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Therapeutic Pretargeting with Gold Nanoparticles as Drug Candidates for Boron Neutron Capture Therapy
Particle & Particle Systems Characterization ( IF 2.7 ) Pub Date : 2020-09-23 , DOI: 10.1002/ppsc.202000200
Irene V. J. Feiner 1 , Krishna R. Pulagam 1 , Vanessa Gómez‐Vallejo 1 , Kepa Zamacola 1 , Zuriñe Baz 1 , María M. Caffarel 2, 3 , Charles H. Lawrie 2, 3, 4 , Ane Ruiz‐de‐Angulo 5 , Mónica Carril 3, 6, 7 , Jordi Llop 1, 8
Affiliation  

Boron neutron capture therapy (BNCT) is a binary approach for cancer treatment in which boron‐10 atoms and thermal neutrons need to colocalize to become effective. Recent research in the development of BNCT drug candidates focuses increasingly on nanomaterials, with the advantages of high boron loadings and passive targeting due to the enhanced permeability and retention (EPR) effect. The use of small boron‐rich gold nanoparticles (AuNPs) in combination with a pretargeting approach is proposed. Small sized polyethylene glycol–stabilized AuNPs (core size 4.1 ± 1.5 nm), are synthesized and functionalized with thiolated cobalt bis(dicarbollide) and tetrazine. To enable in vivo tracking of the AuNPs by positron emission tomography (PET), the core is doped with [64Cu]CuCl2. For the pretargeting approach, the monoclonal antibody Trastuzumab is functionalized with trans‐cyclooctene‐N‐hydroxysuccinimide ester. After proving in vitro occurrence of the antibody conjugation onto the AuNPs by click reaction and the low toxicity of the AuNPs, the boron delivery system is evaluated in vivo using breast cancer xenograft bearing mice and PET imaging. Tumor uptake due to the EPR effect can be witnessed with ≈5% injected dose (ID) cm−3 at 24 h postinjection, but with slower clearance than expected. Therefore, no increased retention can be observed using the pretargeting strategy.

中文翻译:

金纳米粒子作为硼中子俘获疗法的候选药物的治疗预靶向

硼中子俘获疗法(BNCT)是癌症治疗的一种二元方法,其中硼10原子和热中子需要共定位才能生效。BNCT候选药物开发的最新研究越来越集中于纳米材料,由于增强的渗透性和保留(EPR)效应,具有高硼载量和被动靶向的优势。提出了将小富硼金纳米颗粒(AuNPs)与预定位方法结合使用的方法。合成了小尺寸的聚乙二醇稳定的AuNP(核心尺寸为4.1±1.5 nm),并用硫醇化的钴酸糖脂)和四嗪官能化。为了能够通过正电子发射断层扫描(PET)体内跟踪AuNP,该核掺杂了[ 64 Cu] CuCl 2。对于预靶向方法,单克隆抗体曲妥珠单抗可以用反式-环辛烯-N-羟基琥珀酰亚胺酯官能化。在通过点击反应和AuNPs的低毒性证明抗体缀合到AuNPs上的体外发生之后,使用携带乳腺癌异种移植物的小鼠和PET成像在体内评估了硼递送系统。可以在注射后24小时以5%的注射剂量(ID)cm -3观察到由于EPR效应引起的肿瘤吸收,但清除速度比预期的慢。因此,使用预定位策略无法观察到保留率的增加。
更新日期:2020-09-23
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