Cell surface self-assembly of hybrid nanoconjugates via oligonucleotide hybridization induces apoptosis.
Cell surface self-assembly of hybrid nanoconjugates via oligonucleotide hybridization induces apoptosis.
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DOI：
10.1021/nn4053827
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发表时间：
2014-01-28
期刊：
影响因子：
17.1
通讯作者：
Kopecek, Jindrich
中科院分区：
文献类型：
--
作者：
Chu, Te-Wei;Yang, Jiyuan;Zhang, Rui;Sima, Monika;Kopecek, Jindrich
关键词：
由合成和生物组成的杂化纳米材料在纳米药物的设计中具有很大的潜力。使用自组装纳米材料作为“仿生物”可能引发细胞事件并产生新的治疗效果。基于这一原理，我们设计了一个模拟免疫效应细胞交联靶细胞表面受体并诱导细胞凋亡机制的治疗平台。该平台对高表达表面抗原CD20的b细胞淋巴瘤进行了实验。本文合成了两种纳米缀合物：(1)抗cd20 Fab '片段共价连接单链morpholino寡核苷酸（MORF1），以及(2)N-（2-羟丙基）甲基丙烯酰胺（HPMA）的线性聚合物接枝多个互补寡核苷酸MORF2拷贝。我们发现这两个偶联物通过MORF1-MORF2杂交在CD20+恶性b细胞表面自组装，从而交联CD20抗原并启动细胞凋亡。当在人类非霍奇金淋巴瘤的小鼠模型中进行测试时，这两种结合物，无论是连续给药还是作为预混剂，都能根除癌细胞并产生长期幸存者。设计的治疗方法不含小分子细胞毒性化合物，并且不依赖免疫，旨在改善化疗，放疗和免疫治疗。该治疗平台可用于交联任何非内化受体，并有可能治疗其他疾病。
Hybrid nanomaterials composed of synthetic and biological building blocks possess high potential for the design of nanomedicines. The use of self-assembling nanomaterials as “bio-mimics” may trigger cellular events and result in new therapeutic effects. Motivated by this rationale, we designed a therapeutic platform that mimics the mechanism of immune effector cells to crosslink surface receptors of target cells and induce apoptosis. This platform was tested against B-cell lymphomas that highly express the surface antigen CD20. Here, two nanoconjugates were synthesized: (1) an anti-CD20 Fab’ fragment covalently linked to a single-stranded morpholino oligonucleotide (MORF1), and (2) a linear polymer of N-(2-hydroxypropyl)methacrylamide (HPMA) grafted with multiple copies of the complementary oligonucleotide MORF2. We show that the two conjugates self-assemble via MORF1-MORF2 hybridization at the surface of CD20+ malignant B-cells, which crosslinks CD20 antigens and initiates apoptosis. When tested in a murine model of human non-Hodgkin’s lymphoma, the two conjugates, either administered consecutively or as a premixture, eradicated cancer cells and produced long-term survivors. The designed therapeutics contains no small-molecule cytotoxic compounds and is immune-independent, aiming to improve over chemotherapy, radiotherapy and immunotherapy. This therapeutic platform can be applied to crosslink any non-internalizing receptor and potentially treat other diseases.
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DOI：
10.1073/pnas.97.12.6728
发表时间：
2000-06-06
影响因子：
11.1
作者：
Holmes, TC;de Lacalle, S;Zhang, SG
通讯作者：
Zhang, SG
影响因子：
14
作者：
Gungormus M;Branco M;Fong H;Schneider JP;Tamerler C;Sarikaya M
通讯作者：
Sarikaya M
影响因子：
4.7
作者：
Johnson RN;Kopecková P;Kopecek J
通讯作者：
Kopecek J
影响因子：
14
作者：
Chu, Te-Wei;Yang, Jiyuan;Kopecek, Jindrich
通讯作者：
Kopecek, Jindrich
影响因子：
41.2
作者：
Ehrick, JD;Deo, SK;Daunert, S
通讯作者：
Daunert, S