冰片和叶酸共修饰的阿霉素聚酰胺-胺复合物在动物体内的研究

目的 研究用冰片（borneol，BO）和叶酸（folic acid，FA）共修饰阿霉素（doxorubicin，DOX）聚酰胺-胺型树状[poly（amido amine），PAMAM]大分子（FA-BO-PAMAM/DOX），增加药物在脑胶质瘤部位递送。方法 第5代PAMAM树状大分子分别与BO和FA通过共价结合得FA-BO-PAMAM。以FA-BO-PAMAM为纳米载体，制备了FA-BO-PAMAM/DOX，通过尾静脉注射该复合物，考察荷瘤大鼠体内的药动学行为及组织分布情况。结果 BO-PAMAM/DOX和FA-BO-PAMAM/DOX组的大鼠血浆半衰期（plasma half-life，t_1/2）和平均滞留时间（mean retention time，MRT）均较原药组显著延长（P<0.01）；血药浓度-时间曲线下面积（area under the plasma concentration-time curve，AUC）较原药组显著增大（P<0.01）。与DOX相比，BO-PAMAM/DOX和FA-BO-PAMAM/DOX在肿瘤组织中的药物含量明显增加，而在心脏中的药物含量明显降低。结论 采用合成的药物载体FA-BO-PAMAM包载DOX后，可显著改变DOX的部分药动学参数，使药物在血浆中能维持较长时间。另外FA-BO-PAMAM/DOX具有较好的肿瘤靶向治疗效果和较小的心脏不良反应，对提高DOX的治疗指数具有较好的临床价值。

Study of Animals About Borneol and Folic Acid Co-modified Doxorubicin Loaded PAMAM Complex in Vivo

OBJECTIVE To design a multifunctional targeting strategy FA-BO-PAMAM/DOX, in which a novel targeting drug carrier(FA-BO-PAMAM) based on the poly (amido amine)(PAMAM) G5 dendrimer modified with borneol(BO) and folic acid(FA) molecules on the periphery and doxorubicin(DOX) loaded in the interior, so as to increase drug delivery in gliomas. METHODS BO and FA molecules was covalent bound on the PAMAM G5 dendrimer, so as the carrier of FA-BO-PAMAM was synthesized. Then DOX was loaded into the carrier, the FA-BO-PAMAM/DOX was prepared. Besides, pharmacokinetic and tissue biodistribution in vivo were evaluated on tumor bearing rats after caudal vein injection with FA-BO-PAMAM/DOX. RESULTS In comparison with DOX solution, groups of BO-PAMAM/DOX and FA-BO-PAMAM/DOX displayed significant longer t_1/2 and blood retention time(P<0.01), with prolonged AUC(P<0.01). Furthermore, drug content was higher in tumor and lower in heart of the groups of BO-PAMAM/DOX and FA-BO-PAMAM/DOX compared with DOX. CONCLUSION After DOX is loaded in to the prepared carrier FA-BO-PAMAM, part of the pharmacokinetic parameters of DOX can be changed significantly, so that the drug can be maintained in plasma longer. FA-BO-PAMAM/DOX exhibits higher tumor inhibition ratio and lower cardiotoxicity, indicating that FA-BO-PAMAM/DOX has clinic value on improving the treatment index of DOX.