Structural optimization of a "smart" doxorubicin-polypeptide conjugate for thermally targeted delivery to solid tumors
Structural optimization of a "smart" doxorubicin-polypeptide conjugate for thermally targeted delivery to solid tumors
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DOI：
10.1016/j.jconrel.2005.10.006
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发表时间：
2006-01-10
影响因子：
10.8
通讯作者：
Chilkoti, A
中科院分区：
文献类型：
--
作者：
Furgeson, DY;Dreher, MR;Chilkoti, A
摘要合成了一种热响应性的、基因工程的、含有c端半胱氨酸残基的弹性蛋白样多肽（ELP），并通过反过渡循环（ITC）纯化，通过四种不同的ph敏感的、马来酰亚胺激活的肼偶联剂与阿霉素（Dox）分子偶联。本研究量化了Dox的活化效率、与ELP的共轭比、ELP-Dox偶联物的生物物理表征——流体动力学半径（R-h）和温度转变动力学，以及ph介导的Dox释放。马来酰亚胺活化的Dox与ELP中独特的半胱氨酸的硫醇基团的共轭率接近一致。共轭物的R-h随着ELP主链与Dox之间的连接物长度的增加而增加。连接体的结构和长度对ELP- dox共轭物的T-t影响不大，所有共轭物的T-t都与天然ELP相似。然而，与具有较短连接体的ELP-Dox偶联物相比，具有较长连接体的ELP-Dox偶联物表现出较慢的转变动力学。在pH值为4时，ELP-Dox偶联物在72 h内的最高释放率接近80%，并且以最短的连接物为偶联物。(c) 2005 Elsevier B.V.版权所有
A thermoresponsive, genetically engineered, elastin-like polypeptide (ELP) containing a C-terminal cysteine residue was synthesized and purified by inverse transition cycling (ITC) and conjugated to doxorubicin (Dox) molecules through four different pH-sensitive, maleimide-activated, hydrazone linkers. The efficiency of Dox activation, conjugation ratios to ELP and biophysical characterization-hydrodynamic radius (R-h) and the temperature transition kinetics-of the ELP-Dox conjugates and pH-mediated release of Dox were quantified in this study. Conjugation ratios of the maleimide-activated Dox to the thiol group of a unique cysteine in the ELP were close to unity. The R-h of the conjugate increased as the linker length between the ELP backbone and Dox was increased. The linker structure and length had little effect on the T-t of the ELP-Dox conjugates, as all conjugates exhibited T-t's that were similar to the native ELP. However, the ELP-Dox conjugates with longer linkers exhibited slower transition kinetics compared to the ELP-Dox conjugates with shorter linkers. The highest release of the ELP-Dox conjugate by cleavage of the hydrazone bond at pH 4 was nearly 80% over 72 h and was exhibited by the conjugate with the shortest linker. (c) 2005 Elsevier B.V. All rights reserved.