Dimerization-induced self-assembly of a redox-responsive prodrug into nanoparticles for improved therapeutic index
Dimerization-induced self-assembly of a redox-responsive prodrug into nanoparticles for improved therapeutic index
复制标题
二聚化诱导氧化还原响应前药自组装成纳米颗粒以提高治疗指数
DOI：
10.1016/j.actbio.2020.07.007
复制
发表时间：
2020
影响因子：
9.7
通讯作者：
Hangxiang Wang
中科院分区：
文献类型：
--
作者：
Liqian Zhou;Haiyang Xie;Xiaona Chen;Jianqin Wan;Shengjun Xu;Yaxuan Han;Dong Chen;Yiting Qiao;Lin Zhou;Shusen Zheng;Hangxiang Wang
尽管一些形式的纳米药物现在可以用于临床，但将新的纳米药物转化到临床上仍然是一个相当大的挑战。在这里，我们描述了一种简单但具有成本效益的策略，将有毒药物Cabazitaxel转化为安全有效的纳米药物。该策略包括通过自焚间隔区连接药物分子，然后通过二聚化诱导自组装来组装稳定的纳米颗粒。自组装的卡巴紫杉醇二聚体可以通过与适合临床前研究的两亲性聚合物的聚乙二醇化进一步精制。该方案使系统可注射纳米粒(TermedSNPs)的形成具有近乎定量的包封率和极高的载药量(>；86%)。在健康的小鼠中，聚乙二醇化的SNPs显示出良好的安全性，全身毒性降低，免疫毒性可忽略不计。在两种不同的小鼠异种移植癌症模型中，在治疗研究期间，给药SNPs产生有效的抗肿瘤活性和持久的肿瘤抑制。总体而言，这种方法为临床上有用的纳米药物的制备开辟了一条实用而便捷的途径，将一种疏水和剧毒的药物转化为系统的自给药纳米疗法。意义陈述尽管癌症纳米药物取得了很大进展，但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，我们设计了一种基于卡氮紫杉醇二聚体通过可生物激活的连接物可逆连接的自组装纳米平台。这种方法使系统可注射纳米药物的产生具有定量包封率和极高的载药量(>；86%)，这极大地消除了对赋形剂相关副作用的担忧。自组装的二聚体卡氮紫杉醇在动物体内表现出比游离卡氮紫杉醇更高的安全性，免疫毒性可以忽略不计。这是一个实际和方便的例子，如何利用疏水和剧毒的抗癌药物的化学连接来创建自组装递送纳米疗法，这种纳米疗法保留了固有的药理功效，同时降低了体内的全身和免疫毒性。
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 moleculesviaa 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 (termedSNPs) with nearly quantitative entrapment efficiencies and exceptionally high drug loading (> 86%). In healthy mice, PEGylatedSNPsshow a favorable safety profile, with reduced systemic toxicity and negligible immunotoxicity. In two separate mouse xenograft models of cancer, administration ofSNPsproduces 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 SignificanceDespite 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.