共包裹盐霉素-阿霉素的HER2靶向纳米粒制备及其抗耐药乳腺癌作用研究

Cancer stem cells were demonstrated to play crucial roles in tumorigenesis, cancer development, metastasis and recurrence processes, and to have a close relationship with multidrug resistance, which making it a new "hot spots" for cancer treatment research. Recently, salinomycin was identificated to have the ability to efficiently kill tumor stem cells and resistant cells, which conventional chemotherapy drugs haven not, and to have good in vitro anticancer activity combinating with many conventional chemotherapy drugs. However, multiple mammalian toxicity limits the application of salinomycin in clinical use. Development of new formulations to reduce the dosage and toxicity of the drug is an important way for clinical use in the future. The project intends to develop a HER2 targeted salinomycin-doxotubicin co-encapsulated polymer-lipid hybrid nanoparticles with biocompatible nanomaterials, and to study its role in anti-drug-resistant HER2 positive breast cancer. First, the size and distribution, the electric potential, the drug encapsulating and loading efficiency, and the stability of the nanoparticle will be characterized to optimize the prescription and the drug encapsulation ratio. Then, the toxicity and the ability to kill cancer stem cells and to inhibit the xenotransplanted tumors formation and growth in vitro and in vivo will also be validated. The launching of the project will lay a preliminary foundation for the development of salinomycin-doxorubicin or salinomycin-other chemotherapy drugs co-encapsulated nanoparticle formulations to apply in future clinical treatment.

肿瘤干细胞在癌症发生、发展、转移和复发过程中的决定性作用以及与肿瘤多药耐药性产生的密切关系使其成为癌症治疗研究的热点。近来发现，盐霉素具有常规的化疗药物所不具备的杀伤肿瘤干细胞和耐药肿瘤细胞的能力，与阿霉素等常规化疗药物联合用药具有良好的体外抗癌活性。然而，对哺乳动物的多重毒性限制了盐霉素在临床上的应用。研发新剂型，降低给药剂量和毒性是盐霉素将来用于癌症临床治疗的重要途径。本项目应用生物相容性纳米材料，制备HER2靶向的盐霉素-阿霉素共包裹纳米制剂，研究其抗HER2阳性耐药乳腺癌的作用。首先，通过一系列理化表征分析，优化制剂的处方和制备方法。然后，通过体外和体内实验研究制剂的毒性、对肿瘤干细胞的杀伤作用以及抑制异种移植瘤形成和生长的能力。项目的开展能为将来开发用于临床治疗的盐霉素-阿霉素联合靶向纳米制剂，或盐霉素与其他化疗药物的联合靶向纳米制剂奠定前期工作基础和参考。

乳腺癌干细胞是乳腺癌发生、复发和转移的重要原因。有证据表明乳腺癌细胞可以自发的转变为乳腺癌干细胞。因此，同时靶向乳腺癌干细胞和癌细胞是改善乳腺癌治疗效果的基础。HER2已经被证实在部分乳腺癌的肿瘤干细胞和癌细胞都高表达。因此，我们尝试开发一种抗HER2抗体修饰的聚合物-脂质混合纳米粒（Sali-NP-HER2）来靶向递送盐霉素到HER2阳性的乳腺癌干细胞和癌细胞。用抗HER2抗体修饰负载了盐霉素的聚合物-脂质混合纳米粒，并通过体内和体外实验验证盐霉素靶向纳米粒的抗肿瘤活性。相比非靶向纳米粒或盐霉素单独给药，盐霉素靶向纳米粒能更高效的结合并杀伤HER2阳性乳腺癌干细胞和癌细胞，以及抑制肿瘤细胞球成球率和减少肿瘤细胞球内干细胞的比例。通小鼠乳腺癌移植瘤模型实验表明盐霉素靶向纳米粒能抑制肿瘤的生长。HER2靶向的盐霉素纳米粒靶向杀伤乳腺癌干细胞和癌细胞为治疗HER2阳性乳腺癌提供了一种可能的方法。