Octreotide-modified liposomes containing daunorubicin and dihydroartemisinin for treatment of invasive breast cancer

Tumor invasion is considered a major promoter in the initiation of tumor metastasis, which is supposed to cause most cancer-related deaths. In the present study, octreotide (OCT)-modified daunorubicin plus dihydroartemisinin liposomes were developed and characterized. Evaluations were undertaken on breast cancer MDA-MB-435S cells and MDA-MB-435S xenografts nude mice. The liposomes were ∼100 nm in size with a narrow polydispersity index. In vitro results showed that the OCT-modified daunorubicin plus dihydroartemisinin liposomes could enhance cytotoxicity and cellular uptake by OCT-SSTRs (somatostatin receptors)-mediated active targeting, block on tumor cell wound healing and migration by incorporating dihydroartemisinin. The action mechanism might be related to regulations on E-cadherin, α5β1-integrin, TGF-β1, VEGF and MMP2/9 in breast cancer cells. In vivo, the liposomes displayed a prolonged circulating time, more accumulation in tumor location, and a robust overall antitumor efficacy with no obvious toxicity at the test dose in MDA-MB-435S xenograft mice. In conclusion, the OCT-modified daunorubicin plus dihydroartemisinin liposomes could prevent breast cancer invasion, hence providing a possible strategy for treatment of metastatic breast cancer.肿瘤侵袭被认为是肿瘤转移发生的主要驱动因素，而肿瘤转移正是导致绝大多数癌症相关死亡的核心原因。本研究开发并表征了奥曲肽（octreotide, OCT）修饰的柔红霉素联合双氢青蒿素脂质体，以乳腺癌MDA-MB-435S细胞及该细胞株构建的裸鼠异种移植瘤模型为对象开展评价实验。该脂质体粒径约为100 nm，多分散指数（polydispersity index, PDI）较窄。体外实验结果显示，经奥曲肽修饰的柔红霉素联合双氢青蒿素脂质体，可通过奥曲肽-生长抑素受体（somatostatin receptors, SSTRs）介导的主动靶向作用增强细胞毒性与细胞摄取能力，并通过包载双氢青蒿素阻断肿瘤细胞的创伤愈合与迁移过程。其作用机制可能与调控乳腺癌细胞内E-钙粘蛋白（E-cadherin）、α5β1整合素（α5β1-integrin）、转化生长因子-β1（TGF-β1）、血管内皮生长因子（vascular endothelial growth factor, VEGF）及基质金属蛋白酶2/9（matrix metalloproteinase 2/9, MMP2/9）的表达相关。体内实验中，在MDA-MB-435S异种移植瘤裸鼠模型内，该脂质体展现出更长的循环半衰期、更高的肿瘤部位富集量，且在实验剂量下无明显毒性，整体抗肿瘤活性优异。综上，奥曲肽修饰的柔红霉素联合双氢青蒿素脂质体可抑制乳腺癌侵袭，为转移性乳腺癌的治疗提供了潜在策略。