基于尺寸收缩型级联靶向胶束的中药抑制乳腺癌转移效应及机制研究

Metastasis is the leading cause of death in breast cancer patients. It is of great significance for the patients to find new strategies to effectively inhibit breast cancer metastasis. Studies have found that Coptis chinensis and Scutellaria baicalensis, one couplet medicines of Qingrejiedu, can inhibit breast cancer metastasis. However, the poor selectivity and efficacy in vivo seriously restricts its clinical application. The purpose of this study is to improve its selectivity and permeability, and give full play to the effect of inhibiting the metastasis of breast cancer. Using the active ingredients of Coptis chinensis and Scutellaria baicalensis as therapeutic drugs, a novel micelles with microenvironment response, size shrinkage and cascade targeting is to be constructed to realize the selective and efficient delivery of drugs to tumor and the effective inhibtion of tumor metastasis. The micelles can maintain large size in the body circulation, cross the tumor blood vessels by using the active targeting effect of the neurotapeptin receptor, and then enter the tumor tissues. After reaching the microenvironment of tumors, the PEG long chains of the micelles are removed by the matrix metalloproteinases. Thus the particle size of the micelles is significantly reduced and the penetrating peptide residues are exposed, which increase the permeability of drugs into the tumor tissues and the active uptake of drugs by the tumor cells. The mechanism of inhibition of breast cancer metastasis is studied by inhibiting inflammatory environment, angiogenesis, extracellular matrix degradation, and epithelial-mesenchymal transformation. This study can further improve the integration of traditional Chinese medicine theory and modern preparation technology, and expand the application of traditional Chinese medicine in inhibiting the metastasis of cancer.

乳腺癌转移是患者死亡的首要原因，寻找有效抑制转移的新策略，对乳腺癌患者具有重要意义。研究发现清热解毒药对黄连-黄芩具有抑制乳腺癌转移作用，然而因体内选择性差，功效发挥不佳，限制了其临床应用。本研究旨在提高该药对递送的选择性及渗透性，充分发挥抑制乳腺癌转移功效。研究拟构建一种全新的微环境响应的、载体粒径可控收缩的级联靶向胶束，实现该药对的肿瘤选择性高效递送及对肿瘤转移的有效抑制作用。该胶束在体循环中可维持较大的粒径，利用神经毡蛋白受体的主动靶向效应跨越肿瘤血管进入肿瘤组织；到达肿瘤微环境后，在基质金属蛋白酶的作用下脱去外部PEG长链，粒径显著降低并暴露穿膜肽残基，从而增加药物的肿瘤组织渗透性及肿瘤细胞选择性。课题从抑制炎性环境、血管生成、细胞外基质降解及上皮间质转化等方面研究其抑制肿瘤转移的作用机制。本课题可进一步完善中医药理论与现代制剂技术的深入融合，拓展中医药在抑制肿瘤转移方面的应用。

清热解毒是中医抗肿瘤的重要治则之一。本课题通过体内外实验验证清热解毒药对黄连-黄芩药对及其活性成分小檗碱-黄芩苷可有效抑制乳腺癌转移，且两药联用有协同增效作用，同时在动物体内完成了抗肿瘤转移机制研究。然而黄连-黄芩由于体内缺乏选择性，肿瘤蓄积及渗透性差，因而其抑制肿瘤转移功效的发挥极为有限。本课题将传统中医药理论与现代靶向递送技术相结合，通过构建新型肿瘤微环境响应的尺寸收缩级联靶向递送系统，包载清热解毒药对活性成分，增加清热解毒药对肿瘤选择性，提高其在肿瘤区的蓄积、穿透和肿瘤细胞的摄取能力，加快药物在肿瘤部位药物释放速率，从而更有效的抑制肿瘤细胞生长、诱导肿瘤细胞凋亡、破坏肿瘤拟态血管、降低肿瘤微血管密度、改善肿瘤炎性环境、抑制p38MAPK磷酸化、抑制乳腺癌上皮间质转化，显著提高了药物疗效及安全性，从而使得该清热解毒药对高效抑制乳腺癌转移的治疗方案成为可能。课题拓展研究了尺寸收缩型级联靶向胶束抑制肺癌转移效应与机制，发现其能显著增强中药活性成分粉防己碱抗肺癌转移疗效，研究也证明紫杉醇与粉防己碱联用效果更优。课题也拓展研究了几种现代靶向递送技术用以提高中药活性成分抗肿瘤及肿瘤转移活性，如采用靶向脂质体提高了中药活性成分五味子乙素的抗肺癌转移活性；采用双级靶向胶束，提高了蒿甲醚抗脑胶质瘤疗效。研究发现五味子乙素与长春瑞滨联用具有增效作用，蒿甲醚与紫杉醇联用具有协同增效作用。课题的完成，促进了中医药理论与现代药剂学前沿技术的深入融合，为发挥清热解毒药物在抑制肿瘤转移治疗中的作用提供新的思路，并为肿瘤的治疗提供几种可行的联合用药方案。因此，该课题的研究具有重要的学术意义和潜在的临床价值。