Molecular assembly of an aptamer-drug conjugate for targeted drug delivery to tumor cells.
Molecular assembly of an aptamer-drug conjugate for targeted drug delivery to tumor cells.
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DOI：
10.1002/cbic.200800805
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发表时间：
2009-03-23
期刊：
影响因子：
3.2
通讯作者：
Tan, Weihong
中科院分区：
文献类型：
--
作者：
Huang, Yu-Fen;Shangguan, Dihua;Liu, Haipeng;Phillips, Joseph A.;Zhang, Xiaoling;Chen, Yan;Tan, Weihong
抗肿瘤药物与靶向试剂如抗体的偶联是一种有前途的方法，可以提高化疗的疗效并降低其总体毒性。在本文中，我们共价连接的抗肿瘤药物阿霉素（Dox）的DNA适体sgc 8 c，这是通过细胞的选择方法。在这样做时，我们预期这种sgc 8 c-Dox缀合物将特异性地杀死靶CCRF-CEM（T细胞急性淋巴细胞白血病，T细胞ALL）细胞，但对非靶细胞具有最小的毒性。结果表明，sgc 8 c-Dox缀合物具有sgc 8 c适体的许多性质，包括高结合亲和力（Kd = 2.0 ± 0.2 nM）和被靶细胞有效内化的能力。此外，由于特异性缀合方法，连接sgc 8 c-Dox缀合物的酸不稳定键可以在酸性内体环境内裂解。细胞活力测试表明，sgc 8 c-Dox缀合物不仅具有与未缀合的Dox类似的效力，而且具有在大多数当前靶向药物递送策略中缺乏的所需分子特异性。此外，我们发现，非靶细胞系对膜可渗透的Dox的非特异性摄取也可以通过将药物与适体连接来抑制，因此，它使得缀合物对表达更高量的靶蛋白的细胞具有选择性。与报道的不太有效的Dox-免疫缀合物相比，这种sgc 8 c-Dox缀合物使具有各种效力的药物的靶向化疗更可行。当与大量最近创建的特异性靶向各种癌细胞的DNA适体相结合时，这种药物适体缀合方法将对靶向药物递送产生广泛的影响。
The conjugation of antitumor drugs to targeting reagents such as antibodies is a promising method that can increase the efficacy of chemotherapy and reduce their overall toxicity. In this paper, we covalently link an antitumor agent doxorubicin (Dox) to the DNA aptamer sgc8c, which was selected by the cell-SELEX method. In doing so, we expected that this sgc8c-Dox conjugate would specifically kill the target CCRF-CEM (T-cell Acute Lymphoblastic Leukemia, T-cell ALL) cells, but with minimal toxicity towards non-target cells. The results demonstrated that sgc8c-Dox conjugate possesses many of the properties of the sgc8c aptamer, including high binding affinity (Kd = 2.0 ± 0.2 nM), and the capability to be efficiently internalized by target cells. Moreover, due to the specific conjugation method, the acid-labile linkage connecting the sgc8c-Dox conjugate can be cleaved inside the acidic endosomal environment. Cell viability tests demonstrate that the sgc8c-Dox conjugates not only possess potency similar to the unconjugated Dox, but also have the required molecular specificity which is lacking in most current targeted drug delivery strategies. Furthermore, we found that nonspecific uptake of membrane-permeable Dox to non-target cell lines could also be inhibited by linking the drug with the aptamer, thus, it makes the conjugates selective to the cells which express higher amounts of target proteins. Compared to the less effective reported Dox-immunoconjugates, this sgc8c-Dox conjugates make targeted chemotherapy more feasible with drugs having various potencies. When combined with the large number of recently created DNA aptamers that specifically target a wide variety of cancer cells, this drug-aptoconjugation method will have broad implications for targeted drug delivery.
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影响因子：
3.2
作者：
Shangguan, Dihua;Tang, Zhiwen;Tan, Weihong
通讯作者：
Tan, Weihong
影响因子：
11.2
作者：
Chu, Ted C.;Marks, John W., III;Levy, Matthew
通讯作者：
Levy, Matthew
影响因子：
3.5
作者：
LAU, A;BERUBE, G;GALLANT, M
通讯作者：
GALLANT, M
影响因子：
4.8
作者：
Blank, M;Weinschenk, T;Schluesener, H
通讯作者：
Schluesener, H
DOI：
10.1073/pnas.2136683100
发表时间：
2003-12-23
影响因子：
11.1
作者：
Daniels, DA;Chen, H;Gold, L
通讯作者：
Gold, L