Dimerization-induced self-assembly of a redox-responsive prodrug into nanoparticles for improved therapeutic index. (1st September 2020)

• Record Type: Journal Article
• Authors: Zhou, Liqian; Xie, Haiyang; Chen, Xiaona; Wan, Jianqin; Xu, Shengjun; Han, Yaxuan; Chen, Dong; Qiao, Yiting; Zhou, Lin; Zheng, Shusen; Wang, Hangxiang
• Is Part Of: Acta biomaterialia. Volume 113(2020)
• Page Start: 464
• Page End: 477
• Publication Date: 2020-09-01
• Subjects: Cabazitaxel -- Dimerization -- Self-assembly -- Cancer nanomedicine -- Immunotoxicity; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2020.07.007
• Languages: English
• ISSNs: 1742-7061

Abstract

Abstract: 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. Graphical abstract: Image, graphical abstract