Selective photodepletion of malignant T cells in extracorporeal photopheresis with selenorhodamine photosensitizers
| Autor: | Young A Choi, Jason M. Grayson, Gregory A. Schamerhorn, Mark W. Kryman, Geri A. Sawada, Kellie S. Davies, Michelle K. Linder, Zachariah A. McIver, Benjamin N. Coe, Michael R. Detty, Jacqueline E. Hill |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Light Lymphoma T-Lymphocytes T cell medicine.medical_treatment Clinical Biochemistry Population Pharmaceutical Science Biochemistry Article 03 medical and health sciences Interleukin 21 0302 clinical medicine Photopheresis Cell Line Tumor Organoselenium Compounds Drug Discovery Extracorporeal Photopheresis medicine Humans Cytotoxic T cell Photosensitizer ATP Binding Cassette Transporter Subfamily B Member 1 education Molecular Biology education.field_of_study Photosensitizing Agents Rhodamines Chemistry Organic Chemistry Mitochondria 030104 developmental biology medicine.anatomical_structure Verapamil 030220 oncology & carcinogenesis Immunology Cancer research Molecular Medicine CD8 |
| Zdroj: | Bioorganic & Medicinal Chemistry. 24:3918-3931 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2016.05.071 |
| Popis: | Extracorporeal photopheresis (ECP) has been used successfully in the treatment of erythrodermic cutaneous T cell lymphoma (CTCL), and other T cell-mediated disorders. Not all patients obtain a significant or durable response from ECP. The design of a selective photosensitizer that spares desirable lymphocytes while targeting malignant T cells may promote cytotoxic T cell responses and improve outcomes after ECP. A series of selenorhodamines built with variations of the Texas red core targeted the mitochondria of malignant T cells, were phototoxic to malignant T cells presumably via their ability to generate singlet oxygen, and were transported by P-glycoprotein (P-gp). To determine the selectivity of the photosensitizers in the ECP milieu, staphylococcal enterotoxin B (SEB)-stimulated and non-stimulated human lymphocytes were combined with HUT-78 cells (a CTCL) to simulate ECP. The amide-containing analogues of the selenorhodamines were transported more rapidly than the thioamide analogues in monolayers of MDCKII-MDR1 cells and, consequently, were extruded more rapidly from P-gp-expressing T cells than the corresponding thioamide analogues. Selenorhodamine 6 with the Texas red core and a piperidylamide functionality was phototoxic to >90% of malignant T cells while sparing >60% of both stimulated and non-stimulated T cells. In the resting T cells, (63 ± 7)% of the CD4+ T cell compartment, and (78 ± 2.5)% of the CD8+ cytotoxic T cell population were preserved, resulting in an enrichment of healthy and cytotoxic T cells after photodepletion. |
| Databáze: | OpenAIRE |
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