Iminoboronate-based dual-responsive micelles via subcomponent self-assembly for hydrophilic 1,2-diol-containing drug delivery

Abstract

Amphiphilic block copolymer micelles in aqueous solution have been used extensively in delivery of hydrophobic drugs with the hydrophobic core serving as the reservoir. However, encapsulation of hydrophilic drugs by polymeric micelles with hydrophobic core is relatively difficult because of the poor interaction between them. Herein, we report a novel kind of pH/GSH dual-responsive complex micelles with a hydrophilic drug loaded, via direct subcomponent self-assembly of block copolymer poly(ethyleneglycol)-block-poly(L-lysine) (PEG-b-PLys), 2-formylbenzeneboronic acid (2-FPBA) and hydrophilic 1,2-diol-containing drugs (e.g. capecitabine (CAPE)) under physiological pH 7.4 based on the synergistic formation of an iminoboronate structure. The PEG-b-PLys/2-FPBA micelles without CAPE are well-characterized in terms of micellization mechanism, size, morphology, pH-and GSHresponsiveness. Encapsulation of CAPE by forming PEG-b-PLys/2-FPBA/CAPE complex micelles via synergistic formation of the iminoboronate structure is discussed and pH-and GSH-responsive drugrelease studies are carried out. The complex micelles are stable under physiological neutral conditions but could be destroyed in response to the stimuli of physiological acidic condition (pH 5.0) and/or glutathione (GSH) at pH 7.4. pH-and GSH-responsive drug-releases are successfully achieved. The drug-loaded complex micelles could be endocytosed by HepG2 cells and efficiently deliver hydrophilic drugs into them. This type of complex micelles could be used as a promising platform for the delivery of hydrophilic 1,2-diol-containing drugs.

Boronic acids as building blocks for the construction of therapeutically useful bioconjugates

“…The resulting micelles proved to be stable under physiological conditions, while releasing their CAPE cargo when exposed to low pH or glutathione, attesting to this technology as a valid strategy for micelle-based drug delivery that circumvents the difficulties in loading these structures with hydrophilic drugs. 189 Using a similar strategy, the same group reported a stimulisensitive hydrogel as a self-assembled multi-component supramolecular structure composed of an endogenous guanosine, 2-FBBA, tris(2-aminoethyl)amine and a cationic potassium core. Iminoboronates were introduced into the structure to facilitate the formation of the hydrogel and to allow a controlled hydrogel dissociation due to the dynamic interactions upon pH acidification and exposure to saccharide structures (Fig.…”

“…The resulting micelles proved to be stable under physiological conditions, while releasing their CAPE cargo when exposed to low pH or glutathione, attesting to this technology as a valid strategy for micelle-based drug delivery that circumvents the difficulties in loading these structures with hydrophilic drugs. 189…”

Nitrilotriacetic Acid (NTA) and Phenylboronic Acid (PBA) Functionalized Nanogels for Efficient Encapsulation and Controlled Release of Insulin

“…In this study, PBA was incorporated to endow the nanogels with glucose responsiveness. PBA could bind glucose and transform from a neutral, hydrophobic form to a negatively charged, hydrophilic form. − Thus, the nanogels would undergo volume transition upon the stimuli of glucose because of the change from hydrophobicity to hydrophilicity. This enabled us to observe the glucose-responsiveness of the nanogels by monitoring the hydrodynamic diameter distributions f ( D h ).…”

Poly(α-l-lysine)-based nanomaterials for versatile biomedical applications: Current advances and perspectives

“…Several studies attempted to construct pH/GSH dual-responsive PLL-based complex micelles or nanoparticles for drug delivery [ 199 , [203] , [204] , [205] , [206] , [207] , [208] ]. Four-armed PLLs with conjugated CPT through a reduction-responsive disulfide bond were encapsulated by PEG- b -PLL, in which the side chains of the PLL block were modified with charge-conversional citraconic anhydride to form poly-ion nanorods ( Fig.…”

“…Shi et al fabricated a novel kind of pH/GSH dual-responsive drug-loaded complex micelles via direct subcomponent self-assembly of the block copolymer PEG- b -PLL, 2-formylbenzeneboronic acid (2-FPBA) and hydrophilic 1,2-diol-containing drugs ( e.g. , capecitabine) under physiological pH based on the synergistic formation of an iminoboronate structure [ 203 ]. The complex micelles were stable under neutral physiological conditions but could be destroyed for drug release in response to the stimuli of acidic physiological conditions or GSH.…”