Docetaxel-loaded solid lipid nanoparticles suppress breast cancer cells growth with reduced myelosuppression toxicity. Homo sapiens

Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors, however its toxicity and side-effect limits its clinical efficacy. Herein, the docetaxel-loaded solid lipid nanoparticles (DSNs) were developed to reduce systemic toxicity while still keeping its anti-cancer activity. To evaluate its anti-cancer activity and toxicity and understand the molecular mechanisms of DSNs, different cellular, molecular and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel-Taxotere and induced more apoptosis at 24 h treatment in vitro. It can cause the treated cancer cells arrested at G2/M phase in a dose-depend manner as Taxotere. The DSNs can also suppress tumor growth very effectively in a murine breast cancer model. Systemic analysis of gene expression profiles by microarray and the following verification experiments suggested that both DSNs and Taxotere regulate expression of series genes and these genes functions involved in DNA replication, DNA damage response, cell proliferation, apoptosis and cell cycle regulation. Some of these genes expressed differentially at protein level although their transcription level was similar under TAX and DSNs treatment. Moreover, DSNs improved main side-effect of Taxotere by greatly lowering myelosuppression toxicity to bone marrow cells from mice. Taken together, our results expound the anti-tumor efficacy and the potential working mechanisms of DSNs in its anti-cancer activity and toxicity, which provide a theoretical foundation to develop and apply more efficient docetaxel formulation to treat cancer patients. Overall design: Tumor tissues were obtained from tumor-bearing mice after treated with GLU, BSNs, TAX or DSNs. Total RNA was extracted from tumor tissues

多西他赛（Docetaxel）是一种广泛用于治疗多种实体瘤的辅助化疗药物，但其毒性与副作用限制了其临床疗效。本研究中，研究人员开发了负载多西他赛的固体脂质纳米粒（DSNs），在保留其抗癌活性的同时降低全身毒性。为评估DSNs的抗癌活性与毒性，并阐明其分子作用机制，本研究采用了多种细胞、分子及全基因组转录分析手段。体外实验结果显示，与多西他赛市售制剂泰索帝（Taxotere）相比，DSNs展现出更低的细胞毒性，并在处理24小时后诱导更多的细胞凋亡。与泰索帝一致，DSNs可使处理后的癌细胞以剂量依赖的方式阻滞于G2/M期。在小鼠乳腺癌模型中，DSNs同样可高效抑制肿瘤生长。通过微阵列（microarray）对基因表达谱进行系统性分析，并结合后续验证实验，结果显示DSNs与泰索帝均可调控一系列基因的表达，这些基因的功能涉及DNA复制、DNA损伤应答、细胞增殖、细胞凋亡及细胞周期调控。尽管在TAX与DSNs处理后，部分基因的转录水平相近，但这些基因在蛋白水平存在表达差异。此外，DSNs通过显著降低对小鼠骨髓细胞的骨髓抑制毒性，改善了泰索帝的主要副作用。综上，本研究阐明了DSNs的抗肿瘤效力及其抗癌活性与毒性的潜在作用机制，为开发并应用更高效的多西他赛制剂治疗癌症患者提供了理论依据。实验整体设计：将荷瘤小鼠分别给予GLU、BSNs、TAX或DSNs处理，随后采集肿瘤组织并从中提取总RNA。