抗乳腺癌异质性耐药靶向载药脂质体及其效应和机制研究

The heterogeneity drug-resistance plays a major role in the poor prognosis in the chemotherapy of breast cancer. The identification, biomarkers and resistant mechanism of the heterogeneous side population cells of breast cancer remained unclear, and accordingly, it is lack of effective treatment measures. The objectives are to establish the identifications and biomarkers for the heterogeneous categories of drug-resistant cell side populations in breast cancer, and to develop the targeting drug-loaded liposomes for anti-heterogeneous resistance of breast cancer, thus preventing recurrence which is derived from the residual resistant cancer side population cells. The studies covers four aspects, consisting of (1) the investigations on the identification, sorting and biomarkers of breast cancer heterogeneous resistant side population cells;(2)the development and characterization of the targeting drug-loaded liposomes for anti-heterogeneous resistance of breast cancer; (3) the in vitro efficacy and mechanism studies; and (4) the in vivo chemotherapeutic efficacy and pharmacokinetic studies in animals. The studies would provide theoretical and experimental bases for the chemotherapy strategy of drug-resistance due to breast cancer heterogeneity.

科学问题：乳腺癌异质性耐药是乳腺癌化学治疗预后差的主要原因，乳腺癌异质性耐药侧群细胞的鉴定、标志物、机制尚未明确、因此也缺乏相应的治疗措施。目标：确定其异质性耐药细胞侧群类别、鉴定方法和标志物，构建新的抗乳腺癌异质性耐药靶向性脂质体载药系统、在杀伤乳腺癌细胞的同时清除异质性耐药侧群细胞，防止残存细胞导致复发。内容：（1） 乳腺癌异质性耐药侧群细胞分选、鉴定与标志物研究；（2） 抗乳腺癌异质性耐药靶向载药脂质体的构建与表征；（3） 对乳腺癌异质性耐药侧群细胞体外效应与作用机制研究； （4）在动物体内的疗效和药动学研究。意义：对于乳腺癌异质性耐药治疗策略，可望提供新的理论依据并奠定实验基础。

乳腺癌异质性耐药是乳腺癌化学治疗预后差的主要原因。本研究旨在揭示乳腺癌异质性标志物、鉴定方法、构建抗乳腺癌异质性耐药靶向性脂质体，以期在杀伤乳腺癌的同时清除异质性癌细胞，防止残存癌细胞导致复发。该研究分四个部分：（1）乳腺癌异质性细胞分选、鉴定与标志物研究：验证了同种乳腺癌异质性侧群细胞标志物CD44+/CD24-等，建立了其分选和鉴别方法；揭示了乳腺癌病程中拟态血管标志物FAK，PI3K，MMP-9，MMP-2和VE-Cad，建立了其鉴定方法；分析了不同乳腺癌的已知标志物。（2）抗乳腺癌异质性耐药靶向性脂质体的构建与表征：在合成并优选靶向性材料的基础上，构建及表征了功能化长春新碱达沙替尼脂质体、靶向性表阿霉素塞来昔布脂质体、功能化柔红霉素罗非昔布脂质体等3种脂质体。（3）乳腺癌异质性耐药细胞体外效应与作用机制研究：在不同乳腺癌细胞模型上，进行了摄取、定位、杀伤、诱导凋亡、诱导自噬、拟态血管破坏效应以及相关调控信号通路研究。（4）体内验证：在乳腺癌动物模型中验证了疗效与并进行了活体成像研究。该研究为探索乳腺癌异质性耐药治疗新策略，提供了理论与实验依据。