pH-sensitive gold nanoclusters labeling with radiometallic nuclides for diagnosis and treatment of tumor

Abstract

The acidic microenvironment is one of the remarkable features of tumor and is also a reliable target for tumor theranostics. Ultrasmall gold nanoclusters (AuNCs) have good in vivo behaviors, such as non-retention in liver and spleen, renal clearance, and high tumor permeability, and held great potential for developing novel radiopharmaceuticals. Herein, we developed pH-sensitive ultrasmall gold nanoclusters by introducing quaternary ammonium group (TMA) or tertiary amine motifs (C6A) onto glutathione-coated AuNCs (TMA/GSH@AuNCs, C6A-GSH@AuNCs). Density functional theory simulation revealed that radiometal ⁸⁹Sr, ²²³Ra, ⁴⁴Sc, ⁹⁰Y, ¹⁷⁷Lu, ⁸⁹Zr, ^99mTc, ¹⁸⁸Re, ¹⁰⁶Rh, ⁶⁴Cu, ⁶⁸Ga, and ¹¹³Sn could stably dope into AuNCs. Both TMA/GSH@AuNCs and C6A-GSH@AuNCs could assemble into large clusters responding to mild acid condition, with C6A-GSH@AuNCs being more effective. To assess their performance for tumor detection and therapy, TMA/GSH@AuNCs and C6A-GSH@AuNCs were labeled with ⁶⁸Ga, ⁶⁴Cu, ⁸⁹Zr and ⁸⁹Sr, respectively. PET imaging of 4T1 tumor-bearing mice revealed TMA/GSH@AuNCs and C6A-GSH@AuNCs were mainly cleared through kidney, and C6A-GSH@AuNCs accumulated in tumors more efficiently. As a result, ⁸⁹Sr-labeled C6A-GSH@AuNCs eradicated both the primary tumors and their lung metastases. Therefore, our study suggested that GSH-coated AuNCs held great promise for developing novel radiopharmaceuticals that specifically target the tumor acidic microenvironment for tumor diagnosis and treatments.

Keywords: Density functional theory simulation; Gold nanoclusters; Internal radiotherapy; PET imaging; Radionuclide labeling; pH-responsive.