Gold nanorods-mediated efficient synergistic immunotherapy for detection and inhibition of postoperative tumor recurrence

Abstract

Tumor recurrence after surgery is the main cause of treatment failure. However, the initial stage of recurrence is not easy to detect, and it is difficult to cure in the late stage. In order to improve the life quality of postoperative patients, an efficient synergistic immunotherapy was developed to achieve early diagnosis and treatment of post-surgical tumor recurrence, simultaneously. In this paper, two kinds of theranostic agents based on gold nanorods (AuNRs) platform were prepared. AuNRs and quantum dots (QDs) in one agent was used for the detection of carcinoembryonic antigen (CEA), using fluorescence resonance energy transfer (FRET) technology to indicate the occurrence of in situ recurrence, while AuNRs in the other agent was used for photothermal therapy (PTT), together with anti-PDL1 mediated immunotherapy to alleviate the process of tumor metastasis. A series of assays indicated that this synergistic immunotherapy could induce tumor cell death and the increased generation of CD3⁺/CD4⁺ T-lymphocytes and CD3⁺/CD8⁺ T-lymphocytes. Besides, more immune factors (IL-2, IL-6, and IFN-γ) produced by synergistic immunotherapy were secreted than mono-immunotherapy. This cooperative immunotherapy strategy could be utilized for diagnosis and treatment of postoperative tumor recurrence at the same time, providing a new perspective for basic and clinical research.

Keywords: AFP, alpha fetoprotein; AP1-QDs, CEA aptamer-modified CdTe QDs; AP2-AuNRs, CEA aptamer-modified AuNRs; AP2-AuNRs, and interferon-γ; AgNO3, silver nitrate; AuNRs, gold nanorods; CA, cancer antigen; CEA, carcinoembryonic antigen; CTAB, cetrimonium bromide; CTCs, circulating tumor cells; Carcinoembryonic antigen; CdCl2, cadmium chloride; CdTe QDs, CdTe quantum dots; DC, dendritic cells; DLS, dynamic light scattering; EDC, 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide; FBS, fetal bovine serum; FRET, fluorescence resonance energy transfer; Fluorescence resonance energy transfer; GSH, glutathione; Gold nanorods; HAuCl4, gold chloride; Helf, human embryonic lung fibroblasts lines; Hydrogel+IFN-γ+QA, thermal responsive hydrogels co-loaded with AP1-QDs; Hydrogel+IFN-γ, thermal responsive hydrogels loaded with interferon-γ; ICG, indocyanine green; IFN-γ, interferon-γ; IR, infrared; LA+NIR, liposomes encapsulated AuNRs with near-infrared irradiation; LA, liposomes encapsulated AuNRs; LAI, liposomes loaded with ICG and encapsulated AuNRs; LLC, murine lung cancer cells; Lung metastasis; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NHS, N-hydroxysuccinimide; NIR, near-infrared irradiation; NaBH4, sodium borohydride; NaHTe, sodium hydrogen telluride; PD1, programmed cell death protein 1; PDL1, programmed cell death-ligand 1; PI, propidium iodide; PLGA-PEG-PLGA, thermal responsive hydrogel; PTT, photothermal therapy; Phototherapy; Post-surgical tumor recurrence; QDs, quantum dots; Synergistic immunotherapy; TEM, transmission electron microscope; Theranostics; aPDL1-LA+NIR, anti-PDL1-modified liposomes encapsulated AuNRs with near-infrared irradiation; aPDL1-LA, anti-PDL1-modified liposomes encapsulated AuNRs; aPDL1-LAI, anti-PDL1-modified liposomes loaded with ICG and encapsulated AuNRs; anti-PDL1, anti-programmed cell death-ligand 1.