【作者】 朱赛杰； 洪鸣凰； 姜嫣嫣； 裴元英；

【Author】 ZHU Sai-jie,HONG Ming-huang,JIANG Yan-yan,PEI Yuanying (Department of Pharmaceutics,School of Pharmacy,Fudan Univeristy,Shanghai 201203,China)

【机构】 复旦大学药学院；

【摘要】 目的研究聚乙二醇化的聚酰胺-胺树枝状聚合物(PEG-PAMAM)作为阿霉素(DOX)肿瘤靶向递释载体的可行性。方法分别用酸敏感的顺式乌头酸酐和非酸敏感的丁二酸酐共价连接DOX与PEG-PAMAM制备PPCD和PPSD。比较PEG化程度和DOX连接方式对体外释放、肿瘤细胞摄取、细胞毒性、细胞内定位、荷瘤小鼠的体内药动学、组织分布和抗肿瘤活性的影响。结果 DOX从PPCD的释放具有酸敏性,并且随着PEG化程度的增加而增加,PPSD几乎不释放DOX。PPCD表现出比PPSD更强的细胞毒性,且PPCD的细胞毒性随PEG化程度增加而增加。细胞内定位研究表明PPCD在溶酶体弱酸性环境下释放DOX,并进入细胞核。DOX共价结合到PEG-PAMAM后在血液中滞留时间延长,肿瘤部位摄取增加。尽管相同PEG化程度时,PPCD的肿瘤摄取小于PPSD,但是由于其肿瘤部位游离DOX的量较大而表现出更强的抗肿瘤活性。结论 DOX以酸敏感的方式共价结合到较高PEG化程度的PAMAM树枝状聚合物具有较强的抗肿瘤活性,值得进一步研究。更多还原

【Abstract】 OBJECTIVE To explore the potential of PEGylated polyamidoamine dendrimers (PEG-PAMAM) as the carrier for tumor-selective targeting of the anticancer drug doxorubicin (DOX). METHODS Acid-sensitive cis-aconityl linkage or acid-insensitive succinic linkage was introduced between DOX and PEG-PAMAM to produce PPCD or PPSD conjugates, respectively. The effects of PEGylation degree and DOX conjugation style on the in vitro release, cellular uptake, intracellular localization, tissue distribution in tumor-bearing mice and in vivo anti-tumor activity were evaluated. RESULTS DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against murine B16 melanoma cells increased with, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. Confocal laser scanning microscopy confirmed the acid-sensitive release of DOX from PPCD conjugates in the lysosomes and the entrance into nuclei. Pharmacokinetic and biodistribution studies demonstrated that conjugation of DOX with PEG-PAMAM increased circulation time and tumor accumulation of total DOX as compared with DOX solution. Although PPSD conjugates showed more tumor accumulation than PPCD conjugates at the same PEGylation degree, the acid-sensitive DOX release from PPCD conjugates ensured higher concentration of free DOX in tumor and more pronounced antitumor activity. Besides, the antitumor activity of PPCD conjugates increased with increasing PEGylation degree. CONCLUSION PPCD conjugate with the highest PEGylation would be a promising candidate for solid tumor therapy and worthy of further investigation.更多还原