摘要
进一步提高纳米颗粒治疗效果的方法是采用主动定位策略。双特异性抗体(bsAbs)在细胞表面,如地高辛半抗原与肿瘤特异性抗原的结合(Dig)可以直接负载肿瘤细胞。在这项研究中,我们探讨树突状聚甘油的潜力(DPG)结合物,它由阿霉素(DOX)的前体药物,Dig部分,和聚乙二醇(PEG)的外壳,结合抗体,作为有针对性的药物输送的新方法。我们可以发现固定成功的双特异性抗体对dPGDigMal- DOX-PEG 缀合物,以及这些配合物对Lewis Y(LeY)细胞表面结合表达的MCF-7细胞。使用流式细胞仪,我们可以发现优先结合的复杂目标控制共轭缺失Dig部分。浓度通常用于药物递送、抗体复杂纳米粒子(独立特异性抗体)释放有毒的化合物进入细胞中相同程度的未改造的纳米粒子。这表明,在低阿霉素的浓度和温育时间短的时候,抗体附着与不干扰的固有的细胞结合和药物递送特性的纳米粒子中。但是,我们能够看到一个稍微增加目标特异性细胞毒性的体外介导的digoxigeninylated NP 的 Dig结合部分络合,络合BsAb变成直接的靶细胞。这项研究表明,潜在的digoxigeninylated DPG药物缀合物结合双特异性抗体作为一个新的平台,输送到肿瘤组织靶向药。然而,纳米粒子的设计需要进一步优化,从而更加显著且有针对性的传输。
关键词: 主动靶向;双特异性抗体;树突状聚甘油;阿霉素;聚合物的治疗;靶向给药。
Current Cancer Drug Targets
Title:Bispecific Antibodies for Targeted Delivery of Dendritic Polyglycerol (dPG) Prodrug Conjugates
Volume: 16 Issue: 7
Author(s): Fatemeh Sheikhi Mehrabadi, Juliane Adelmann, Shilpi Gupta, Stefanie Wedepohl, Marcelo Calderón, Ulrich Brinkmann, Rainer Haag
Affiliation:
关键词: 主动靶向;双特异性抗体;树突状聚甘油;阿霉素;聚合物的治疗;靶向给药。
摘要: One approach to further improve the therapeutic efficacy of nanoparticles is employment of active targeting strategies. Bispecific antibodies (bsAbs) that bind to both tumor specific antigens on the cell surface and to haptens such as digoxigenin (Dig) can direct digoxigeninylated payloads to tumor cells. In this study, we investigate the potential of dendritic polyglycerol (dPG) conjugates, which consist of a doxorubicin (DOX) prodrug, Dig moiety, and a poly (ethylene glycol) (PEG) shell, in combination with bsAb, as a novel approach for targeted prodrug delivery. We could show successful binding of the bsAbs to dPGDigMal-DOX-PEG conjugates, as well as binding of these complexes to the cell surface of Lewis Y (LeY) expressing MCF-7 cells. Using flow cytometry, we could show the preferential binding of the targeting complex over the complex of control conjugate lacking Dig moieties. At concentrations that are usually applied for drug delivery, antibodycomplexed nanoparticles (independent of antibody specificity) released cytotoxic compounds into cells to the same degree as unmodified nanoparticles. This indicates that antibody-attachment does not interfere with the inherent cell binding and drug delivery properties of nanoparticles. At low doxorubicin concentrations and short incubation times, however, we were able to see a slightly increased target specific cytotoxicity in vitro which is mediated by complexation of the digoxigeninylated NP with the Dig-binding moiety of a bsAb that in turns direct the complexed bsAb to target cells. This study demonstrates the potential of digoxigeninylated dPG prodrug conjugates in combination with bsAbs as a new platform for targeted prodrug delivery into cancerous tissues. However the nanoparticle design needs to be further optimized for significant targeted delivery.
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Fatemeh Sheikhi Mehrabadi, Juliane Adelmann, Shilpi Gupta, Stefanie Wedepohl, Marcelo Calderón, Ulrich Brinkmann, Rainer Haag , Bispecific Antibodies for Targeted Delivery of Dendritic Polyglycerol (dPG) Prodrug Conjugates, Current Cancer Drug Targets 2016; 16 (7) . https://dx.doi.org/10.2174/1568009616666160208142910
DOI https://dx.doi.org/10.2174/1568009616666160208142910 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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