将治疗剂与聚合物缀合以增强向靶细胞的递送，然后在细胞内触发释放已被证明是一种有效的药物递送方法。该方法适用于递送免疫刺激性未甲基化胞嘧啶-磷酸-鸟嘌呤 (CpG) 寡核苷酸，以在肿瘤内给药后产生抗肿瘤免疫反应。平均有四个 CpG-1668 分子通过不可逆（CpG-葡聚糖）或细胞内氧化还原响应二硫键（CpG-SS-葡聚糖）与 40 kDa 氨基功能化葡聚糖聚合物共价连接。动态光散射分析表明，两种缀合物具有相似的粒径和表面电荷，分别为17nm和-10mV。琼脂糖凝胶电泳分析表明，CpG-SS-dextran 在细胞外低谷胱甘肽 (GSH) 浓度范围（即 10-20μM）内稳定，在细胞内较高 GSH 浓度（5mM）下被裂解，而 CpG-dextran 稳定两种 GSH 浓度。骨髓源性树突状细胞的摄取和活化测定显示游离 CpG、CpG-葡聚糖和 CpG-SS-葡聚糖之间没有显着差异。在小鼠皮下结直肠肿瘤模型中，与 CpG-葡聚糖或游离 CpG 相比，CpG-SS-葡聚糖显示出统计学上显着更强的肿瘤生长抑制作用 (p<0.03) 和延长的存活时间 (p<0.001)。这些结果表明，氧化还原触发的 CpG 从葡聚糖聚合物载体的细胞内释放有望用于肿瘤内治疗性疫苗接种以对抗癌症。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Conjugation of a therapeutic agent to a polymer for enhanced delivery into target cells followed by its intracellular triggered release has proved to be an effective drug delivery approach. This approach is applied to the delivery of the immune-stimulatory unmethylated cytosine-phosphate-guanine (CpG) oligonucleotide for an anti-tumour immune response after intratumoral administration. On average four CpG-1668 molecules were covalently linked to a 40-kDa amino-functionalised dextran polymer via either a non-reversible (CpG-dextran) or an intracellular redox-responsive disulfide linkage (CpG-SS-dextran). Dynamic light scattering analysis showed that both conjugates had a similar particle size and surface charge of 17 nm and -10 mV, respectively. Agarose gel electrophoresis analysis showed that CpG-SS-dextran was stable in the extracellular low glutathione (GSH) concentration range (i.e. 10-20 μM) and was cleaved at the higher intracellular GSH concentration (5 mM), while CpG-dextran was stable in both GSH concentrations. Uptake and activation assays on bone-marrow-derived dendritic cells showed no significant difference between free CpG, CpG-dextran and CpG-SS-dextran. In a mouse subcutaneous colorectal tumour model the CpG-SS-dextran showed a statistically significantly greater inhibition of tumour growth (p < 0.03) and prolonged survival (p < 0.001) compared to CpG-dextran or free CpG. These results demonstrate that the redox-triggered intracellular release of CpG from a dextran polymer carrier has promise for intratumoral therapeutic vaccination against cancer.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.