基于二维材料黑磷的新型P53/MDM2多肽抑制剂纳米递药体系构建及其靶向肿瘤和肿瘤干细胞治疗的研究

Cancer is one of the most serious diseases all over the world, and which also is the leading cause of human death worldwide. In recent years, a growing number of studies have shown that, the real reason of cancer recurrence, metastasis and resistance to chemotherapy is the existence of a handful of cells with stem cell properties, called cancer stem cells (CSC). However, there are no CSC-targeted drugs so far. In previous studies, our research group developed a novel peptide inhibitor PHR, which can inhibit the interaction between P53 and MDM2. Furthermore, PHR can not only selectively affect P53-sensitive cancer cells, but also inhibit the growth of cancer stem cell PA-1. In this project, we propose to design and develop black phosphorus nanosheets based novel delivery system to deliver P53/MDM2 peptide for targeting cancer and cancer stem cells. With the cooperation of BP NSs-based drug delivery system,the novel P53/MDM2 peptide inhibitors can be specifically delivered into cancer and cancer stem cells and possess promising anticancer efficacy, both in vitro and in vivo. Our project is highly significant on the development of clinical anticancer drugs, which may provide innovative paradigm to target cancer cells with stem cell properties in clinical therapies.

肿瘤是全球范围内危害程度最大的疾病之一。近年来，越来越多的研究证明，肿瘤复发、转移和抗放化疗的原因是肿瘤干细胞的存在。迄今为止并没有能够靶向肿瘤干细胞的小分子药物。在前期研究中，我们课题组自主开发了针对P53/MDM2蛋白的新型多肽抑制剂PHR，不仅能够选择性杀死对P53敏感的恶性肿瘤细胞，并且对肿瘤干细胞PA-1有很强的杀伤作用。本项目以课题组自主开发的P53/MDM2蛋白的新型多肽抑制剂PHR的体内肿瘤靶向性运输为切入点，构建以肿瘤干细胞PA-1为例的靶向性多肽纳米载体。该体系以二维黑磷纳米片（BP NSs）为载体，将多肽抑制剂PHR传输至肿瘤细胞中，并通过BP NSs本身的光热效应发挥协同抗癌症效果。本项目将纳米技术与多肽技术、光热治疗联合应用，为开发临床抗癌新药，尤其是抗癌症干细胞药物提供开创性思维与研究基础。

肿瘤是全球范围内危害程度最大的疾病之一。近年来，越来越多的研究证明，肿瘤复发、转移和抗放化疗的原因是肿瘤干细胞的存在。迄今为止并没有能够靶向肿瘤干细胞的小分子药物。在前期研究中，我们课题组自主开发了针对P53/MDM2蛋白的新型多肽抑制剂PHR，不仅能够选择性杀死对P53敏感的恶性肿瘤细胞，并且对肿瘤干细胞PA-1有很强的杀伤作用。本项目以课题组自主开发的P53/MDM2蛋白的新型多肽抑制剂PHR的体内肿瘤靶向性运输为切入点，构建以肿瘤干细胞PA-1为例的靶向性多肽纳米载体。该体系以二维黑磷纳米片（BP NSs）为载体，将多肽抑制剂PHR传输至肿瘤细胞中，并通过BP NSs本身的光热效应发挥协同抗癌症效果。本项目在执行期取得的结果如下：1）将有机硅、顺铂和环肽引入到黑磷材料表面，建立稳定黑磷二维材料的新方法；2）通过微观表征和细胞生物学评价，确定黑磷纳米片的稳定性和抗肿瘤活性，并将其该体系应用于顺铂药物以及多肽药物的递送中；3）成功筛选出P53/MDM2的多肽抑制剂，实现对P53敏感的恶性肿瘤细胞（如乳腺癌MCF7 细胞）和肿瘤干细胞的靶向治疗。本项目将纳米技术与多肽技术、光热治疗联合应用，为开发临床抗癌新药，尤其是抗癌症干细胞药物提供开创性思维与研究基础。