State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Biomaterials. 2014 Aug;35(26):7610-21. doi: 10.1016/j.biomaterials.2014.05.040. Epub 2014 Jun 7.
Refractoriness of invasive breast cancer is closely related with the vasculogenic mimicry (VM) channels, which exhibit highly drug resistance to conventional chemotherapies. In the present study, the nanostructured targeting epirubicin plus celecoxib liposomes were developed by modifying a human immunodeficiency virus peptide lipid-derivative conjugate (DSPE-PEG2000-PTDHIV-1) for elimination of invasive breast cancer cells along with their VM channels. The studies were undertaken on invasive human breast cancer MDA-MB-435S cells and MDA-MB-435S xenografts in nude mice. The constructed targeting epirubicin plus celecoxib liposomes were approximately 100 nm in size. In vitro results showed that the targeting liposomes exhibited strong transport ability across cell and nuclei membranes of invasive breast cancer, were able to penetrate and destruct the invasive breast cancer spheroids, initiated apoptosis via activating apoptotic enzymes (caspase 8, 3), and destroyed the VM channels via down-regulating the protein indicators (MMP-9, VE-Cad, FAK, EphA2 and HIF-1α) in invasive breast cancer cells. In vivo results demonstrated that the targeting liposomes displayed a prolonged circulation time in blood system, accumulated more in tumor location, were able to eliminate the VM channels and angiogenesis in tumor tissues, and resulted in a robust overall anticancer efficacy in invasive breast cancer MDA-MB-435S xenografts in nude mice. In conclusion, the nanostructured targeting epirubicin plus celecoxib liposomes could eliminate invasive breast cancer along with the VM channels, hence providing a promising strategy for treatment of invasive breast cancer.
侵袭性乳腺癌的耐药性与脉管生成拟态（VM）通道密切相关，VM 通道对常规化疗具有高度耐药性。在本研究中，通过修饰一种人类免疫缺陷病毒肽脂质衍生物缀合物（DSPE-PEG2000-PTDHIV-1），开发了具有纳米结构的靶向表阿霉素加塞来昔布脂质体，用于消除侵袭性乳腺癌细胞及其 VM 通道。该研究在侵袭性人乳腺癌 MDA-MB-435S 细胞和裸鼠 MDA-MB-435S 异种移植瘤上进行。构建的靶向表阿霉素加塞来昔布脂质体大小约为 100nm。体外研究结果表明，靶向脂质体具有很强的跨侵袭性乳腺癌细胞膜和核膜的转运能力，能够穿透并破坏侵袭性乳腺癌球体，通过激活凋亡酶（caspase 8、3）引发细胞凋亡，并通过下调侵袭性乳腺癌细胞中的蛋白标志物（MMP-9、VE-Cad、FAK、EphA2 和 HIF-1α）破坏 VM 通道。体内研究结果表明，靶向脂质体在血液系统中表现出延长的循环时间，在肿瘤部位更多地积累，能够消除肿瘤组织中的 VM 通道和血管生成，并在裸鼠侵袭性乳腺癌 MDA-MB-435S 异种移植瘤中产生强大的整体抗癌疗效。总之，纳米结构的靶向表阿霉素加塞来昔布脂质体可以消除侵袭性乳腺癌及其 VM 通道，为侵袭性乳腺癌的治疗提供了一种有前途的策略。
