Department of Chemistry, Chemistry of Life Processes Institute, Evanston, Illinois 60208, USA.
Clin Cancer Res. 2010 Jul 15;16(14):3607-17. doi: 10.1158/1078-0432.CCR-10-0068. Epub 2010 Jun 2.
The clinical success of arsenic trioxide (As(2)O(3)) in hematologic malignancies has not been replicated in solid tumors due to poor pharmacokinetics and dose-limiting toxicity. We have developed a novel nanoparticulate formulation of As(2)O(3) encapsulated in liposomal vesicles or "nanobins" [(NB(Ni,As)] to overcome these hurdles. We postulated that nanobin encapsulation of As(2)O(3) would improve its therapeutic index against clinically aggressive solid tumors, such as triple-negative breast carcinomas.
The cytotoxicity of NB(Ni,As), the empty nanobin, and free As(2)O(3) was evaluated against a panel of human breast cancer cell lines. The plasma pharmacokinetics of NB(Ni,As) and free As(2)O(3) were compared in rats to measure drug exposure. In addition, the antitumor activity of these agents was evaluated in an orthotopic model of human triple-negative breast cancer.
The NB(Ni,As) agent was much less cytotoxic in vitro than free As(2)O(3) against a panel of human breast cancer cell lines. In contrast, NB(Ni,As) dramatically potentiated the therapeutic efficacy of As(2)O(3) in vivo in an orthotopic model of triple-negative breast cancer. Reduced plasma clearance, enhanced tumor uptake, and induction of tumor cell apoptosis were observed for NB(Ni,As).
Nanobin encapsulation of As(2)O(3) improves the pharmacokinetics and antitumor efficacy of this cytotoxic agent in vivo. Our findings demonstrate the therapeutic potential of this nanoscale agent and provide a foundation for future clinical studies in breast cancer and other solid tumors.
三氧化二砷（As(2)O(3)）在血液系统恶性肿瘤中的临床疗效并未在实体瘤中得到复制，这是由于其药代动力学不佳和剂量限制毒性所致。我们已经开发了一种新型纳米颗粒制剂，将 As(2)O(3)包裹在脂质体囊泡或“纳米盒”[(NB(Ni,As)]中，以克服这些障碍。我们假设纳米盒封装的 As(2)O(3)将提高其针对临床侵袭性实体瘤（如三阴性乳腺癌）的治疗指数。
评估 NB(Ni,As)、空纳米盒和游离 As(2)O(3)对一系列人乳腺癌细胞系的细胞毒性。比较 NB(Ni,As)和游离 As(2)O(3)在大鼠体内的血浆药代动力学，以测量药物暴露量。此外，还评估了这些药物在人三阴性乳腺癌的原位模型中的抗肿瘤活性。
与游离 As(2)O(3)相比，NB(Ni,As)在体外对一系列人乳腺癌细胞系的细胞毒性要小得多。相比之下，NB(Ni,As)在三阴性乳腺癌的原位模型中显著增强了 As(2)O(3)的体内治疗效果。观察到 NB(Ni,As)降低了血浆清除率、增强了肿瘤摄取并诱导了肿瘤细胞凋亡。
As(2)O(3)的纳米盒封装改善了该细胞毒性药物在体内的药代动力学和抗肿瘤疗效。我们的研究结果表明了这种纳米级药物的治疗潜力，并为乳腺癌和其他实体瘤的未来临床研究提供了基础。
