Intelligent Gold Nanoparticles for Synergistic Tumor Treatment via Intracellular Ca2+ Regulation and Resulting On-demand Photothermal Therapy

Abstract Designing therapeutics to utilize and manipulate the aberrant high concentration of Ca2+ in tumor cells would be a promising approach for effective tumor therapy. Herein, we fabricated a nanohybrid to significantly reduce the intracellular Ca2+ of tumor cells meanwhile to perform Ca2+ triggered photothermal therapy under 660 nm irradiation for synergistic tumor treatment. This nanohybrid contains gold nanoparticle as core, ethylene glycol bis (2-aminoethyl ether)-N, N, N', N'-tetraacetic acid (EGTA, Ca2+ chelating agent) as shell and folic acid (FA, tumor targeting agent) conjugated polyethylene glycol 4000 (PEG) as corona, where the EGTA shell and PEG-FA corona was connected by esterase-cleavable ester bonds. After injection, the nanohybrid maintained a stable “off state” during blood circulation due to the anti-fouling property and EGTA-blocking performed by PEG section. The PEG-FA would be removed by over-expressed esterase in tumor cells after FA mediated tumor accumulation and endocytosis, which activated EGTA to capture Ca2+ in tumor cells, resulting in the truncation of Ca2+ signaling for tumor inhibition. Moreover, the specific chelation between Ca2+ and the nanohybrid would further cause the intracellular assembly of these nanoparticles in tumor cells, which in situ generated an excellent photothermal agent for enhanced tumor therapy under 660 nm irradiation. Both in vitro and in vivo results showed excellent tumor inhibition and high survival rate of tumor-bearing mice after treatment by our AEPF nanohybrid, indicating this synergistic therapy via on-demand Ca2+ manipulation and Ca2+ triggered photothermal therapy could be a green approach for tumor treatment with high efficiency and minimum side effects.