(Invited) Reducing-Environment-Responsive Gel Capsules Prepared Via Inverse Miniemulsion Periphery RAFT Polymerization from Water-Soluble Emulsifier Stabilizing W/O Emulsions

Abstract

Nano and micron-sized capsules having an inner water phase, such as liposomes and polymersomes, have been extensively studied as drug carriers because they can load water-soluble protein drugs. However, they have a few disadvantages of low mechanical strength and low loading efficiency of drugs. Therefore, the preparation of stable capsules having an inner water phase is required for constructing carriers for water-soluble protein drugs. In this study, the gel capsules consisting of an amphiphilic capsule membrane and an inner water phase were strategically prepared via inverse miniemulsion periphery reversible addition fragmentation chain transfer (RAFT) polymerization. This paper also describes the release of encapsulated model drugs from the gel capsules in response to a reducing environment. A water-soluble block copolymer emulsifier composed of PMPC block as a hydrophilic component and an amphiphilic poly[oligo(ethylene glycol) methacrylate] (POEGMA) block as a lipophilic component was synthesized via RAFT polymerization. The 1H NMR and gel permeation chromatography measurements revealed that the synthesized PMPC-b-POEGMA had 22 repeating units of PMPC and 171 repeating units of POEGMA with a narrow molecular weight distribution. The water-in-oil (W/O) emulsions were successfully formed by sonication of the water-chloroform mixture containing the resulting PMPC-b-POEGMA, which acted as a stabilizer of water droplets in a chloroform continuous phase because the PMPC and POEGMA blocks were distributed to the water and chloroform phases, respectively. The concentration of the PMPC-b-POEGMA emulsifier affected the droplet size and colloidal stability of the W/O emulsions, which was a similar attribute of conventional surfactants. The optimization of the PMPC-b-POEGMA concentration revealed that the 10 % (w/v) (relative to dispersed phase) of the PMPC-b-POEGMA emulsifier was suitable for the formation of W/O emulsions when chloroform and water were used as a continuous and a dispersed phase, respectively. Next, the amphiphilic poly[poly(ethylene glycol) methacrylate] (PPEGMA) gel layer, which contained bis(2-methacryloyl)oxyethyl disulfide (BMOD) as a reducing-environment-responsive crosslinker, was prepared by inverse miniemulsion periphery RAFT polymerization from the PMPC-b-POEGMA that stabilized the W/O emulsions. The resulting PPEGMA gel capsules were colloidally stable in not only chloroform but also water without additional hydrophilic surface modification because of the amphiphilicity of their gel capsule layer. The PPEGMA gel capsules were taken up by L929 cells with low cytotoxity. Furthermore, the drug-release behavior from the PPEGMA gel capsules in response to dithiothreitol (DTT), which is a reducing agent, was investigated using fluorescein-conjugated dextran (FITC-Dex) as a model drug. The FITC-Dex release rate from the gel capsules in a phosphate buffer (PB) solution (pH 7.4, 20 mM) with DTT was fast compared to that without DTT. When the BMOD-based crosslinks, which contain disulfide bonds, in the PPEGMA gel capsules layer are cleaved in a PB solution with DTT, a decrease in the crosslinking density of the layer induced an increase in the diffusion coefficient of FITC-Dex within the gel capsule layer. Therefore, the FITC-Dex release from the PPEGMA gel capsules was enhanced under a reducing environment. Although the application of PPEGMA gel capsules as smart drug carriers require further research regarding their structural change in response to reducing environments and controlling the drug release rate, the smart functions of the gel capsules can provide useful platforms for constructing a drug carrier that can deliver water-soluble drugs, such as low-molecular-weight drugs, proteins, and DNAs into the cytosol, which has a reducing environment. Figure 1