School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, Henan Province, China.
Theranostics. 2023 Mar 21;13(6):1906-1920. doi: 10.7150/thno.83912. eCollection 2023.
Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance. Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist (PPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core (PPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part. PPA-TRPP/Tab reassembled into a micellar structure with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by PPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. results indicated that PPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response. The study offers potential in tumor eradication via exploiting an "all-in-one" smart polymeric nanoplatform.
化免疫疗法是癌症免疫疗法中一种很有前途的方法。然而，其治疗效果受到肿瘤微环境（TME）中高活性氧（ROS）水平、丰富的癌相关成纤维细胞（CAFs）以及免疫检查点逃避免疫监视的限制。在此，当将程序性死亡配体-1 的 D-肽拮抗剂（PPA-1）连接到表面时，构建了一种新型的 TME 和还原双重响应聚合物胶束前药（TRPP）纳米平台，并将甲磺酸塔拉唑斯汀（Tab，成纤维细胞激活蛋白抑制剂）包裹在水核中（PPA-TRPP/Tab）。链上的阿霉素（DOX）缀合作为免疫原性细胞死亡（ICD）诱导剂和疏水性部分。PPA-TRPP/Tab 重新组装成胶束结构，通过 Tab 调节 TME，2,2'-二硒代双（乙-1-醇）消耗 ROS，PPA-1 阻断免疫检查点和 DOX 产生 ICD。这解决了 TME 中亲水性 Tab 释放以抑制 CAF 和弱酸性 TME 中通过聚合物胶束转化进行细胞内疏水性 DOX 释放以产生 ICD 之间的困境。结果表明，PPA-TRPP/Tab 可以增加肿瘤积累，抑制 CAF 形成，下调调节性 T 细胞并促进 T 淋巴细胞浸润。在小鼠中，它使 60%的肿瘤完全消退，产生长期免疫记忆反应。该研究通过利用“一体化”智能聚合物纳米平台为肿瘤根除提供了潜力。
