Hu Wen Yao, Wu Zhi Min, Yang Qian Qian, Liu Yue Jin, Li Juan, Zhang Can Yang
School of Chemical Engineering, Xiangtan University, Xiangtan, 411105, PR China.
School of Chemical Engineering, Xiangtan University, Xiangtan, 411105, PR China.
Colloids Surf B Biointerfaces. 2019 Nov 1;183:110443. doi: 10.1016/j.colsurfb.2019.110443. Epub 2019 Aug 17.
The development of intelligent oral drug delivery carrier aiming at efficiently bring insulin to intestine is of great significance for diabetes mellitus therapy. In the present study, a series of amphiphilic pH-sensitive block copolymer poly(methyl methacrylate-co-methacrylicacid)-b-poly(2-amino ethyl methacrylate) [P(MMA-co-MAA)-b-PAEMA] was synthesized via activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and further self-assembled into pH-responsive cationic polymeric micelles (PCPMs) for oral insulin delivery. The structure and molecular weight were confirmed by proton nuclear magnetic resonance (H-NMR), Fourier transforming infrared spectrum (FT-IR) and gel permeation chromatography (GPC), respectively. The critical micelle concentration (CMC) values of these copolymers were measured by fluorescent probe method at pH 1.2 (8-15 μg/mL) and pH 7.4 (22-42 μg/mL), respectively, demonstrating high stability at acidic environment. A decrease in the particle size of PCPMs was associated with an increased pH at beginning, which reached around 200 nm at neutral pH, while the particle size increased obviously with pH increase, indicating the pH-sensitivity of PCPMs. The insulin was entrapped into the core of PCPMs (Ins-loaded PCPMs) with high loading efficiency via diafiltration method. The in vitro experiments show Ins-loaded PCPMs have low toxicity and exhibit pH-triggered release profile with remitted initial burst release. The results indicate that the PCPMs self-assembled from P(MMA-co-MAA)-b-PAEMA may be potential carriers for efficient oral delivery of insulin with controlled release property.
旨在将胰岛素高效输送至肠道的智能口服给药载体的研发对糖尿病治疗具有重要意义。在本研究中，通过电子转移活化剂再生原子转移自由基聚合（ARGET ATRP）合成了一系列两亲性pH敏感嵌段共聚物聚（甲基丙烯酸甲酯-共-甲基丙烯酸）-b-聚（甲基丙烯酸2-氨基乙酯）[P（MMA-共-MAA）-b-PAEMA]，并进一步自组装成用于口服胰岛素递送的pH响应性阳离子聚合物胶束（PCPMs）。分别通过质子核磁共振（H-NMR）、傅里叶变换红外光谱（FT-IR）和凝胶渗透色谱（GPC）对其结构和分子量进行了确认。这些共聚物的临界胶束浓度（CMC）值分别通过荧光探针法在pH 1.2（8 - 15μg/mL）和pH 7.4（22 - 42μg/mL）下测定，表明在酸性环境中具有高稳定性。PCPMs的粒径在开始时随pH升高而减小，在中性pH下达到约200nm，而粒径随pH升高明显增大，表明PCPMs具有pH敏感性。通过透析法将胰岛素以高负载效率包封在PCPMs的核心中（负载胰岛素的PCPMs）。体外实验表明，负载胰岛素的PCPMs具有低毒性，并呈现pH触发释放曲线，初始突释得到缓解。结果表明，由P（MMA-共-MAA）-b-PAEMA自组装而成的PCPMs可能是具有控释性能的高效口服胰岛素递送的潜在载体。
