Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin
Development of elastin-like polypeptide for thermally targeted delivery of doxorubicin
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DOI：
10.1016/j.bcp.2006.10.028
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发表时间：
2007-03-01
影响因子：
5.8
通讯作者：
Raucher, Drazen
中科院分区：
文献类型：
--
作者：
Bidwell, Gene L., III;Fokt, Izabela;Raucher, Drazen
化疗药物阿霉素（Dox）作为一种抗肿瘤药物广泛应用于血液系统恶性肿瘤和实体肿瘤。然而，其临床应用的局限性之一是全身给予有效剂量的Dox会导致非选择性心脏毒性和骨髓抑制。为了尽量减少这种非特异性毒性，研究人员检测了弹性蛋白样多肽（ELP）作为热靶向递送Dox的大分子载体的能力。基于ELP的阿霉素递送载体（Tat-ELP-GFLG- dox）包括：(1)从HIV-1 Tat蛋白衍生的肽，以促进其细胞摄取，(2)ELP允许热靶向，以及(3)溶酶体可降解的glycylphenylalanylleucylglycine （GFLG）间隔物和与硫醇反应性阿霉素衍生物偶联的半胱氨酸残基。高温诱导ELP聚集时，tas -ELP- gflg - dox对MES-SA子宫肉瘤细胞的细胞毒性增强20倍。ELP递送的阿霉素显示细胞质分布，并诱导温度依赖性半胱天冬酶激活。(c) 2006爱思唯尔公司版权所有。
The chemotherapeutic drug doxorubicin (Dox) is widely used as an antitumor agent in hematological malignancies and solid tumors. However, one of the limitations of its clinical use is that systemic administration of an effective dose of Dox results in nonselective cardiac toxicity and myelosuppression. In order to minimize this nonspecific toxicity, Elastin-like polypeptide (ELP) was examined for its ability to serve as a macromolecular carrier for thermally targeted delivery of Dox. The ELP-based doxorubicin delivery vehicle (Tat-ELP-GFLG-Dox) consists of: (1) a peptide derived from the HIV-1 Tat protein to facilitate its cellular uptake, (2) ELP to allow thermal targeting, and (3) the lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer and a cysteine residue conjugated to a thiol reactive doxorubicin derivative. Cytotoxicity of Tat-ELP-GFLG-Dox in MES-SA uterine sarcoma cells was enhanced 20-fold when aggregation of ELP was induced with hyperthermia. The ELP delivered doxorubicin displayed a cytoplasmic distribution and induced temperature dependent caspase activation. (c) 2006 Elsevier Inc. All rights reserved.