Synthesis and properties of star-comb polymers and their doxorubicin conjugates.
Synthesis and properties of star-comb polymers and their doxorubicin conjugates.
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DOI：
10.1021/bc100400u
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发表时间：
2011-04-20
影响因子：
4.7
通讯作者：
Szoka, Francis C.
中科院分区：
文献类型：
--
作者：
Chen, Bo;van der Poll, Derek G.;Jerger, Katherine;Floyd, William C.;Frechet, Jean M. J.;Szoka, Francis C.
我们描述了通过原子转移自由基聚合(ATRP)六步合成载多柔比星(DOX)的可生物降解的水溶性聚乙二醇化星形梳状聚合物。在37℃、pH 5.0或pH 7.4的条件下，低多分散度聚合物在15天内逐步降解为低分子量(MW)碎片。星梳聚合物在血液中的半衰期与分子质量有关，44 kDa星梳的t1/2，β为30.5±2.1h，当6.6wt%的DOX通过pH敏感的联接剂连接到星梳上时，t1/2无明显变化(2 8.6±2.7h)。星冠聚合物在器官中的蓄积较低，但在Balb/C小鼠体内移植的C26侧翼肿瘤中有较高的蓄积。动态光散射法测得聚合物-DOX偶联物的流体力学直径随负载从6.6增加到8.4再增加到10.2wt%，从8 nm增大到35 nm到41 nm。尽管C-26肿瘤的T1/2、β或聚合物-阿霉素的蓄积量没有显著差异，但阿霉素负载量大于6.6wt%的聚合物在脾中的摄取显著高于前者。聚合物在其他重要器官中的积累与DOX的负荷无关。该药物具有合成简便、生物降解性好、循环时间长、肿瘤积累量大等特点，表明该水溶性星梳聚合物具有良好的治疗应用前景。
We describe a six step synthesis to water soluble doxorubicin (DOX)-loaded biodegradable PEGylated star-comb polymers with favorable pharmaceutical properties by atom transfer radical polymerization (ATRP) starting with a commercially available tripentaerythritol carrying eight reactive sites. The low polydispersity polymers degrade in a stepwise manner into lower molecular weight (MW) fragments by 15 days at 37 °C at either pH 5.0 or pH 7.4. The half-life of the star-comb polymers in blood is dependent upon the molecular weight; the 44 kDa star-comb has a t1/2, β of 30.5 ± 2.1 h, which is not significantly changed (28.6 ±2.7 h) when 6.6 wt% of DOX is attached to it via a pH-sensitive hydrazone linker. The star-comb polymers have low accumulation in organs but a high accumulation in C26 flank tumors implanted in Balb/C mice. The hydrodynamic diameter of polymer-DOX conjugates measured by dynamic light scattering increases from 8 to 35 to 41 nm as the loading is increased from 6.6 to 8.4 to 10.2 wt%. Although there is no significant difference in the t1/2, β or in the accumulation of polymer-DOX in C-26 tumors, the uptake of polymer in the spleen is significantly higher for polymers with DOX loadings greater than 6.6 wt%. Polymer accumulation in other vital organs is independent of the DOX loading. The facile synthesis, biodegradability, long circulation time and high tumor accumulation of the attached drug suggests that the water-soluble star-comb polymers have promise in therapeutic applications.
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影响因子：
4.9
作者：
Lo, Su-Tang;Stern, Stephan;Simanek, Eric E.
通讯作者：
Simanek, Eric E.
影响因子：
4.7
作者：
van der Poll, Derek G.;Kieler-Ferguson, Heidi M.;Floyd, William C.;Guillaudeu, Steven J.;Jerger, Katherine;Szoka, Francis C.;Frechet, Jean M.
通讯作者：
Frechet, Jean M.
影响因子：
4.7
作者：
Kim Y;Hechler B;Gao ZG;Gachet C;Jacobson KA
通讯作者：
Jacobson KA
影响因子：
4.7
作者：
Jones, MC;Ranger, M;Leroux, JC
通讯作者：
Leroux, JC
影响因子：
6.2
作者：
Fukukawa, Ken-ichi;Rossin, Raffaella;Hawker, Craig J.
通讯作者：
Hawker, Craig J.