叶酸修饰壳聚糖纳米复合物介导的CXCL10靶向基因治疗联合放疗抗宫颈癌作用的实验研究

Radiotherapy is an important means for anti-cervical cancer, but its efficacy remains to be improved. Therefore, it is necessary to find new methods for combination with radiotherapy to improve the efficacy. Our research team demonstrated the CXC chemokine ligand 10 (of CXCL10) could induce apoptosis, inhibit angiogenesis and HPV virus for anti-cervical cancer, and further found that CXCL10 can make cervical cancer cells to avoid the S phase of cell cycle. Thus, we assume that the combination of CXCL10 gene therapy and radiotherapy could better inhibit cervical cancer through a variety of mechanism, to achieve effective coordination in treatment of cervical cancer. In order to solve the targeting of gene therapy, a new type of folic acid modified chitosan complex was used in this subject. This new complex could target folate receptor, with advantages of good stability, high utilization, safety, targeting the cervical cancer cells expressing folate receptor. The above idea was preliminarily confirmed in our previous experiments. This subject was performed to further systematically explore the effect and mechanism of combination therapy to provide the basis for effective coordination of CXCL10 gene therapy and radiotherapy in treatment of cervical cancer.

放疗是宫颈癌治疗的重要手段，但其疗效仍有待提高，因此有必要探寻新的方法与放疗有效协同以提高宫颈癌的治疗效果。我们课题组研究证实CXC趋化因子配体10（CXCL10）基因治疗具有诱导凋亡、抑制血管生成、抗HPV病毒等多种抗宫颈癌作用，进一步还发现CXCL10可以使宫颈癌细胞避开细胞周期的S期。由此我们设想，CXCL10基因治疗与放疗的联合可以通过多种不同机理发挥抗宫颈癌作用，以达到基因治疗与放疗的有效协同。为解决基因治疗的靶向性问题，本课题采用了一种新型的叶酸修饰壳聚糖纳米复合物，使其具有叶酸受体的主动靶向性，具有稳定性好、利用度高和安全可靠等优点,能够靶向叶酸受体高表达的宫颈癌细胞。我们在前期的体外实验中初步证实了上述的研究设想，拟计划进一步深入系统地探讨其联合治疗的作用及机理，为寻求CXCL10与放疗在抗宫颈癌作用中的有效协同提供依据。

前期研究证实，CXCL10可抑制肿瘤组织的新生血管生成，抑制引起宫颈癌主要病因的人乳头状瘤病毒（HPV）E6、E7蛋白的表达，而且能够诱导HPV阳性的宫颈癌细胞凋亡，在抗宫颈癌方面具有潜在的应用前景。本项目在此理论基础上进行动物实验，建立了宫颈癌裸鼠模型，证实CXCL10基因联合放射治疗较单独放射和基因治疗能明显降低肿瘤血管密度，减慢细胞增殖，增高凋亡率，进而抑制肿瘤生长。同时为进一步推进CXCL10的临床应用。课题组合成了具有高转染率、低细胞毒性的mPEG-PCL-g-PEI纳米材料介导CXCL10基因完成联合放疗抗宫颈癌作用的体外实验，证实CXCL10细胞因子能提高宫颈癌细胞体外放疗敏感性。这一系列工作为CXCL10基因治疗联合放疗抗宫颈癌的疗效提高了直接证据，实现生物治疗和放疗的有机结合，为进一步阐明CXCL10联合放疗抗宫颈癌的作用机制，及CXCL10联合放疗抗宫颈癌临床应用奠定了基础。