Bioorthogonal, two-component delivery systems based on antibody and drug-loaded nanocarriers for enhanced internalization of nanotherapeutics.
Bioorthogonal, two-component delivery systems based on antibody and drug-loaded nanocarriers for enhanced internalization of nanotherapeutics.
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DOI：
10.1016/j.biomaterials.2013.11.075
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发表时间：
2014-02
期刊：
影响因子：
14
通讯作者：
Artemov, Dmitri
中科院分区：
文献类型：
--
作者：
Hapuarachchige, Sudath;Zhu, Wenlian;Kato, Yoshinori;Artemov, Dmitri
纳米载体在肿瘤靶向化疗中发挥着重要作用。最佳的纳米载体递送系统应该提供对靶细胞的高效和高度特异性的识别和治疗货物的快速内化，以减少全身毒性，并增加对癌细胞的细胞毒性。为此，我们开发了一种基于抗体和载药纳米载体的两步、两组分靶向递送系统，该系统利用生物正交点击反应实现纳米治疗药物的特异性内化。预靶向成分，抗HER2人源化单抗，曲妥珠单抗，用叠氮基团功能化，标记过表达HER2表面受体的癌细胞。药物载体组分，与紫杉醇偶联的二苄基环辛炔取代白蛋白，与预靶向组分发生特异性反应。这两个组分在细胞表面形成交联簇，这有助于复合体的内化。这一策略表明，由HER2受体、修饰的曲妥珠单抗和紫杉醇负载的白蛋白纳米载体组成的簇具有显著的细胞内化作用，随后在HER2阳性的BT-474乳腺癌细胞中具有显著的细胞毒性。我们的结果表明，这一策略对于靶向纳米疗法具有很高的效率。我们预计将使用放射性核素、毒素和干扰RNA等试剂来扩大这一策略的应用范围。
Nanocarriers play an important role in targeted cancer chemotherapy. The optimal nanocarrier delivery system should provide efficient and highly specific recognition of the target cells and rapid internalization of the therapeutic cargo to reduce systemic toxicity as well as to increase the cytotoxicity to cancer cells. To this end, we developed a two-step, two-component targeted delivery system based on antibody and drug-loaded nanocarrier that uses bioorthogonal click reactions for specific internalization of nanotherapeutics. The pretargeting component, anti-HER2 humanized monoclonal antibody, trastuzumab, functionalized with azide groups labels cancer cells that overexpress HER2 surface receptors. The drug carrier component, dibenzylcyclooctyne substituted albumin conjugated with paclitaxel, reacts specifically with the pretargeting component. These two components form cross-linked clusters on the cell surface, which facilitates the internalization of the complex. This strategy demonstrated substantial cellular internalization of clusters consisted of HER2 receptors, modified trastuzumab and paclitaxel-loaded albumin nanocarriers, and subsequent significant cytotoxicity in HER2-positive BT-474 breast cancer cells. Our results show high efficacy of this strategy for targeted nanotherapeutics. We foresee to broaden the applications of this strategy using agents such as radionuclides, toxins, and interfering RNA.
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DOI：
10.1164/rccm.200504-613pp
发表时间：
2005-12-15
影响因子：
24.7
作者：
Gelperina, S;Kisich, K;Heifets, L
通讯作者：
Heifets, L
影响因子：
64.8
作者：
Cho, HS;Mason, K;Leahy, DJ
通讯作者：
Leahy, DJ
影响因子：
17.1
作者：
Peterson VM;Castro CM;Lee H;Weissleder R
通讯作者：
Weissleder R
影响因子：
45.3
作者：
Burris, Howard A., III;Rugo, Hope S.;O'Shaughnessy, Joyce A.
通讯作者：
O'Shaughnessy, Joyce A.
DOI：
10.1158/1078-0432.ccr-09-0636
发表时间：
2009-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Pohlmann PR;Mayer IA;Mernaugh R
通讯作者：
Mernaugh R