Turning Fluvastatin into a supramolecular immuno-sensitizer towards augmented tumor immunotherapy
Turning Fluvastatin into a supramolecular immuno-sensitizer towards augmented tumor immunotherapy
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DOI：
10.1016/j.cej.2022.135310
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发表时间：
2022-02-17
影响因子：
15.1
通讯作者：
Liu, Wenjia
中科院分区：
文献类型：
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作者：
Ma, Fang;Liu, Tianya;Liu, Wenjia
尽管免疫检查点阻滞剂的临床应用提高了晚期恶性肿瘤患者的生存率和生活质量，但其抗癌作用始终受到低氧肿瘤微环境（TME）的影响。为了开发一种具有临床翻译潜力的肿瘤靶向治疗方法，氟伐他汀（fda批准的3-羟基-3-甲基戊二酰辅酶a还原酶抑制剂）通过抑制辅酶q的合成来抑制线粒体呼吸。通过部分还原性HSA和疏水性氟伐他汀之间的超分子自组装，开发了一种全新的温和高效的策略来构建具有球形形貌的尺寸可调纳米结构。正如预期的那样，这种白蛋白结合氟伐他汀（AB-Flu）纳米药物显著提高了肿瘤细胞内的药物浓度，恢复了氟伐他汀治疗TME缺氧的作用。结果，在MC38同种移植小鼠模型和人源化患者源异种移植（PDX）小鼠模型中，b - flu使t细胞相对免疫微环境正常化，从而有效地增强了Anti-PD1抗结直肠癌的效力，同时保持了良好的安全性。总之，构建AB-Flu的超分子自组装策略不仅为解决TME中的缺氧问题和增强肿瘤免疫治疗提供了新的候选药物，而且为开发一类新的hsa衍生的超分子用于多种肿瘤的位点特异性精确治疗提供了有希望的工具。
Although the clinical application of immune checkpoint blockers has been improving survival and living quality for patients with advanced malignant tumors, their anti-cancer action always suffered from the hypoxic tumor microenvironment (TME). To develop a tumor-targeting therapeutic for the redressment of the hypoxia with clinical translation potential, Fluvastatin, a FDA-approved inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was used to suppress mitochondrial respiration through the synthesis inhibition of coenzyme Q. Towards tumor targeting, a de novo mild and efficient strategy was developed to construct a size-tunable nanostructure with spherical morphology through the supramolecular self-assembly between the partially reductive HSA and the hydrophobic Fluvastatin. As expected, this Albumin-bound Fluvastatin (AB-Flu) nano medicine significantly enriched the drug concentration in tumor cells, and resurrected the action of Fluvastatin to redress the hypoxia of TME. As a result, AB-Flu normalized T-cell-relative immune microenvironment, thereby effectively sensitizing the potency of Anti-PD1 against colorectal cancer in the MC38 homograft mouse model and the humanized patient-derived xenograft (PDX) mouse model, while keeping a favorable profile of safety. Collectively, the supramolecular self-assembled strategy for the AB-Flu construction not only provided a new drug candidate for redressing the hypoxia in TME and augmenting tumor immunotherapy consequently, but also offered a promising tool to develop a new class of HSA-derived supramolecules for the site-specific precise therapy of multifarious tumors.