School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland.
J Control Release. 2010 Jun 15;144(3):324-31. doi: 10.1016/j.jconrel.2010.02.026. Epub 2010 Feb 25.
The benefit of polymeric immuno-nanoparticles (NPs-Tx-HER), consisting of paclitaxel (Tx)-loaded nanoparticles coated with anti-HER2 monoclonal antibodies (Herceptin, trastuzumab), in cancer treatment was assessed in a disseminated xenograft ovarian cancer model induced by intraperitoneal inoculation of SKOV-3 cells overexpressing HER2 antigens. The study was focused on the evaluation of therapeutic efficacy and biodistribution of NPs-Tx-HER compared to other Tx formulations. The therapeutic efficacy was determined by two methods: bioluminescence imaging and survival rate. The treatment regimen consisted in an initial dose of 20mg/kg Tx administered as 10mg/kg intravenously (IV) and 10mg/kg intraperitonealy (IP), followed by five alternative IP and IV injections of 10mg/kg Tx every 3 days. The bioluminescence study has clearly shown the superior anti-tumor activity of NPs-Tx-HER compared to free Tx. As a confirmation of these results, a significantly longer survival of mice was observed for NPs-Tx-HER treatment compared to free Tx, Tx-loaded nanoparticles coated with an irrelevant mAb (Mabthera, rituximab) or Herceptin alone, indicating the potential of immuno-nanoparticles in cancer treatment. The biodistribution pattern of Tx was assessed on healthy and tumor bearing mice after IV or IP administration. An equivalent biodistribution profile was observed in healthy mice for Tx encapsulated either in uncoated nanoparticles (NPs-Tx) or in NPs-Tx-HER. No significant difference in Tx biodistribution was observed after IV or IP injection, except for a lower accumulation in the lungs when NPs were administered by IP. Encapsulated Tx accumulated in the organs of the reticulo-endothelial system (RES) such as the liver and spleen, whereas free Tx had a non-specific distribution in all tested organs. Compared to free Tx, the single dose injection (IV or IP) of encapsulated Tx in mice bearing tumors induced a higher tumor accumulation. However, no difference in overall tumor accumulation between NPs-Tx-HER and NPs-Tx was observed. In conclusion, the encapsulation of Tx into NPs-Tx-HER immuno-nanoparticles resulted in an improved efficacy of drug in the treatment of disseminated ovarian cancer overexpressing HER2 receptors.
载紫杉醇（Tax）的纳米颗粒（NPs-Tx-HER）由包裹着抗 HER2 单克隆抗体（赫赛汀，曲妥珠单抗）的纳米颗粒组成，在过表达 HER2 抗原的 SKOV-3 细胞腹腔接种诱导的播散性异种卵巢癌模型中评估了其在癌症治疗中的益处。该研究侧重于评估 NPs-Tx-HER 与其他 Tax 制剂相比的治疗效果和生物分布。治疗效果通过两种方法确定：生物发光成像和存活率。治疗方案包括初始剂量为 20mg/kg Tax，分为 10mg/kg 静脉注射（IV）和 10mg/kg 腹腔注射（IP），随后每 3 天交替进行 5 次 10mg/kg Tax 的 IP 和 IV 注射。生物发光研究清楚地表明 NPs-Tx-HER 比游离 Tax 具有更好的抗肿瘤活性。作为这些结果的证实，与游离 Tax、负载 Tax 的纳米颗粒（用无关 mAb（美罗华，利妥昔单抗）或赫赛汀包裹）或单独的赫赛汀治疗相比，NPs-Tx-HER 治疗的小鼠存活时间明显更长，表明免疫纳米颗粒在癌症治疗中的潜力。在 IV 或 IP 给药后，在健康和荷瘤小鼠中评估了 Tax 的生物分布模式。在健康小鼠中，无论是包裹在未涂层纳米颗粒（NPs-Tx）中还是包裹在 NPs-Tx-HER 中的 Tax，都观察到了等效的生物分布谱。除了 NPs 通过 IP 给药时肺部积累较少外，IV 或 IP 注射后没有观察到 Tax 生物分布的显著差异。包裹的 Tax 积聚在网状内皮系统（RES）的器官中，如肝脏和脾脏，而游离 Tax 在所有测试的器官中分布不均匀。与游离 Tax 相比，荷瘤小鼠单次注射（IV 或 IP）包裹的 Tax 可诱导更高的肿瘤积累。然而，在 NPs-Tx-HER 和 NPs-Tx 之间未观察到总体肿瘤积累的差异。总之，将 Tax 包裹到 NPs-Tx-HER 免疫纳米颗粒中可提高药物在治疗过表达 HER2 受体的播散性卵巢癌中的疗效。
