Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678 Nicosia, Cyprus.
Polymers and Polymer Processing Laboratories, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678 Nicosia, Cyprus.
ACS Nano. 2023 Dec 26;17(24):24654-24667. doi: 10.1021/acsnano.3c03305. Epub 2023 Dec 6.
Ongoing research is actively exploring the use of immune checkpoint inhibitors to treat solid tumors by inhibiting the PD-1/PD-L1 axis and reactivating the function of cytotoxic T effector cells. Many types of solid tumors, however, are characterized by a dense and stiff stroma and are difficult to treat. Mechanotherapeutics have formed a recent class of drugs that aim to restore biomechanical abnormalities of the tumor microenvironment, related to increased stiffness and hypo-perfusion. Here, we have developed a polymeric formulation containing pirfenidone, which has been successful in restoring the tumor microenvironment in breast tumors and sarcomas. We found that the micellar formulation can induce similar mechanotherapeutic effects to mouse models of 4T1 and E0771 triple negative breast tumors and MCA205 fibrosarcoma tumors but with a dose 100-fold lower than that of the free pirfenidone. Importantly, a combination of pirfenidone-loaded micelles with immune checkpoint inhibition significantly delayed primary tumor growth, leading to a significant improvement in overall survival and in a complete cure for the E0771 tumor model. Furthermore, the combination treatment increased CD4 and CD8 T cell infiltration and suppressed myeloid-derived suppressor cells, creating favorable immunostimulatory conditions, which led to immunological memory. Ultrasound shear wave elastography (SWE) was able to monitor changes in tumor stiffness during treatment, suggesting optimal treatment conditions. Micellar encapsulation is a promising strategy for mechanotherapeutics, and imaging methods, such as SWE, can assist their clinical translation.
目前的研究正在积极探索通过抑制 PD-1/PD-L1 轴并重新激活细胞毒性 T 效应细胞的功能来用免疫检查点抑制剂治疗实体瘤。然而，许多类型的实体瘤的特征是基质致密且坚硬，难以治疗。力学治疗剂形成了最近一类旨在恢复肿瘤微环境生物力学异常的药物，这些异常与硬度增加和低灌注有关。在这里，我们开发了一种含有吡非尼酮的聚合物制剂，该制剂已成功地恢复了乳腺癌和肉瘤中的肿瘤微环境。我们发现胶束制剂可以在 4T1 和 E0771 三阴性乳腺癌以及 MCA205 纤维肉瘤肿瘤的小鼠模型中诱导类似的力学治疗效果，但剂量比游离吡非尼酮低 100 倍。重要的是，吡非尼酮载药胶束与免疫检查点抑制的联合治疗显著延迟了原发性肿瘤的生长，导致 E0771 肿瘤模型的总生存率显著提高，并完全治愈。此外，联合治疗增加了 CD4 和 CD8 T 细胞浸润并抑制了髓系来源的抑制细胞，创造了有利的免疫刺激条件，从而产生了免疫记忆。超声剪切波弹性成像（SWE）能够监测治疗过程中肿瘤硬度的变化，提示最佳治疗条件。胶束包封是力学治疗剂的一种有前途的策略，成像方法（如 SWE）可以辅助其临床转化。
