Enhanced chemotherapeutic efficacy of the low-dose doxorubicin in breast cancer via nanoparticle delivery system crosslinked hyaluronic acid

Despite the development of treatment options in breast cancer, many patients die of recurrence and metastasis. Owing to enhanced permeability and retention in solid tumor tissue, nanoparticle (NP) delivery systems have been emerged as novel strategy in cancer chemotherapy. As extracellular matrix, glycosaminoglycan hyaluronan (HA) could bind its surface receptor adhesion molecule CD44 which is strongly expressed on breast cancer. We have previously reported a doxorubicin (DOX)-loaded HA-Lys-LA X-NPs (X-NP-DOX) NP delivery system for breast cancer treatment. In this study, we further investigated the antitumor effect of X-NP-DOX NP delivery system using low-dose DOX in both <i>in vitro</i> and <i>in vivo</i> systems. We demonstrated that low-dose X-NP-DOX possessed the ability for inhibiting MCF-7 breast cancer cell growth, invasion, and migration, and inducing apoptosis <i>in vitro</i>. In <i>in vivo</i> experiments, injection of low-dose X-NP-DOX into tumor-bearing mouse resulted in significant reduction of tumor size. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining further revealed that low-dose X-NP-DOX induced higher percentage of apoptotic cells compared with free DOX or saline. Furthermore, our study demonstrated that low-dose X-NP-DOX inhibited Notch1 and Ras/MAPK pathways, decreased cancer stem cell population, and reduced tumorigenesis compared to free DOX in both <i>in vitro</i> and <i>in vivo</i> settings. Owing to its enhanced efficacy and higher targetability compared to free DOX, low-dose DOX delivered by NP system may be a promising novel strategy for breast cancer treatment.

尽管乳腺癌治疗手段已取得显著进展，但仍有大量患者因肿瘤复发与转移死亡。鉴于实体瘤组织具备增强渗透滞留（EPR）效应，纳米颗粒（NP）递送系统已成为癌症化疗领域的新型策略。作为细胞外基质组分的糖胺聚糖类物质——透明质酸（HA），可与乳腺癌细胞表面高表达的黏附分子受体CD44特异性结合。本团队此前曾报道一种负载阿霉素（DOX）的HA-Lys-LA X型纳米颗粒（X-NP-DOX）递送系统用于乳腺癌治疗。本研究进一步探究了搭载低剂量阿霉素的X-NP-DOX递送系统在体外（in vitro）与体内（in vivo）模型中的抗肿瘤活性。体外实验结果显示，低剂量X-NP-DOX可抑制MCF-7乳腺癌细胞的增殖、侵袭与迁移，并诱导细胞凋亡。体内实验中，向荷瘤小鼠注射低剂量X-NP-DOX可显著缩小肿瘤体积。末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色进一步证实，相较于游离阿霉素组与生理盐水组，低剂量X-NP-DOX诱导的细胞凋亡比例显著更高。此外，本研究证实，相较于游离阿霉素，低剂量X-NP-DOX在体外与体内模型中均可抑制Notch1及Ras/MAPK信号通路、降低肿瘤干细胞群体比例，并减弱肿瘤发生能力。相较于游离阿霉素，该纳米递送系统不仅疗效更优且靶向性更强，因此搭载低剂量阿霉素的纳米递送策略有望成为乳腺癌治疗的极具潜力的新型方案。