Drug Delivery and Formulation Group, Medicinal Chemistry Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Biomaterials. 2012 Feb;33(5):1445-54. doi: 10.1016/j.biomaterials.2011.10.061. Epub 2011 Nov 9.
We have developed a polymer conjugate (Cellax) composed of acetylated carboxymethylcellulose (CMC), docetaxel (DTX), and PEG, designed to enhance the pharmacokinetics (PK) and antitumor efficacy of DTX. Our design placed an emphasis on nanoparticle self-assembly to protect DTX during blood transport, stability of the nanoparticle, and PEGylation to enhance PK. Compared to Taxotere, Cellax exhibited a 38.6 times greater area under the curve (AUC), and significantly lower clearance (2.5%) in PK. Less than 10% of DTX was released from Cellax in the blood circulation, indicating that Cellax were stable during blood transport. Cellax reduced non-specific distribution of DTX to the heart, lung and kidney by 48, 90, and 90%, respectively, at 3 h, compared to Taxotere. The uptake of Cellax at 3 h in the liver and spleen was high (15-45 μg DTX/g) but declined rapidly to <10 μg DTX/g in 24 h, and induced no measurable toxicity at 170 mg DTX/kg. Taxotere, on the other hand, displayed non-specific uptake in all the examined normal tissues and induced significant apoptosis in the lung and kidney at 40 mg DTX/kg. The tumor uptake of Cellax was 5.5-fold more than that by Taxotere and the uptake occurred within 3 h after injection and persisted for 10 days. The conjugate exhibited enhanced efficacy in a panel of primary and metastatic mouse tumor models. These results clearly demonstrated that Cellax improved the pharmacokinetics, biodistribution and efficacy of DTX compared to Taxotere with reduced toxicity.
我们开发了一种由乙酰化羧甲基纤维素（CMC）、多西紫杉醇（DTX）和 PEG 组成的聚合物缀合物（Cellax），旨在增强 DTX 的药代动力学（PK）和抗肿瘤疗效。我们的设计重点是纳米粒子自组装，以在血液运输过程中保护 DTX、纳米粒子的稳定性和 PEG 化以增强 PK。与 Taxotere 相比，Cellax 的曲线下面积（AUC）增加了 38.6 倍，PK 中的清除率（2.5%）显著降低。在血液循环中，少于 10%的 DTX 从 Cellax 中释放出来，表明 Cellax 在血液运输过程中是稳定的。与 Taxotere 相比，Cellax 在 3 小时时将 DTX 向心脏、肺和肾脏的非特异性分布分别减少了 48%、90%和 90%。在 3 小时时，肝和脾中的 Cellax 摄取量较高（15-45μg DTX/g），但在 24 小时时迅速下降至<10μg DTX/g，在 170mg DTX/kg 时没有引起可测量的毒性。另一方面，Taxotere 在所有检查的正常组织中均表现出非特异性摄取，并在 40mg DTX/kg 时引起肺和肾脏的明显细胞凋亡。Cellax 的肿瘤摄取量是 Taxotere 的 5.5 倍，摄取发生在注射后 3 小时内，并持续 10 天。该缀合物在一系列原发性和转移性小鼠肿瘤模型中表现出增强的疗效。这些结果清楚地表明，与 Taxotere 相比，Cellax 改善了 DTX 的药代动力学、生物分布和疗效，同时降低了毒性。
