In vivo molecular imaging for immunotherapy using ultra-bright near-infrared-IIb rare-earth nanoparticles

• Published in: Nature biotechnology Vol. 37; no. 11; pp. 1322 - 1331
• Main Authors: Zhong, Yeteng, Ma, Zhuoran, Wang, Feifei, Wang, Xi, Yang, Yijun, Liu, Yulai, Zhao, Xiang, Li, Jiachen, Du, Haotian, Zhang, Mingxi, Cui, Qiuhong, Zhu, Shoujun, Sun, Qinchao, Wan, Hao, Tian, Ye, Liu, Qiang, Wang, Weizhi, Garcia, K. Christopher, Dai, Hongjie
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2019; Nature Publishing Group
• Subjects: 631/250/251; 639/925/352/2734; 639/925/357/354; Agriculture; Animals; Antibodies; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Agents, Immunological - chemistry; Antineoplastic Agents, Immunological - pharmacology; Apoptosis; B7-H1 Antigen - immunology; Biocompatibility; Bioinformatics; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedical materials; Biomedicine; Biotechnology; Cancer; Cancer immunotherapy; CD8 antigen; CD8 Antigens - metabolism; Cell death; Cell Line, Tumor; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - immunology; Crosslinking; Cytotoxicity; Erbium; Erbium - chemistry; I.R. radiation; Imaging; Immune response; Immunotherapy; Infrared Rays; Lead sulfides; Life Sciences; Luminescence; Lymphocytes; Lymphocytes T; Methods; Mice; Molecular diagnostic techniques; Nanoparticles; Optical Imaging; PD-1 protein; PD-L1 protein; Polymers; Quantum Dots; Rare earth elements; Rare earth metals; Spleen; Sulfides; T-Lymphocytes, Cytotoxic - immunology; Toxicity; Tumor Microenvironment - drug effects; Tumors; Xenograft Model Antitumor Assays; United States
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/s41587-019-0262-4

The near-infrared-IIb (NIR-IIb) (1,500–1,700 nm) window is ideal for deep-tissue optical imaging in mammals, but lacks bright and biocompatible probes. Here, we developed biocompatible cubic-phase (α-phase) erbium-based rare-earth nanoparticles (ErNPs) exhibiting bright downconversion luminescence at ~1,600 nm for dynamic imaging of cancer immunotherapy in mice. We used ErNPs functionalized with cross-linked hydrophilic polymer layers attached to anti-PD-L1 (programmed cell death-1 ligand-1) antibody for molecular imaging of PD-L1 in a mouse model of colon cancer and achieved tumor-to-normal tissue signal ratios of ~40. The long luminescence lifetime of ErNPs (~4.6 ms) enabled simultaneous imaging of ErNPs and lead sulfide quantum dots emitting in the same ~1,600 nm window. In vivo NIR-IIb molecular imaging of PD-L1 and CD8 revealed cytotoxic T lymphocytes in the tumor microenvironment in response to immunotherapy, and altered CD8 signals in tumor and spleen due to immune activation. The cross-linked functionalization layer facilitated 90% ErNP excretion within 2 weeks without detectable toxicity in mice. Biocompatible rare-earth nanoparticles with an emission maximum at 1,600 nm enable sensitive in vivo imaging.