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

doi:10.1016/j.isci.2023.107409

Dynamic nanoassemblies derived from small-molecule homodimeric prodrugs for in situ drug activation and safe osteosarcoma treatment

iScience. 2023 Jul 17;26(8):107409. doi: 10.1016/j.isci.2023.107409. eCollection 2023 Aug 18.

Authors

Jian Wang¹, Peirong Xu^{2

3

4}, Yeyong Zhang⁵, Shuai Han¹, Gongteng Wang⁵, Hangxiang Wang^{2

3}, Haihan Song⁶, Shufeng Li⁵

Affiliations

¹ Department of Orthopedics, Shanghai Pudong New Area People's Hospital, Shanghai, P.R. China.
² Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province 250117, P.R. China.
³ The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, P.R. China.
⁴ Department of Chemical Engineering, Zhejiang University, Hangzhou, Zhejiang Province 310027, P.R. China.
⁵ 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.
⁶ Central Lab, Shanghai Key Laboratory of Pathogenic Fungi Medical Testing, Shanghai Pudong New Area People's Hospital, Shanghai, P.R. China.

Abstract

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.

Keywords: Medical physics; Therapeutics.