bearing pendant cinnamyl groups for enhanced solubilization of caffeic acid phenethyl ester. Polym J 52, 435–447 (2020). https://doi.org/10.1038/s41428-019-0297-x

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