Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. China.
Biomacromolecules. 2020 Oct 12;21(10):4063-4075. doi: 10.1021/acs.biomac.0c00879. Epub 2020 Sep 24.
In this paper, we synthesized a block copolymer containing pendent thioether functionalities by reversible addition-fragmentation chain transfer polymerization of a -butyloxycarbonyl (Boc)-l-methionine-(2-methacryloylethyl)ester (Boc-METMA) monomer using a poly(ethylene glycol) (PEG)-based chain transfer agent. The deprotection of Boc groups resulted in an oxidation and pH dual-responsive cationic block copolymer PEG--P(METMA). The block copolymer PEG--P(METMA) possessing protonable amine groups was water-soluble at pH < 6.0 and self-assembled to form spherical micelles at pH > 6.0. In the presence of HO, the micelles first became highly swollen with time and completely disassembled at last, demonstrating the HO-responsive feature because of the oxidation of hydrophobic thioether to hydrophilic sulfoxide. The anticancer drug curcumin (Cur) was entrapped in the polymeric micelles and the Cur-loaded micelles displayed a HO-triggered release profile as well as a pH-dependent release behavior, making PEG--P(METMA) micelles promising nanocarriers for reactive oxygen species-responsive drug delivery. Taking advantage of the protonated amine groups, the cationic polyelectrolyte PEG--P(METMA) formed polyion complex micelles with glucose oxidase (GOx) through electrostatic interactions at pH 5.8. By cross-linking the cores of PIC micelles with glutaraldehyde, the PIC micelles were fixed to generate stable GOx nanogels under physiological conditions. The GOx nanogels were glucose-responsive and exhibited glucose-dependent HO-generation activity and improved storage and thermal stability of GOx. Cur can be encapsulated in the GOx nanogels, and the Cur-loaded GOx nanogels demonstrate the glucose-responsive release profile. The GOx nanogels displayed high cytotoxicity to 4T1 cells and were effectively internalized by the cells. Therefore, these GOx nanogels have potential applications in the areas of cancer starvation and oxidation therapy.
在本文中，我们通过可逆加成-断裂链转移聚合反应，使用基于聚乙二醇（PEG）的链转移剂，合成了一种含有侧硫醚官能团的嵌段共聚物，该共聚物由 -丁氧基羰基（Boc）-L-蛋氨酸-（2-甲基丙烯酰基乙基）酯（Boc-METMA）单体聚合而成。Boc 基团的脱保护作用导致氧化和 pH 双重响应的阳离子嵌段共聚物 PEG--P（METMA）。具有可质子化胺基的嵌段共聚物 PEG--P（METMA）在 pH <6.0 时水溶性好，在 pH >6.0 时自组装形成球形胶束。在 HO 的存在下，胶束首先随时间发生剧烈溶胀，最后完全解体，表现出 HO 响应特性，这是由于疏水性硫醚氧化为亲水性亚砜。抗癌药物姜黄素（Cur）被包封在聚合物胶束中，载药胶束显示出 HO 触发的释放特性以及 pH 依赖性释放行为，这使得 PEG--P（METMA）胶束成为活性氧响应药物递送的有前途的纳米载体。利用质子化的胺基，阳离子聚电解质 PEG--P（METMA）在 pH 5.8 时通过静电相互作用与葡萄糖氧化酶（GOx）形成聚离子复合物胶束。通过戊二醛交联 PIC 胶束的核，在生理条件下将 PIC 胶束固定以生成稳定的 GOx 纳米凝胶。GOx 纳米凝胶是葡萄糖响应的，表现出葡萄糖依赖性 HO 生成活性，并提高了 GOx 的储存和热稳定性。Cur 可以包封在 GOx 纳米凝胶中，载药的 GOx 纳米凝胶显示出葡萄糖响应的释放特性。GOx 纳米凝胶对 4T1 细胞具有高细胞毒性，并被细胞有效内化。因此，这些 GOx 纳米凝胶在癌症饥饿和氧化治疗领域具有潜在的应用前景。
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