Dynamic nanoassemblies derived from small-molecule homodimeric prodrugs for in situ drug activation and safe osteosarcoma treatment
Jian Wang,
Peirong Xu,
Yeyong Zhang,
Shuai Han,
Gongteng Wang,
Hangxiang Wang,
Haihan Song,
Shufeng Li
Affiliations
Jian Wang
Department of Orthopedics, Shanghai Pudong New Area People’s Hospital, Shanghai, P.R. China
Peirong Xu
Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province 250117, P.R. China; The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, P.R. China; Department of Chemical Engineering, Zhejiang University, Hangzhou, Zhejiang Province 310027, P.R. China
Yeyong Zhang
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, P.R. China
Shuai Han
Department of Orthopedics, Shanghai Pudong New Area People’s Hospital, Shanghai, P.R. China
Gongteng Wang
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, P.R. China
Hangxiang Wang
Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province 250117, P.R. China; The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, P.R. China; Corresponding author
Haihan Song
Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People’s Hospital, Shanghai, P.R. China; Corresponding author
Shufeng Li
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, P.R. China; Corresponding author
Summary: Supramolecular prodrug self-assembly is a cost-effective and powerful approach for creating injectable anticancer nanoassemblies. Herein, we describe the self-assembly of small-molecule prodrug nanotherapeutics for tumor-restricted pharmacology that can be self-activated and independent of the exogenous stimuli. Covalent dimerization of the anticancer agent cabazitaxel via reactive oxygen species (ROS)- and esterase-activatable linkages produced the homodimeric prodrug diCTX, which was further coassembled with an ROS generator, dimeric dihydroartemisinin (diDHA). The coassembled nanoparticles were further refined in an amphiphilic matrix, making them suitable for in vivo administration. The ROS obtained from the coassembled diDHA synergized with intracellular esterase to activate the neighboring diCTX, which in turn induced potent cytotoxicity. In a preclinical orthotopic model of human osteosarcomas, nanoparticle administration exhibited durable antitumor efficacy. Furthermore, this smart, dual-responsive nanotherapeutic exhibited lower toxicity in animals than those of free drug combinations. We predict that this platform has great potential for further clinical translation.
