Han Han, Davis Mark E
Chemical Engineering, California Institute of Technology , Pasadena, California 91125, United States.
Mol Pharm. 2013 Jul 1;10(7):2558-67. doi: 10.1021/mp300702x. Epub 2013 May 29.
We have developed a new method for assembling targeted nanoparticles that utilizes the complexation between targeting agents that contain boronic acids and polymer-drug conjugates that possess diols. Here, we report the first in vivo, antitumor results of a nanoparticle formed via this new assembly methodology. A nanoparticle consisting of a mucic acid polymer conjugate of camptothecin (CPT), MAP-CPT, and containing on average one Herceptin antibody is investigated in nude mice bearing HER2 overexpressing BT-474 human breast cancer tumors. Nontargeted MAP-CPT and antibody-containing MAP-CPT nanoparticles of ca. 30-40 nm diameter and slightly negative zeta potential show prolonged in vivo circulation and similar biodistributions after intravenous tail vein injections in mice. The maximum tolerated dose (MTD) of the nontargeted and Herceptin-containing MAP-CPT nanoparticles is found to be 10 and 8 mg of CPT/kg, respectively, in mice. Mice bearing BT-474 human breast tumors treated with nontargeted MAP-CPT nanoparticles at 8 mg of CPT/kg show significant tumor growth inhibition (mean tumor volume of 63 mm(3)) when compared to irinotecan at 80 mg/kg (mean tumor volume of 575 mm(3)) and CPT at 8 mg/kg (mean tumor volume of 808 mm(3)) at the end of the study. Herceptin antibody treatment at 5.9 mg/kg results in complete tumor regressions in 5 out of 8 mice, with a mean tumor volume of 60 mm(3) at the end of the study. Mice treated with MAP-CPT nanoparticles at 1 mg of CPT/kg do not show tumor inhibition. However, all mice receiving administrations of MAP-CPT nanoparticles (1 mg of CPT/kg) that contain on average a single Herceptin molecule per nanoparticle (5.9 mg of Herceptin equivalent/kg) show complete tumor regression by the end of the study. These results demonstrate that the antitumor efficacy of nanoparticles carrying anticancer drugs can be enhanced by incorporating on average a single antibody.
我们开发了一种组装靶向纳米颗粒的新方法，该方法利用含硼酸的靶向剂与具有二醇的聚合物-药物缀合物之间的络合作用。在此，我们报告通过这种新组装方法形成的纳米颗粒的首个体内抗肿瘤结果。研究了一种纳米颗粒，其由喜树碱（CPT）的粘酸聚合物缀合物MAP-CPT组成，平均含有一个赫赛汀抗体，用于接种过表达HER2的BT-474人乳腺癌肿瘤的裸鼠。直径约30-40nm且zeta电位略为负值的非靶向MAP-CPT和含抗体的MAP-CPT纳米颗粒在小鼠尾静脉注射后显示出体内循环时间延长且生物分布相似。在小鼠中，非靶向和含赫赛汀的MAP-CPT纳米颗粒的最大耐受剂量（MTD）分别为10和8mg CPT/kg。在研究结束时，用8mg CPT/kg的非靶向MAP-CPT纳米颗粒治疗的携带BT-474人乳腺肿瘤的小鼠与80mg/kg的伊立替康（平均肿瘤体积575mm³）和8mg/kg的CPT（平均肿瘤体积808mm³）相比，显示出显著的肿瘤生长抑制（平均肿瘤体积63mm³）。5.9mg/kg的赫赛汀抗体治疗使8只小鼠中的5只肿瘤完全消退，研究结束时平均肿瘤体积为60mm³。用1mg CPT/kg的MAP-CPT纳米颗粒治疗的小鼠未显示肿瘤抑制。然而，所有接受平均每个纳米颗粒含有一个赫赛汀分子（相当于5.9mg赫赛汀/kg）的MAP-CPT纳米颗粒（1mg CPT/kg）给药的小鼠在研究结束时均显示肿瘤完全消退。这些结果表明，通过平均掺入单个抗体可以提高携带抗癌药物的纳米颗粒的抗肿瘤功效。
