EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer

Ovarian cancer is the most lethal gynecological malignancy due to late detection associated with dissemination throughout the abdominal cavity. Targeted photodynamic therapy (tPDT) aimed at epithelial cell adhesion molecule (EpCAM), overexpressed in over 90% of ovarian cancer metastatic lesions, is a promising novel therapeutic modality. Here, we tested the specificity and activity of conjugates of EpCAM-directed designed ankyrin repeat proteins (DARPins) with the photosensitizer IRDye 700DX in in vitro and in vivo ovarian cancer models. EpCAM-binding DARPins (Ec1: Kd = 68 pM; Ac2: Kd = 130 nM) and a control DARPin were site-specifically functionalized with fluorophores or IRDye 700DX. Conjugation of anti-EpCAM DARPins with fluorophores maintained EpCAM-specific binding in cell lines and patient-derived ovarian cancer explants. Penetration of DARPin Ec1 into tumor spheroids was slower than that of Ac2, indicative of a binding site barrier effect for Ec1. DARPin-IRDye 700DX conjugates killed EpCAM-expressing cells in a highly specific and illumination-dependent fashion in 2D and 3D cultures. Furthermore, they effectively homed to EpCAM-expressing subcutaneous OV90 xenografts in mice. In conclusion, the high activity and specificity observed in preclinical ovarian cancer models, combined with a high specificity in patient material, warrant a further investigation of EpCAM-targeted PDT for ovarian cancer.

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An In Vitro and In Vivo Investigation of the Antimetastatic Effects of a Chinese Medicinal Decoction, Erxian Decoction, on Human Ovarian Cancer Models

Integrative Cancer Therapies ◽

10.1177/1534735412464519 ◽

2012 ◽

Vol 12 (4) ◽

pp. 336-346 ◽

Cited By ~ 9

Author(s):

Ellie S. M. Chu ◽

Stephen C. W. Sze ◽

Ho P. Cheung ◽

Qing Liu ◽

Tzi B. Ng ◽

...

Keyword(s):

Ovarian Cancer ◽

Human Ovarian Cancer ◽

Erxian Decoction ◽

Cancer Models

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Abstract 1525: SY-1365, a selective CDK7 inhibitor, exhibits potent antitumor activity against ovarian cancer models in vitro and in vivo

10.1158/1538-7445.am2018-1525 ◽

2018 ◽

Cited By ~ 1

Author(s):

Panagiotis A. Konstantinopoulos ◽

Graeme Hodgson ◽

Nisha Rajagopal ◽

Liv Johannessen ◽

Joyce F. Liu ◽

...

Keyword(s):

Ovarian Cancer ◽

Antitumor Activity ◽

Cancer Models

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Verteporfin-Loaded Lipid Nanoparticles Improve Ovarian Cancer Photodynamic Therapy In Vitro and In Vivo

Cancers ◽

10.3390/cancers11111760 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1760 ◽

Cited By ~ 12

Author(s):

Michy ◽

Massias ◽

Bernard ◽

Vanwonterghem ◽

Henry ◽

...

Keyword(s):

Ovarian Cancer ◽

Photodynamic Therapy ◽

Side Effects ◽

Laser Light ◽

Light Exposure ◽

Gynecological Cancer ◽

Ovarian Cancer Cells ◽

Pharmacokinetic Studies

Advanced ovarian cancer is the most lethal gynecological cancer, with a high rate of chemoresistance and relapse. Photodynamic therapy offers new prospects for ovarian cancer treatment, but current photosensitizers lack tumor specificity, resulting in low efficacy and significant side-effects. In the present work, the clinically approved photosensitizer verteporfin was encapsulated within nanostructured lipid carriers (NLC) for targeted photodynamic therapy of ovarian cancer. Cellular uptake and phototoxicity of free verteporfin and NLC-verteporfin were studied in vitro in human ovarian cancer cell lines cultured in 2D and 3D-spheroids, and biodistribution and photodynamic therapy were evaluated in vivo in mice. Both molecules were internalized in ovarian cancer cells and strongly inhibited tumor cells viability when exposed to laser light only. In vivo biodistribution and pharmacokinetic studies evidenced a long circulation time of NLC associated with efficient tumor uptake. Administration of 2 mg.kg−1 free verteporfin induced severe phototoxic adverse effects leading to the death of 5 out of 8 mice. In contrast, laser light exposure of tumors after intravenous administration of NLC-verteporfin (8 mg.kg−1) significantly inhibited tumor growth without visible toxicity. NLC-verteporfin thus led to efficient verteporfin vectorization to the tumor site and protection from side-effects, providing promising therapeutic prospects for photodynamic therapy of cancer.

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Inhibition of Inhibitor of Nuclear Factor-κB Phosphorylation Increases the Efficacy of Paclitaxel in in Vitro and in Vivo Ovarian Cancer Models

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-04-0958 ◽

2004 ◽

Vol 10 (22) ◽

pp. 7645-7654 ◽

Cited By ~ 92

Author(s):

Seiji Mabuchi ◽

Masahide Ohmichi ◽

Yukihiro Nishio ◽

Tadashi Hayasaka ◽

Akiko Kimura ◽

...

Keyword(s):

Ovarian Cancer ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Cancer Models

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Preclinical photodynamic therapy research in Spain 3: Localization of photosensitizers and mechanisms of cell deathin vitro

Journal of Porphyrins and Phthalocyanines ◽

10.1142/s1088424609000516 ◽

2009 ◽

Vol 13 (04n05) ◽

pp. 544-551 ◽

Cited By ~ 11

Author(s):

Magdalena Cañete ◽

Juan C. Stockert ◽

Angeles Villanueva

Keyword(s):

Cell Death ◽

Photodynamic Therapy ◽

Cell Cultures ◽

Cellular Localization ◽

Cell Damage ◽

Therapeutic Modality ◽

Action Mechanisms ◽

Cell Death Mechanisms

Photodynamic therapy (PDT) is a subject of increasing biomedical research and represents a very promising therapeutic modality for palliative or even curative treatment of some superficial or endoscopically accessible tumors. In addition to the first photosensitizers (PSs) applied (hematoporphyrin-based drugs), second generation PSs with improved photophysical and photobiological properties are now studied using cell cultures, experimental tumors and clinical trials. On the other hand, there is a growing interest in the analysis of cell death mechanisms by apoptosis, which is especially relevant in oncology, because many anticancer drugs work, at least in part, by triggering apoptosis in neoplastic cells both in vitro and in vivo. The evaluation of cell death mechanisms is an important parameter to determine the efficacy and the potential toxicity of a treatment, allowing better adjustment of protocol. Using cell cultures, our research team has studied the mechanisms of cell damage and death implicated in the photodynamic processes, as well as the relationship between the cellular localization of the PS and the organelle damage during photosensitization. The results obtained in our laboratory provide a deeper understanding on the action mechanisms that lead to cell inactivation by PDT, and also allow selection of PSs with higher potential for clinical application than those currently in use.

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Targeted Photodynamic Therapy and Photochemical Internalization of Human Head and Neck Cancer: a preclinical study in vitro and in vivo

10.33612/diss.167799500 ◽

2021 ◽

Author(s):

◽

Wei Peng

Keyword(s):

Head And Neck Cancer ◽

Photodynamic Therapy ◽

Head And Neck ◽

Neck Cancer ◽

Human Head ◽

Preclinical Study ◽

Photochemical Internalization ◽

Targeted Photodynamic Therapy

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Targeted photodynamic therapy selectively kills activated fibroblasts in experimental arthritis

Rheumatology ◽

10.1093/rheumatology/keaa295 ◽

2020 ◽

Vol 59 (12) ◽

pp. 3952-3960 ◽

Cited By ~ 1

Author(s):

Daphne N Dorst ◽

Mark Rijpkema ◽

Marti Boss ◽

Birgitte Walgreen ◽

Monique M A Helsen ◽

...

Keyword(s):

Photodynamic Therapy ◽

Therapeutic Potential ◽

Ex Vivo ◽

Synovial Fibroblasts ◽

Knee Joints ◽

Specific Cell ◽

Collagen Induced Arthritis ◽

Targeted Photodynamic Therapy

Abstract Objective In RA, synovial fibroblasts become activated. These cells express fibroblast activation protein (FAP) and contribute to the pathogenesis by producing cytokines, chemokines and proteases. Selective depletion in inflamed joints could therefore constitute a viable treatment option. To this end, we developed and tested a new therapeutic strategy based on the selective destruction of FAP-positive cells by targeted photodynamic therapy (tPDT) using the anti-FAP antibody 28H1 coupled to the photosensitizer IRDye700DX. Methods After conjugation of IRDye700DX to 28H1, the immunoreactive binding and specificity of the conjugate were determined. Subsequently, tPDT efficiency was established in vitro using a 3T3 cell line stably transfected with FAP. The biodistribution of [111In]In-DTPA-28H1 with and without IRDye700DX was assessed in healthy C57BL/6N mice and in C57BL/6N mice with antigen-induced arthritis. The potential of FAP-tPDT to induce targeted damage was determined ex vivo by treating knee joints from C57BL/6N mice with antigen-induced arthritis 24 h after injection of the conjugate. Finally, the effect of FAP-tPDT on arthritis development was determined in mice with collagen-induced arthritis. Results 28H1-700DX was able to efficiently induce FAP-specific cell death in vitro. Accumulation of the anti-FAP antibody in arthritic knee joints was not affected by conjugation with the photosensitizer. Arthritis development was moderately delayed in mice with collagen-induced arthritis after FAP-tPDT. Conclusion Here we demonstrate the feasibility of tPDT to selectively target and kill FAP-positive fibroblasts in vitro and modulate arthritis in vivo using a mouse model of RA. This approach may have therapeutic potential in (refractory) arthritis.

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