新型生物纳米结构在肝细胞癌靶向治疗中的应用研究

Hepatocellular carcinoma (HCC) is one of the most lethal maligancies worldwide, and currently there is no effective treatment available. Therefore it becomes imperative to develop new therapeutic apparoaches for HCC. Recently, exosome-based immunotherapy has found its way in the treatment of other cancers as reported, however there is no report on HCC. Exosomes are 30 to 90 nm vesicles secreted by a wide range of mammalian cell types after multivesicular bodies from endosomes fuse with the plasma membrane. Importantly,exosomes contain all the molecules derived from their parental cells, which makes them an alternative to their parental cells in some aspects. It has been demonstrated that exosomes can be substitutes for dentritic cells (DCs) to induce cytotoxic T lymphocytes(CTLs). Our results showed that exosomes derived from DCs are effective in inducing CTLs and killing HCC cells in vitro. In addition, our previous study proved that it is feasible to genetically modify exosomes. Based on this, in this proposal we plan to understake a systematic study to exploit the potential of exosomes as a novel vaccine for HCC by modifying exosomes with alpha-fetoprotein (AFP), a HCC specific antigen, which confers exosomes HCC-targeting properties, followed by detailed evaluation of modified exosomes in inducing CTLs in vitro and in HCC animal models and elucidation of the mechanisms underpining exosome-based immunotherapy.

肝癌严重危害人类的健康，但目前对肝癌的治疗还亟待提高。最近，以生物纳米结构-exosome为基础的新型免疫治疗技术，在若干癌症的临床治疗研究上取得了可喜的进展，而在肝细胞癌治疗上的相关应用研究却非常有限。Exosome是细胞分泌的一种膜性囊泡纳米结构，可携带源细胞的相关蛋白组分，作为免疫细胞的取代物可诱导毒性T淋巴细胞产生，发挥抑癌效果。我们前期研究结果表明：exosome可在体外有效地诱导细胞毒性T淋巴细胞，杀伤肝癌细胞；并证明了对exosome的基因修饰是切实可行的。在此基础上，本项目拟对exosome在肝细胞癌免疫治疗上的可行性和应用潜力展开系统的研究。利用肝细胞癌相对特异的抗原片段甲胎蛋白靶向修饰exosome，并对修饰的exosome展开系统的体外、体内肝细胞癌特异性抑癌功效的测试和相关作用机理的研究，以期为肝细胞癌的靶向治疗提供一种新的思路和途径。

肝癌是严重危害人类健康的重大疾病，但目前对肝癌的治疗还亟待提高。为研发更高效、安全的治疗方法，本项目以生物纳米结构-exosome 为基础，利用基因修饰的手段，获得了表达肝癌抗原（AFP）的树突状细胞，通过收集树突状细胞分泌的exosome（DEXAFP），以作为一种新的非细胞疫苗。通过检测发现，DEXAFP富含其他免疫共调控因子，可以作为树突状细胞的取代物，诱导毒性T 淋巴细胞产生，发挥抑癌效果。通过在不同肝癌细胞和动物模型上的验证，我们证明DEXAFP 可在体外有效地诱导细胞毒性T 淋巴细胞，杀伤肝癌细胞。在肝癌皮下瘤、移植型原位瘤及DENA诱导的原发性肝癌模型上，均能介导高效的肿瘤杀伤，并改善其免疫和肿瘤微环境。通过对其作用效果的动态观测，发现DEXAFP的抑瘤效果与其免疫调控呈正相关。同时，我们还测试肝癌细胞来源的exosome作为肝癌抗原载体的可行性，发现其能够活化并介导树突状细胞高效的肿瘤杀伤，而且对其他肿瘤也具有交叉保护作用。这些研究为肝癌的免疫治疗提供了一条新的途径和新手段。

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