新型靶向穿膜肽修饰纳米颗粒介导DAB2IP功能片段(P10)增强宫颈癌放疗敏感性及其分子机制研究

Radiotherapy resistance is a risk factor affecting the prognosis of cervical cancer; at the same time, developing tumor-targeting nanoparticles with specificity, safety and efficiency is a bottleneck in finding the solution for cervical radio-resistance. Our previous studies confirmed that R11-SSPEI- nanoparticles could be up-taken specifically by tumor tissue to biological effect and the DAB2IP functional fragment, P10 peptide, could be an effective cancer radio-sensitizer. Therefore, this project intends to design and synthesis R11-SSPEI-P10 nanoparticles and explores tumor specificity, stability and polypeptides released in in vitro cell systems and in an animal model. The therapeutic effect of R11-SSPEI-P10 nanoparticles toward radiotherapy resistance will be tested in tumor bearing nude mice. The impact of P10 to Caveolin-1-ERBB2-DSB repair pathway will be also tested in an in vitro model, clarifying the molecular mechanism to radiotherapy resistance in cervical cancer. This study will help to reveal the molecular mechanism of radiotherapy resistance in cervical cancer and to provide a new and efficient targeted peptide nano-drug delivery system. If successful, this results will have important implications for the treatment of cervical radiotherapy resistance and tumor recurrence.

肿瘤放疗耐受是影响宫颈癌预后的重要因素，而构建特异、安全、高效的肿瘤靶向纳米颗粒是解决宫颈癌放疗耐受的瓶颈。申请人前期研究证实：R11-SSPEI-纳米颗粒可以特异性被肿瘤组织摄取并发挥生物学作用；同时发现DAB2IP功能片段P10可能成为宫颈癌放疗增敏的有效多肽片段，因而本课题拟设计合成R11-SSPEI-P10纳米颗粒，探索其在体外细胞和动物体内系统中的肿瘤靶向性、稳定性以及多肽释放情况，并利用宫颈癌荷瘤鼠模型验证R11-SSPEI-P10纳米颗粒对肿瘤放疗耐受的治疗效果；进一步在细胞体外模型中研究P10对Caveolin-1-ERBB2-DSB repair通路的影响，揭示其增强宫颈癌放疗耐受的分子机制。本课题有助于阐明宫颈癌放疗耐受的分子机制，为宫颈癌治疗提供了一种新型高效的多肽靶向纳米药物递送系统，对宫颈癌放疗耐受和肿瘤复发的治疗策略具有重要意义。

肿瘤放疗耐受是影响宫颈癌预后的重要因素，而构建特异、安全、高效的肿瘤靶向纳米颗粒是解决宫颈癌放疗耐受的瓶颈。本课题拟设计合成R11-SSPEI-P10纳米颗粒，探索其在体外细胞和动物体内系统中的肿瘤靶向性、稳定性以及多肽释放情况。并在体内外宫颈癌放疗耐受模型中发现R11-SSPEI-纳米颗粒可以特异性被肿瘤组织摄取并发挥生物学作用；同时发现DAB2IP功能片段P10可能成为宫颈癌放疗增敏的有效多肽片段；进一步在细胞体外模型中研究P10对Caveolin-1-ERBB2DSB repair通路的影响，揭示其增强宫颈癌放疗耐受的分子机制。本课题有助于阐明宫颈癌放 疗耐受的分子机制，为宫颈癌治疗提供了一种新型高效的多肽靶向纳米药物递送系统，对宫颈 癌放疗耐受和肿瘤复发的治疗策略具有重要意义。