Application of Click Chemistry in the Preparation of Poly(ethylene oxide)-block-poly(ε-caprolactone) with Hydrolyzable Cross-Links in the Micellar Core

The aim of this study is to develop degradable core-cross-linked polymeric micelles based on poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) structures using click chemistry. Substituted monomer, that is, α-propargyl carboxylate-ε-caprolactone, was synthesized by anionic activation of ε-caprolactone and further treatment with propargyl chloroformate. Ring-opening polymerization of α-propargyl carboxylate-ε-caprolactone with methoxy PEO (5000 g/mol) as initiator and stannous octoate as catalyst was used to prepare PEO-b-poly(α-propargyl carboxylate-ε-caprolactone) (PEO-b-PPCL) block copolymer. The block copolymers were found to spontaneously associate in aqueous solution forming well-defined micelles. Stabilization of the micelles was obtained by cross-linking the core via click reaction between the azide group of tetraethylene glycol (bis)azide reagent and the alkyne group on the PPCL block in the presence of copper catalyst at room temperature. Successful cross-linking was evidenced by 1H NMR, IR spectroscopy, and X-ray photoelectron spectroscopy (XPS). This was followed by the characterization of micellar morphology and size by transmission electron microscopy and light-scattering. Extent of bovine serum albumin (BSA) adsorption for cross-linked and non-cross-linked micelles illustrated the better stability of cross-linked micelles against protein adsorption. Finally, paclitaxel (PTX) was physically encapsulated in the micellar cores, where a similar PTX encapsulation and in vitro release profile for PTX from non-cross-linked and cross-linked micelles was observed. The results pointed to the increased stability of prepared cross-linked micelles and their potential in drug delivery.