Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, MaRS Centre South Tower, Suite 800,Toronto, Ontario M5G 0A3, Canada.
Cancer Res. 2013 Aug 1;73(15):4862-71. doi: 10.1158/0008-5472.CAN-13-0062.
Docetaxel-conjugate nanoparticles, known as Cellax, were synthesized by covalently conjugating docetaxel and polyethylene glycol to acetylated carboxymethylcellulose via ester linkages, yielding a polymeric conjugate that self-assembled into 120 nm particles suitable for intravenous administration. In 4T1 and MDA-MB-231 orthotopic breast tumor models, Cellax therapy reduced α-smooth muscle actin (α-SMA) content by 82% and 70%, respectively, whereas native docetaxel and nab-paclitaxel (albumin-paclitaxel nanoparticle, Abraxane) exerted no significant antistromal activity. In Cellax-treated mice, tumor perfusion was increased by approximately 70-fold (FITC-lectin binding), tumor vascular permeability was enhanced by more than 30% (dynamic contrast-enhanced magnetic resonance imaging), tumor matrix was decreased by 2.5-fold (immunohistochemistry), and tumor interstitial fluid pressure was suppressed by approximately 3-fold after Cellax therapy compared with the control, native docetaxel, and nab-paclitaxel groups. The antistromal effect of Cellax treatment corresponded to a significantly enhanced antimetastatic effect: lung nodules were reduced by 7- to 24-fold by Cellax treatment, whereas native docetaxel and nab-paclitaxel treatments were ineffective. Studies of the 4T1 tumor showed that more than 85% of the Cellax nanoparticles were delivered to the α-SMA+ stroma. Significant tumor stromal depletion occurred within 16 hours (∼50% depletion) postinjection, and the α-SMA+ stroma population was almost undetectable (∼3%) by 1 week. The 4T1 tumor epithelial cell population was not significantly reduced in the week after Cellax injection. These data suggest that Cellax targets tumor stroma and performs more efficaciously than docetaxel and nab-paclitaxel.
多西紫杉醇缀合物纳米粒，称为 Cellax，是通过酯键将多西紫杉醇和聚乙二醇共价连接到乙酰化羧甲基纤维素上合成的，得到一种自组装成适合静脉内给药的 120nm 颗粒的聚合物缀合物。在 4T1 和 MDA-MB-231 原位乳腺癌模型中，Cellax 治疗分别使α-平滑肌肌动蛋白（α-SMA）含量减少 82%和 70%，而天然多西紫杉醇和 nab-紫杉醇（白蛋白紫杉醇纳米粒，Abraxane）则没有明显的抗基质活性。在 Cellax 治疗的小鼠中，肿瘤灌注增加了约 70 倍（FITC-凝集素结合），肿瘤血管通透性增强了 30%以上（动态对比增强磁共振成像），肿瘤基质减少了 2.5 倍（免疫组织化学），肿瘤间质液压力降低了约 3 倍接受 Cellax 治疗后与对照组、天然多西紫杉醇和 nab-紫杉醇组相比。Cellax 治疗的抗基质作用与显著增强的抗转移作用相对应：用 Cellax 治疗可使肺结节减少 7-24 倍，而天然多西紫杉醇和 nab-紫杉醇治疗无效。对 4T1 肿瘤的研究表明，超过 85%的 Cellax 纳米颗粒被递送到α-SMA+基质中。注射后 16 小时内（约 50%耗尽）发生了明显的肿瘤基质耗竭，1 周时α-SMA+基质群几乎无法检测到（约 3%）。在 Cellax 注射后一周内，4T1 肿瘤上皮细胞群没有明显减少。这些数据表明，Cellax 靶向肿瘤基质，比多西紫杉醇和 nab-紫杉醇更有效。
