Preclinical and First-in-Human Study of a Compact Radionuclide Labeled Self-Assembly Nanomedicine for Chemo-Radio-Theranostics of Cancer
Hehe Xiong, Rongxi Wang, Heng Zhang, Qianyu Zhang, Yatong Qin, Chao Du, Xinyi Zhang, Jinmin Ye, Changrong Shi, Huaxiang Shen, Zhaohui Zhu, Zijian Zhou, Xiaoyuan Chen, Jingjing Zhang
Abstract
The emerging combination of chemotherapy and radionuclide therapy has been actively investigated to overcome the limitations of monotherapy and augment therapeutic efficacy. However, it remains a challenge to design a single delivery vehicle that can incorporate chemotherapeutics and radionuclides into a compact structure. Here, a chelator DOTA- or NOTA-modified Evans blue conjugated camptothecin molecule (EB-CPT) nanoprodrug was synthesized, which could self-assemble into nanoparticles due to its inherent amphiphilicity. The nanoparticles could then be effectively labeled with therapeutic radionuclide lutetium-177 ( 177 Lu) or diagnostic radionuclides gallium-68 ( 68 Ga)/copper-64 ( 64 Cu) with high radiolabeling efficiency and radiochemical stability. Impressively, a single-dose chemoradiation therapy of [ 177 Lu]Lu-DOTA-EB-CPT plus EB-CPT effectively inhibited tumor growth in HCT116 tumor-bearing mice compared to the respective individual therapeutic approach. The [ 64 Cu]Cu-NOTA-EB-CPT nanoparticles also exhibited excellent in vivo characteristics including favorable blood circulation properties and prolonged tumor retention in tumor-bearing mice. The safety, feasibility, tolerability, and biodistribution of [ 68 Ga]Ga-NOTA-EB-ss-CPT were also preliminarily characterized in a first-in-human study. This study presents a simple but robust EB-CPT radiopharmaceutical that leverages EB as an albumin binder to strike a delicate balance between enhanced tumor accumulation, safety, and diagnostic efficacy, facilitating an integrated theranostic strategy within a single molecular structure. This radionuclide-labeled EB-CPT nanomedicine presents a step toward clinical translation of the combination of chemotherapy and radiotheranostics.