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Dimerization-induced self-assembly of a redox-responsive prodrug into nanoparticles for improved therapeutic index.
Acta Biomaterialia ( IF 9.7 ) Pub Date : 2020-07-08 , DOI: 10.1016/j.actbio.2020.07.007
Liqian Zhou 1 , Haiyang Xie 1 , Xiaona Chen 1 , Jianqin Wan 1 , Shengjun Xu 1 , Yaxuan Han 1 , Dong Chen 1 , Yiting Qiao 1 , Lin Zhou 1 , Shusen Zheng 2 , Hangxiang Wang 2
Affiliation  

Although some formats of nanomedicines are now available for clinical use, the translation of new nanoparticles to the clinic remains a considerable challenge. Here, we describe a simple yet cost-effective strategy that converts a toxic drug, cabazitaxel, into a safe and effective nanomedicine. The strategy involves the ligation of drug molecules via a self-immolating spacer, followed by dimerization-induced self-assembly to assemble stable nanoparticles. Self-assembled cabazitaxel dimers could be further refined by PEGylation with amphiphilic polymers suitable for preclinical studies. This protocol enables the formation of systemically injectable nanoparticles (termed SNPs) with nearly quantitative entrapment efficiencies and exceptionally high drug loading (> 86%). In healthy mice, PEGylated SNPs show a favorable safety profile, with reduced systemic toxicity and negligible immunotoxicity. In two separate mouse xenograft models of cancer, administration of SNPs produces efficient antitumor activity with durable tumor suppression during therapeutic studies. Overall, this methodology opens up a practical and expedient route for the fabrication of clinically useful nanomedicines, transforming a hydrophobic and highly toxic drug into a systemic self-deliverable nanotherapy.

Statement of Significance

Despite the great progress in cancer nanomedicines, clinical translation of nanomedicines still remains a considerable challenge. In this study, we designed a self-assembling nanoplatform based on cabazitaxel dimer reversibly ligated via a bioactivatable linker. This approach enabled the generation of systemically injectable nanomedicines with quantitative entrapment efficiencies and exceptionally high drug loading (> 86%), which greatly obviates concerns about excipient-associated side effects. Self-assembled dimeric cabazitaxel exhibited a higher safety profile than free cabazitaxel and negligible immunotoxicity in animals. This is a practical and expedient example how the chemical ligation of a hydrophobic and highly toxic anticancer drug can be leveraged to create a self-assembling delivery nanotherapy which preserves inherent pharmacologic efficacy while reduces in vivo systemic and immune toxicity.



中文翻译:

二聚化诱导的氧化还原反应前药自组装成纳米颗粒,以提高治疗指数。

尽管现在可以将某些形式的纳米药物用于临床,但是将新的纳米粒子翻译到临床仍然是一个巨大的挑战。在这里,我们描述了一种简单但具有成本效益的策略,该策略可将有毒药物卡巴他赛转化为安全有效的纳米药物。该策略涉及通过自消旋间隔基连接药物分子,然后进行二聚化诱导的自组装,以组装稳定的纳米颗粒。自组装的卡巴他赛二聚体可通过适用于临床前研究的两亲聚合物通过PEG化进一步完善。该协议可以形成可全身注射的纳米颗粒(称为SNP))具有几乎定量的包封效率和极高的载药量(> 86%)。在健康小鼠中,PEG化的SNPs显示出良好的安全性,具有降低的全身毒性和可忽略的免疫毒性。在两个单独的小鼠癌症异种移植模型中,在治疗研究期间,单核苷酸多态性的产生可产生有效的抗肿瘤活性,并具有持久的肿瘤抑制作用。总体而言,该方法为临床上有用的纳米药物的制备开辟了一条实用且方便的途径,将疏水性和高毒性药物转变为全身可自我递送的纳米疗法。

重要声明

尽管在癌症纳米药物方面取得了巨大的进步,但是纳米药物的临床翻译仍然是一个相当大的挑战。在这项研究中,我们基于可生物活化的接头可逆连接的卡巴他赛二聚体设计了一种自组装纳米平台。这种方法能够产生具有定量包封效率和异常高的载药量(> 86%)的全身可注射纳米药物,从而大大消除了对与赋形剂相关的副作用的担忧。自组装的二聚卡巴他赛比自由卡巴他赛具有更高的安全性,并且对动物的免疫毒性可忽略不计。

更新日期:2020-08-05
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