Synthesis of a phenylboronic ester-linked PEG-lipid conjugate for ROS-responsive drug delivery

Abstract

Stimuli-responsive drug delivery systems (DDSs) offering spatial-temporal and dosage controlled transport of drugs in vivo have attracted much attention for anticancer drug delivery. In the present work, a kind of phenylboronic ester-linked PEG-lipid conjugate was designed and synthesized for H₂O₂-responsive drug delivery. Firstly, a chain-end alkynyl functionalized methoxy poly(ethylene glycol) with a phenylboronic pinacol ester linker was synthesized via a classical Passerini reaction of carboxyl functionalized methoxy poly(ethylene glycol)₂₀₀₀ (mPEG_2k-COOH), 4-formylphenylboronic pinacol ester and propargyl isocyanoacetamide. The obtained polymer was denoted as mPEG_2k-PBPE-alkynyl. Then, the oxidation-responsive cleavage of the phenylboronic pinacol ester linker between the mPEG_2k-COOH and alkynyl chain-end was verified by in situ¹H NMR and mass spectra characterization. Furthermore, the amphiphilic PEG-lipid conjugate was synthesized by the Cu(I)-catalyzed click reaction of mPEG_2k-PBPE-alkynyl and 3-azido-1,2-propanediol distearate (N₃-DSA). The resultant mPEG_2k-PBPE-DSA could self-assemble into stable micelles in aqueous media. Nile red was used as the model drug and was loaded into the micelles. The obtained drug loaded micelles exhibited a typical H₂O₂-responsive drug release behavior and could be effectively internalized by MCF-7 cells. In addition, the synthesized mPEG_2k-PBPE-DSA was tested to be nontoxic towards RAW264.7 cells. Therefore, this biocompatible mPEG_2k-PBPE-DSA conjugate would be promising for applications in ROS-responsive drug delivery.