酶促自组装用于癌细胞溶酶体成像和肿瘤治疗

Cancer has become a great threat to human health. Developing targeted drugs and overcoming drug resistance has become the key to cancer diagnosis and therapy. Supramolecular self-assembly is ubiquitous process in nature. The self-assembly of amphiphilic oligopeptides has been widely used in life science. Herein, we design a drug fluorescent probe based on diphenylalanine derivative, which is modified by a lysosome-targetable group. On the surface of cancer cells, probes are hydrolyzed by highly expressed alkaline phosphatase (ALP) to form supramolecular gelators, those can self-assemble into nanofibers. The nanofibers enter lysosomes of cancer cells via endocytosis and lead to lysosome fluorescence imaging. Due to the self-assembly and lysosome-targetable groups, the nanofibers are enriched in lysosomes and cannot be pumped out by cancer cells, which can induce lysosomal membrane permeabilization, lead to lysosome-dependent cell death, and overcome drug resistance. Research on the mechanism of lysosome-dependent cell death induced by the drug probe may improve the theory about cell death, and may provide guide for the design of anticancer drugs. By in vivo treatment of tumors, we can evaluate the efficacy of the drug probe, study its metabolism, and research the pharmacological characteristics of the drug probe. The development of the drug probe may provide new ideas and technical support for the theranostic of cancer.

癌症已成为人类健康的重大威胁，研发靶向药物并克服癌细胞耐药性已成为癌症诊断和治疗的关键。超分子自组装是大自然中一种常见的现象，两亲性寡肽的自组装已被广泛应用于生命科学领域。本项目拟设计被亲溶酶体基团修饰的双苯丙氨酸衍生物药物荧光探针。在癌细胞表面，该探针在高表达的碱性磷酸酶作用下生成超分子成胶因子，并自组装形成纳米纤维，经由内吞作用进入癌细胞溶酶体，实现癌细胞溶酶体荧光成像。自组装和亲溶酶体基团使纳米纤维富集于溶酶体，无法被细胞泵出，引发溶酶体膜透化作用，实现癌细胞的溶酶体致细胞死亡，并克服癌细胞耐药性。研究探针引发溶酶体致细胞死亡的作用机理，可完善细胞死亡理论，为抗癌药物的设计提供指导。使用动物肿瘤模型进行肿瘤治疗实验，评估该探针的疗效并研究其代谢特点，可进一步了解该药物探针的药理特点。该药物探针的顺利研发可为癌症的诊疗一体化研究提供新的思路和技术支持。

癌症已成为人类健康的重大威胁，研发靶向药物并克服癌细胞耐药性已成为癌症诊断和治疗的关键。超分子自组装是大自然中一种常见的现象，两亲性多肽的自组装已被广泛应用于生命科学领域。本项目设计了一种富亮氨酸的磷酸化多肽，在碱性磷酸酶作用下，该探针可选择性杀死骨肉瘤细胞。在癌细胞高表达的碱性磷酸酶作用下，该探针依次自组装形成胶束和纳米带。自组装体起初聚集在癌细胞的膜表面，之后通过内吞作用进入细胞，最后富集在细胞核（主要是核仁）内。蛋白组学研究证明，这种细胞核内的富集主要是由于多肽与细胞核内的组蛋白发生了共组装。使用该探针处理各种细胞可发现，该探针可选择性杀死骨肉瘤细胞，但对正常细胞和其他癌细胞无害。此外，重复使用该探针刺激癌细胞不仅不会引发癌细胞的耐药性，反而会使细胞变得更加敏感。该项目不仅提出了一种新的细胞核靶向方法，还为靶向抗癌药物的设计和耐药性的克服提供了新的思路。