Cancer immunotherapy is a promising method for cancer therapy. Imiquimod (R837) is a molecule that could activate immune systems for cancer immunotherapy, but an easily manufactured biocompatible carrier to deliver R837 may be needed to overcome the disadvantages of R837. Micelles formed by biocompatible copolymers have been widely used to deliver chemotherapeutic drugs but not immunotherapeutic drugs. In this study, R837 was linked to an amphiphilic biodegradable copolymer mPEG‐b‐PLA via acid‐sensitive Schiff bases. The molecular structures were investigated by ¹H nuclear magnetic resonance, gel permeation chromatography and Fourier transform infrared spectroscopy. The product could be self‐assembled into micelles with R837 content as high as 22.4%. Owing to acid‐cleavable Schiff bases, the release of R837 from micelles was markedly accelerated under acidic media. Consequently, the micelles linked with R837 stimulated the expression of major histocompatibility complex II‐stimulating molecules on the surface of RAW 264.7 macrophages at pH 6.5 but not pH 7.4. By using human umbilical vein endothelial cells as the in vitro model, it was shown that the polymer carriers and R837‐linked micelles were minimally cytotoxic and did not induce the activation of endothelial cells under physiological pH, which suggested the relatively high biocompatibility. In conclusion, this study successfully developed pH‐responsive immunotherapeutic drug‐loaded micelles that could activate macrophages at acidic pH in vitro. The high biocompatibility of the micelles to endothelial cells also indicated the potential uses under in vivo conditions.

中文翻译：

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一种与免疫调节药物相连的 pH 响应聚合物：合成、特性和体外生物相容性

癌症免疫疗法是一种很有前景的癌症治疗方法。咪喹莫特 (R837) 是一种可以激活免疫系统进行癌症免疫治疗的分子，但可能需要一种易于制造的生物相容性载体来传递 R837，以克服 R837 的缺点。由生物相容性共聚物形成的胶束已被广泛用于递送化疗药物，而不是免疫治疗药物。在这项研究中，R837 通过对酸敏感的席夫碱与一种两亲性生物可降解共聚物 mPEG-b-PLA 相连。分子结构通过¹H 核磁共振、凝胶渗透色谱和傅里叶变换红外光谱。该产品可以自组装成R837含量高达22.4%的胶束。由于酸可裂解的席夫碱，R837 从胶束中的释放在酸性介质下显着加速。因此，与 R837 连接的胶束刺激了 RAW 264.7 巨噬细胞表面上主要组织相容性复合物 II 刺激分子在 pH 6.5 而非 pH 7.4 的表达。通过使用人脐静脉内皮细胞作为体外模型，表明聚合物载体和 R837 连接的胶束具有最小的细胞毒性，并且在生理 pH 下不会诱导内皮细胞的活化，这表明具有相对较高的生物相容性。综上所述，该研究成功开发了 pH 响应性免疫治疗载药胶束，该胶束可以在体外在酸性 pH 下激活巨噬细胞。胶束对内皮细胞的高生物相容性也表明在体内条件下的潜在用途。