基于抑制癌细胞侵袭迁移并调控微环境的结构可调性纳米载体联合中药药对抑制乳腺癌转移的研究

The metastasis of breast cancer involves a series of distinct steps associated with multiple factors. Therefore, the strategies focused on the single step or individual factor have shown some limitations in achieving desirable therapeutic effects, and treating metastasis is still challenging. Based on the core reason for metastasis and the key role of inhibition of the tumor cell proliferation,invasion and migration and modulating the tumor microenvironment in the metastatic process, the decoction of the Chinese Medicine Herb Pairs of platycodon grandiflorum with rhizome curcumae possessing the capacity to “detoxify and resolve masses” combined with tumor microenvironment targeting drug of silibinin-loaded novel nanoparticles were administered orally to enhance therapeutic efficiency by inhibiting metastasis of breast cancer. It was hypothesized that inhibition of metastasis could be achieved using the Chinese Medicine Herb Paris and the silibinin-loaded nanoparticles, in which the former plays a role in the “Guiding action upward” to the tumor and metastatic sites, and the latter contributing to the higher efficiency of delivering silibinin by oral route. Based on our previous study on mucus penetration and cytoadhesion, in this study we developed a novel nanoparticles with the tunable coating layer to further improve the cellular uptake. In addition, the influence of the combination of Chinese Medicine Herb Pair with silibinin loaded nanoparticles on the proliferation, invasion, and migration of the tumor cells was investigated. Furthermore, the influence of the combination on the tumor microenvironment including the proliferation of tumor cells under the cross-talk between the tumor-associated macrophages and breast cancer cells, angiogenesis，breast cancer cells breaching the basement membrane and the related regulation was evaluated. The mechanisms will be revealed during the studies mentioned above. By combining the traditional Chinese medicine (TCM) with modern efficient drug delivery system, this study will provide a new strategy to solve the limitation of Tradition Chinese Medicine due to undisirable therapeutic effect. It also provides a new strategy in inhibiting the metastasis of breast cancer and a scientific basis for the application of TCM on the metastasis of breast cancer.

乳腺癌转移是多环节、多因素参与的复杂过程。因此，作用于单一环节或因素的治疗策略难以发挥理想效果。本课题针对乳腺癌转移核心病机，基于癌细胞增殖侵袭与迁移及肿瘤微环境在该过程中的关键作用，将“解毒散结、引药上行”类中药药对桔梗-莪术汤剂联合载微环境靶向药物水飞蓟宾新型纳米粒口服给药，旨在通过药对引经之功和纳米粒高效递药性能对癌细胞和微环境发挥双重作用而增强药效。在前期纳米粒粘液层穿越和细胞黏附研究基础上，本课题利用结构可调性包被层构建新型纳米载体促进细胞摄取；研究药对联合纳米粒对乳腺癌细胞增殖、侵袭和迁移的影响；对微环境调控作用（巨噬细胞参与下两者对细胞增殖的影响、血管生成、癌细胞侵袭基底膜），阐述相关机制。该纳米载体的构建及其与药对配伍抑制乳腺癌转移口服给药新模式国内外尚无报道。本项目将传统中药与现代高效递药系统相结合，为解决中药药效发挥受限制的问题提供新思路，也为抑制乳腺癌转移提供新策略。

乳腺癌转移是多环节、多因素参与的复杂过程。因此，作用于单一环节或因素的治疗策略难以发挥理想效果。针对乳腺癌转移核心病机，本研究将中药药对桔梗-莪术与口服纳米粒相联合，利用前者“解毒散结、引药上行”之功，结合后者克服黏液层和细胞层生理屏障高效递药的性能，对乳腺癌细胞及其赖以生存的肿瘤微环境发挥双重作用以增强药效。首先，本项目利用亲水性聚合物为包被层构建了结构可调性纳米载体，通过高效黏液层穿越、细胞黏附与细胞摄取三者联动共促进肠细胞吸收和转运，提高了中药活性成分口服生物利用度。药对与纳米粒联合可抑制体外4T1乳腺癌细胞的增殖和迁移。利用乳腺癌4T1原位转移模型，药对联合纳米粒增强了对乳腺癌肺转移的抑制作用，作用机制涉及诱导肿瘤细胞凋亡，抑制肿瘤血管生成，调控肿瘤细胞外基质和上皮-间质转化等。因此，药对联合口服纳米载体通过作用于肿瘤细胞和调控肿瘤微环境，实现了增强抑制乳腺癌转移的作用。总之，我们探索了一种抑制乳腺癌转移的策略，为解决难溶性中药药效发挥受限制的问题提供了新思路，也为更好地发挥中药在抑制乳腺癌转移方面的作用提供了科学依据。