Anti-Scarring Drug Screening with Near-Infrared Molecular Probes Targeting Fibroblast Activation Protein-α

2018 ◽  
Vol 1 (6) ◽  
pp. 2054-2061 ◽  
Author(s):  
David C. Yeo ◽  
Christian Wiraja ◽  
Qingqing Miao ◽  
Xiaoyu Ning ◽  
Kanyi Pu ◽  
...  
Keyword(s):  
Drug Screening ◽  
Near Infrared ◽  
Fibroblast Activation Protein ◽  
Molecular Probes ◽  
Fibroblast Activation

scholarly journals Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryoichi Katsube ◽  
Kazuhiro Noma ◽  
Toshiaki Ohara ◽  
Noriyuki Nishiwaki ◽  
Teruki Kobayashi ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Near Infrared ◽  
Fibroblast Activation Protein ◽  
Therapeutic Resistance ◽  
Fibroblast Activation ◽  
Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

A novel fibroblast activation protein-targeted near-infrared fluorescent off–on probe for cancer cell detection, in vitro and in vivo imaging

2018 ◽  
Vol 6 (10) ◽  
pp. 1449-1451 ◽  
Author(s):  
Jie Xing ◽  
Qiuyu Gong ◽  
Ruifen Zou ◽  
Zihou Li ◽  
Yuanzhi Xia ◽  
...  
Keyword(s):  
Fluorescent Probe ◽  
In Vivo Imaging ◽  
Near Infrared ◽  
Fibroblast Activation Protein ◽  
Cell Detection ◽  
Fibroblast Activation ◽  
Design And Synthesis ◽  
Cancer Cell Detection

Design and synthesis of a novel fibroblast activation protein “off–on” near-infrared fluorescent probe for cell detection, in vitro and in vivo imaging.

Eliminating fibroblast activation protein-α expressing cells by photoimmunotheranostics

2021 ◽  
Author(s):  
Jiefu Jin ◽  
James D Barnett ◽  
Balaji Krishnamachary ◽  
Yelena Mironchik ◽  
Catherine K Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Near Infrared ◽  
Human Cancer ◽  
Fibroblast Activation Protein ◽  
Breast Cancer Tissue ◽  
Cancer Tissue ◽  
Specific Cell ◽  
Dependent Manner ◽  
Fibroblast Activation

Photoimmunotherapy (PIT) using an antibody conjugated to a near infrared dye IR700 is achieving significant success in target-specific elimination of cells. Fibroblast activation protein alpha (FAP-α) is an important target in cancer because of its expression by cancer associated fibroblasts (CAFs) as well as by some cancer cells. CAFs that express FAP-α have protumorigenic and immune suppressive functions. Using immunohistochemistry of human breast cancer tissue microarrays, we identified an increase of FAP-α+ CAFs in invasive breast cancer tissue compared to adjacent normal tissue. We found FAP-α expression increased in fibroblasts co-cultured with cancer cells. In proof-of-principle studies, we engineered human FAP-α overexpressing MDA-MB-231 and HT-1080 cancer cells and murine FAP-α overexpressing NIH-3T3 fibroblasts to evaluate several anti-FAP-α antibodies and selected AF3715 based on its high binding-affinity with both human and mouse FAP-α. After conjugation of AF3715 with the phthalocyanine dye IR700, the resultant antibody conjugate, FAP-α-IR700, was evaluated in cells and tumors for its specificity and effectiveness in eliminating FAP-α expressing cell populations with PIT. FAP-α-IR700-PIT resulted in effective FAP-α-specific cell killing in the engineered cancer cells and in two patient-derived CAFs in a dose-dependent manner. Following an intravenous injection, FAP-α-IR700 retention was three-fold higher than IgG-IR700 in FAP-α overexpressing tumors, and two-fold higher compared to wild-type tumors. FAP-α-IR700-PIT resulted in significant growth inhibition of tumors derived from FAP-α overexpressing human cancer cells. A reduction of endogenous FAP-α+ murine CAFs was identified at 7 days after FAP-α-IR700-PIT. FAP-α-targeted NIR-PIT presents a promising strategy to eliminate FAP-α+ CAFs.

scholarly journals Targeting the Tumor Microenvironment with Fluorescence-Activatable Bispecific Endoglin/Fibroblast Activation Protein Targeting Liposomes

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 370 ◽  
Author(s):  
Felista L. Tansi ◽  
Ronny Rüger ◽  
Ansgar M. Kollmeier ◽  
Markus Rabenhold ◽  
Frank Steiniger ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Fibroblast Activation Protein ◽  
Target Cells ◽  
Single Chain ◽  
High Concentration ◽  
Single Chain Antibody ◽  
Stromal Fibroblasts ◽  
Fibroblast Activation

Liposomes are biocompatible nanocarriers with promising features for targeted delivery of contrast agents and drugs into the tumor microenvironment, for imaging and therapy purposes. Liposome-based simultaneous targeting of tumor associated fibroblast and the vasculature is promising, but the heterogeneity of tumors entails a thorough validation of suitable markers for targeted delivery. Thus, we elucidated the potential of bispecific liposomes targeting the fibroblast activation protein (FAP) on tumor stromal fibroblasts, together with endoglin which is overexpressed on tumor neovascular cells and some neoplastic cells. Fluorescence-quenched liposomes were prepared by hydrating a lipid film with a high concentration of the self-quenching near-infrared fluorescent dye, DY-676-COOH, to enable fluorescence detection exclusively upon liposomal degradation and subsequent activation. A non-quenched green fluorescent phospholipid was embedded in the liposomal surface to fluorescence-track intact liposomes. FAP- and murine endoglin-specific single chain antibody fragments were coupled to the liposomal surface, and the liposomal potentials validated in tumor cells and mice models. The bispecific liposomes revealed strong fluorescence quenching, activatability, and selectivity for target cells and delivered the encapsulated dye selectively into tumor vessels and tumor associated fibroblasts in xenografted mice models and enabled their fluorescence imaging. Furthermore, detection of swollen lymph nodes during intra-operative simulations was possible. Thus, the bispecific liposomes have potentials for targeted delivery into the tumor microenvironment and for image-guided surgery.

scholarly journals Activatable Near-Infrared Fluorescent Probe for In Vivo Imaging of Fibroblast Activation Protein-alpha

2012 ◽  
Vol 23 (8) ◽  
pp. 1704-1711 ◽  
Author(s):  
Jinbo Li ◽  
Kai Chen ◽  
Hongguang Liu ◽  
Kai Cheng ◽  
Meng Yang ◽  
...  
Keyword(s):  
Fluorescent Probe ◽  
In Vivo Imaging ◽  
Near Infrared ◽  
Fibroblast Activation Protein ◽  
Fibroblast Activation ◽  
Fibroblast Activation Protein Alpha

An improved production and purification protocol for recombinant soluble human fibroblast activation protein alpha

2021 ◽  
Vol 181 ◽  
pp. 105833
Author(s):  
Cecy R. Xi ◽  
Arianna Di Fazio ◽  
Naveed Ahmed Nadvi ◽  
Michelle Sui Wen Xiang ◽  
Hui Emma Zhang ◽  
...  
Keyword(s):  
Human Fibroblast ◽  
Fibroblast Activation Protein ◽  
Fibroblast Activation ◽  
Fibroblast Activation Protein Alpha ◽  
Purification Protocol
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