Tao Pu

Obstetrics and Gynecology Hospital of Fudan University

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Congjian Xu

Yichang Central People's Hospital

Qiyu Liu

Chinese Academy of Medical Sciences & Peking Union Medical College

Fuyou Li

Fudan University

Xiaoyan Zhang

Chinese Academy of Medical Sciences & Peking Union Medical College

Yu Kang

Obstetrics and Gynecology Hospital of Fudan University

Guiling Li

Union Hospital

Jing Peng

Obstetrics and Gynecology Hospital of Fudan University

Mingxing Zhang

Northeastern University

Yuetian Pei

Fudan University

Yawei Liu

Fudan University

Cooperative Institutions

Obstetrics and Gynecology Hospital of Fudan University

Fudan University

Shanghai Medical College of Fudan University

Shanghai Jiao Tong University

Chinese Academy of Medical Sciences & Peking Union Medical College

Sun Yat-sen University

Southern Medical University

Zhejiang University

Wenzhou Medical University

Beijing Normal University

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A follicle-stimulating hormone receptor-targeted near-infrared fluorescent probe for tumor-selective imaging and photothermal therapy

Materials Today Bio (2023)

Qiyu Liu Tao Pu Xiaobo Zhou Jiaan Sun Wei Yuan

Late detection, peritoneal dissemination, chemoresistance and weak response to targeted therapeutics lead to high mortality in ovarian cancer. More efficient and specific tumor imaging and therapeutic agents are needed to improve the resection rate of surgery and to eliminate residual disease. The expression patterns of follicle-stimulating hormone (FSH) receptor make it a suitable target for ovarian cancer. Here, we report a strategy to develop an organic near-infrared probe for FSH receptor-targeted tumor imaging and photothermal therapy. The FSH-Rh760 probe was conjugated from the Rh760 fluorophore with the FSH β subunit 33-53 peptide. FSH-Rh760 specifically distinguished peritoneal metastatic ovarian cancerous foci from surrounding normal tissues with a high tumor-to-background ratio. The fluorescence signals in tumors peaked at 2 h and were cleared at 120 h postinjection. FSH-Rh760 treatment rapidly increased the abdomen temperature of mice up to ∼43 °C upon exposure to a near-infrared laser and effectively suppressed peritoneal tumor growth with tumor specificity. No significant systemic toxicities were observed. This study demonstrates the targeting ability and biocompatibility of FSH receptor-targeted theranostics and highlights its potential for clinical application in imaging-guided precision tumor resection and photothermal therapy to eliminate cancer lesions intraoperatively and postoperatively.

Fluorescence-lifetime imaging microscopy

Targeted Therapy

Bioluminescence imaging

Molecular Imaging

10.1016/j.mtbio.2023.100904

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Citations (4)

Gonadotropin-Releasing Hormone Receptor-Targeted Near-Infrared Fluorescence Probe for Specific Recognition and Localization of Peritoneal Metastases of Ovarian Cancer

Frontiers in Oncology (2020)

Qiyu Liu Xiaobo Zhou Wei Feng Tao Pu Xiaoping Li

Background: Peritoneal dissemination is common in advanced ovarian cancer. The completeness of cytoreduction is an independent prognostic factor. The intraoperative fluorescence imaging via tumor-specific near-infrared fluorophore might improve staging and surgical completeness. A promising target for ovarian cancer is the gonadotropin-releasing hormone receptor (GnRHR). This study aimed to develop a GnRHR-targeted near-infrared imaging probe for the detection of peritoneal metastases of ovarian cancer. Methods: Indocyanine green (ICG) was conjugated with GnRH antagonist peptide to develop an ovarian cancer-selective fluorescence probe GnRHa-ICG. GnRHR expression was detected in ovarian cancer tissues. The binding capacity of GnRHa-ICG and ICG was detected in both cancer cell lines and mouse models of peritoneal metastatic ovarian cancer using fluorescence microscopy, flow cytometry, and near-infrared fluorescence imaging. Results: Tissue microarray analysis revealed the overexpression of GnRHR in ovarian cancer. GnRH-ICG exhibited the binding capacity in a panel of cancer cell lines with different expression levels of GnRHR. In ovarian cancer mouse models, GnRHa-ICG signals were detected in peritoneal tumor lesions rather than normal peritoneal and intestines tissues. ICG showed intensive fluorescence signals in intestines. The tumor-to-muscle ratio and tumor-to-intestine ratio of GnRHa-ICG was 7.41 ± 2.82 and 4.37 ± 1.66, higher than that of ICG (4.60 ± 0.50 and 0.57 ± 0.06) at 2 h post administration. The fluorescence signal of peritoneal metastases peaked in intensity at 2 h and maintained for up to 48 h. ICG also showed a weak signal in the tumor lesions due to the enhanced permeability and retention effect, but the intensity decreased quickly within 48 h. Conclusions: The developed GnRHR-targeted imaging agent GnRHa-ICG could specifically detected peritoneal tumor lesions from normal peritoneal and intestines tissues because of the modification of GnRHa to ICG. The plateau period of GnRHa-ICG accumulation may be feasible for clinical applications in fluorescence-guided surgery. Our GnRHR imaging concept may be effective in other hormone-related tumors with upregulated GnRHR expression.

GNRHR

Indocyanine Green

Imaging agent

10.3389/fonc.2020.00266

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NIR-II Fluorescence Imaging for the Detection and Resection of Cancerous Foci and Lymph Nodes in Early-Stage Orthotopic and Advanced-Stage Metastatic Ovarian Cancer Models

ACS Applied Materials & Interfaces (2023)

Tao Pu Yawei Liu Yuetian Pei Jing Peng Zehua Wang

The high mortality rate of ovarian cancer can be primarily attributed to late diagnosis and early lymph node (LN) metastasis. The anatomically deep-located ovaries own intricate anatomical structures and lymphatic drainages that compromise the resolution and sensitivity of near-infrared first-window (NIR-I) fluorescence imaging. Reported NIR-II imaging studies of ovarian cancer focused on late-stage metastasis detection via the intraperitoneal xenograft model. However, given the significant improvement in patient survival associated with early-stage cancer detection, locating tumors that are restricted within the ovary is equally crucial. We obtained the polymer nanoparticles with bright near-infrared-II fluorescence (NIR-II NPs) by nanoprecipitation of DSPE-PEG, one of the ingredients of FDA-approved nanoparticle products, and benzobisthiadiazole, an organic NIR-II dye. The one-step synthesis and safe component lay the groundwork for its clinical translation. Benefiting from the NIR-II emission (∼1060 nm), NIR-II NPs enabled a high signal-to-noise (S/N) ratio (13.4) visualization of early-stage orthotopic ovarian tumors with NIR-II fluorescence imaging for the first time. Imaging with orthotopic xenograft allows a more accurate mimic of human ovarian cancer origin, thereby addressing the dilemma of translating existing nanoprobe preclinical research by providing the nano-bio interactions with early local tumor environments. After PEGylation, the desirable-sized probe (∼80 nm) exhibited high lymphophilicity and relatively extended circulation. NIR-II NPs maintained their accurate detection of orthotopic tumors, tumor-regional LNs, and minuscule (<1 mm) disseminated peritoneal metastases simultaneously (with S/N ratios all above 5) in mice with advanced-stage cancer in real time ∼36 h after systematic delivery. With NIR-II fluorescence guidance, we achieved accurate surgical staging in tumor-bearing mice and complete tumor removal comparable to clinical practice, which provides preclinical data for translating NIR-II fluorescence image-guided surgery.

Fluorescence-lifetime imaging microscopy

Nanoprobe

Ovarian tumor

10.1021/acsami.3c04949

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Autofluorescence-free in vivo imaging using a cyclometalated iridium complex with afterglow luminescence

New Journal of Chemistry (2023)

Yawei Liu Yanzhong Li Tao Pu Yuetian Pei Yiwei Fan

We present an iridium complex (SO-IrD) with afterglow luminescence by photochemical reaction driven by singlet oxygen.

Autofluorescence

Persistent luminescence

10.1039/d3nj03430e

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Gengnianchun Against H₂O₂‐Induced Oxidative Damage in KGN Cells via miR‐548m/FOXO3 Signaling

Journal of Cellular Biochemistry (2025)

Jun Li Yanqiu Rao Tao Pu Ting Xu Wenjun Wang

ABSTRACT Gengnianchun (GNC) is a traditional remedy used for diminished ovarian reserve, but its underlying mechanisms remain unclear. This study aimed to explore these mechanisms in human granulosa‐like cancer (KGN) cells pretreated with medicated rat serum (MRS) before H 2 O 2 exposure. MRS pretreatment significantly alleviated H 2 O 2 ‐induced cell damage, including improvements in cell viability, superoxide dismutase and GSH‐Px activities, and Bcl‐2 expression. Conversely, H 2 O 2 treatment increased apoptosis, autophagosomes, IL‐1β, TNF‐α, reactive oxygen species, malondialdehyde levels, and the expression of LC‐II/LC3‐I, Bax, and Beclin‐1. GEO database analysis revealed significant differential expression of several miRNAs, including miR‐548m. qPCR confirmed that MRS upregulated miR‐548m expression, which was downregulated by H 2 O 2 in a dose‐dependent manner. Preincubation with MRS prevented the decline in miR‐548m expression and mitigated H 2 O 2 ‐induced damage, including improvements in cell viability, apoptosis, autophagy, and oxidative stress. miR‐548m suppressed FOXO3 3'‐UTR luciferase activity, and anti‐miR‐548m enhanced it. Transfection with miR‐548m reduced FOXO3 mRNA and protein levels, while anti‐miR‐548m increased them. These findings suggest that GNC protects against H 2 O 2 ‐induced ovarian damage by modulating the miR‐548m/FOXO3 axis, triggering autophagy and apoptosis.

FOXO3

Viability assay

Malondialdehyde

10.1002/jcb.30701

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Olaparib increases chemosensitivity by upregulating miR-125a-3p in ovarian cancer cells

Research Square (Research Square) (2023)

Zehua Wang Tao Pu Yi Gao Jianwen Gao Congjian Xu

Abstract Objective Ovarian cancer has the highest mortality rate among malignant gynecological tumors. PolyADP-ribose polymerase (PARP) inhibitor maintenance therapy is the standard treatment. Olaparib is a widely used oral PARP inhibitor for tumors with BRCA mutations, but its effect and molecular mechanism in non-BRCA-mutated tumors remain unclear. Methods The antitumor effect of cisplatin alone or in combination with olaparib was analyzed in an ovarian cancer subcutaneous transplantation tumor model in nude mice. miRNA expression was analyzed through an miRNA array and real-time PCR. The effect of miR-125a-3p on proliferation in non-BRCA-mutated A2780 and OVCAR-3 ovarian cancer cells was detected with cell counting kit-8. Changes in cell invasion and migration ability were detected via cell scratch assays and Transwell assays. β-Galactosidase (SA-β-Gal) was used to detect expression changes related to cellular senescence. Cell cycle changes were detected by flow cytometry, and the expression of DNA damage repair proteins was detected by western blotting. Results In vivo, cisplatin plus olaparib significantly reduced tumor volume in mice subjected to subcutaneous tumor transplantation (A2780 and OVCAR-3 cells) (p < 0.01) and inhibited tumor growth. Additionally, olaparib induced senescence in A2780 and OVCAR-3 cells by upregulating miRNA-125a-3p. miRNA-125a-3p overexpression significantly inhibited invasion and migration in A2780 and OVCAR-3 cells. The cell cycle was blocked in G0/G1 phase, and the expression of the DNA damage protein gamma-H2AX (γ-H2AX) increased. Transfection of miRNA-125a-3p inhibitors reversed these phenotypes. Conclusions Olaparib induces DNA damage and senescence in ovarian cancer cells by upregulating miR-125a-3p expression, improving therapeutic sensitivity.

Olaparib

PARP inhibitor

10.21203/rs.3.rs-3254677/v1

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Citations (1)

Delineation of retroperitoneal metastatic lymph nodes in ovarian cancer with near-infrared fluorescence imaging

Oncology Letters (2017)

Tao Pu Liqin Xiong Qiyu Liu Minxing Zhang Qingqing Cai

Lymph node metastasis occurs in early-stage and late-stage ovarian cancers. Systematic lymphadenectomy is frequently conducted in an attempt to prevent disease progression. However, this method is associated with multiple complications. Therefore, it is necessary to develop a less invasive and more sensitive method for detecting lymphatic metastasis in ovarian cancer. The aim of the present study was to develop an appropriate fluorescent label for the analysis of lymphatic metastasis in vivo. To this end, epithelial ovarian cancer cells with high potential for lymph node metastasis were labeled using mCherry fluorescence. The cells were then imaged in vitro to determine the expression of mCherry, and in a mouse xenograft model in vivo. The data demonstrated the successful identification of metastatic retroperitoneal lymph nodes by co-localization with lymph nodes labeled by near-infrared fluorescence nanoparticles in vivo. These data provided important insights into the further development of methods for intra-operative identification of lymphatic metastasis and the mechanisms underlying lymphatic metastasis.

10.3892/ol.2017.6521

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Targeted Imaging of Endometriosis and Image-Guided Resection of Lesions Using Gonadotropin-Releasing Hormone Analogue-Modified Indocyanine Green

Molecular Imaging (2023)

Jing Peng Qiyu Liu Tao Pu Zhang Ming-xing Meng Zhang

In this study, we utilized gonadotropin-releasing hormone analogue-modified indocyanine green (GnRHa-ICG) to improve the accuracy of intraoperative recognition and resection of endometriotic lesions.Gonadotropin-releasing hormone receptor (GnRHR) expression was detected in endometriosis tissues and cell lines via immunohistochemistry and western blotting. The in vitro binding capacities of GnRHa, GnRHa-ICG, and ICG were determined using fluorescence microscopy and flow cytometry. In vivo imaging was performed in mouse models of endometriosis using a near-infrared fluorescence (NIRF) imaging system and fluorescence navigation system. The ex vivo binding capacity was determined using confocal fluorescence microscopy.GnRHa-ICG exhibited a significantly stronger binding capacity to endometriotic cells and tissues than ICG. In mice with endometriosis, GnRHa-ICG specifically imaged endometriotic tissues (EMTs) after intraperitoneal administration, whereas ICG exhibited signals in the intestine. GnRHa-ICG showed the highest fluorescence signals in the EMTs at 2 h and a good signal-to-noise ratio at 48 h postadministration. Compared with traditional surgery under white light, targeted NIRF imaging-guided surgery completely resected endometriotic lesions with a sensitivity of 97.3% and specificity of 77.8%. No obvious toxicity was observed in routine blood tests, serum biochemicals, or histopathology in mice.GnRHa-ICG specifically recognized and localized endometriotic lesions and guided complete resection of lesions with high accuracy.

Indocyanine Green

GNRHR

Ex vivo

Fluorescence-lifetime imaging microscopy

Gonadotropin-releasing hormone receptor

Histopathology

10.1155/2023/6674054

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Citations (2)

Identification of lymphatic metastasis-associated genes in a metastatic ovarian cancer cell line

Molecular Medicine Reports (2015)

Yu Kang Tao Pu Qingqing Cai Shanshan Hong Mingxing Zhang

Ovarian cancer (OC) is the gynecological malignancy with the highest rate of mortality, and lymphatic metastasis is a critical factor in disease recurrence and prognosis. In the current study, the SKOV‑3/LN403 cell line, which has high potential for lymph node metastasis was established as a result of four rounds of selection from retroperitoneal lymph nodes following intraperitoneal injections of SKOV‑3 ovarian adenocarcinoma cells. In comparison to the parental SKOV‑3 cell line, SKOV‑3/LN403 has a higher rate of proliferation, is more invasive and exhibits greater resistance to paclitaxel. Subsequently, a novel animal model of OC lymphatic metastasis was developed with SKOV‑3/LN403 cells and a high incidence of positive metastatic lymph nodes, peritoneal dissemination and bloody ascites were observed, which mimicked the clinical outcome of patients with OC. Analysis of the gene expression profiles of SKOV‑3 and SKOV‑3/LN403 cells identified several genes and pathways that may be involved in lymphatic metastasis of OC. The induction of focal adhesion kinase expression provides a potential therapeutic target for OC lymphatic metastasis.

10.3892/mmr.2015.3743

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Citations (3)