Lee Cameron C, Gillies Elizabeth R, Fox Megan E, Guillaudeu Steven J, Fréchet Jean M J, Dy Edward E, Szoka Francis C
College of Chemistry, University of California, Berkeley, CA 94720-1460, USA.
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16649-54. doi: 10.1073/pnas.0607705103. Epub 2006 Oct 30.
The antitumor effect of doxorubicin (DOX) conjugated to a biodegradable dendrimer was evaluated in mice bearing C-26 colon carcinomas. An asymmetric biodegradable polyester dendrimer containing 8-10 wt % DOX was prepared. The design of the dendrimer carrier optimized blood circulation time through size and molecular architecture, drug loading through multiple attachment sites, solubility through PEGylation, and drug release through the use of pH-sensitive hydrazone linkages. In culture, dendrimer-DOX was >10 times less toxic than free DOX toward C-26 colon carcinoma cells after exposure for 72 h. Upon i.v. administration to BALB/c mice with s.c. C-26 tumors, dendrimer-DOX was eliminated from the serum with a half-life of 16 +/- 1 h, and its tumor uptake was ninefold higher than i.v. administered free DOX at 48 h. In efficacy studies performed with BALB/c mice bearing s.c. C-26 tumors, a single i.v. injection of dendrimer-DOX at 20 mg/kg DOX equivalents 8 days after tumor implantation caused complete tumor regression and 100% survival of the mice over the 60-day experiment. No cures were achieved in tumor-implanted mice treated with free DOX at its maximum tolerated dose (6 mg/kg), drug-free dendrimer, or dendrimer-DOX in which the DOX was attached by means of a stable carbamate bond. The antitumor effect of dendrimer-DOX was similar to that of an equimolar dose of liposomal DOX (Doxil). The remarkable antitumor activity of dendrimer-DOX results from the ability of the dendrimer to favorably modulate the pharmacokinetics of attached DOX.
在携带C-26结肠癌的小鼠中评估了与可生物降解树枝状聚合物偶联的阿霉素（DOX）的抗肿瘤效果。制备了一种含有8-10 wt% DOX的不对称可生物降解聚酯树枝状聚合物。树枝状聚合物载体的设计通过尺寸和分子结构优化了血液循环时间，通过多个连接位点实现了药物负载，通过聚乙二醇化提高了溶解度，并通过使用pH敏感的腙键实现了药物释放。在培养中，树枝状聚合物-DOX在暴露72小时后对C-26结肠癌细胞的毒性比游离DOX低10倍以上。静脉注射给患有皮下C-26肿瘤的BALB/c小鼠后，树枝状聚合物-DOX从血清中消除的半衰期为16±1小时，其在48小时时的肿瘤摄取量比静脉注射的游离DOX高9倍。在用患有皮下C-26肿瘤的BALB/c小鼠进行的疗效研究中，在肿瘤植入8天后以20 mg/kg DOX当量单次静脉注射树枝状聚合物-DOX，在60天的实验中导致肿瘤完全消退，小鼠存活率达100%。在以最大耐受剂量（6 mg/kg）的游离DOX、无药物的树枝状聚合物或通过稳定的氨基甲酸酯键连接DOX的树枝状聚合物-DOX治疗的肿瘤植入小鼠中未实现治愈。树枝状聚合物-DOX的抗肿瘤效果与等摩尔剂量的脂质体DOX（Doxil）相似。树枝状聚合物-DOX显著的抗肿瘤活性源于树枝状聚合物对附着DOX的药代动力学进行有利调节的能力。
