Selective photodepletion of malignant T cells in extracorporeal photopheresis with selenorhodamine photosensitizers

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• 作者：Zachariah A. McIver^a ; ^{zmciver@wakehealth.edu" class="auth_mail" title="E-mail the corresponding author} ; Mark W. Kryman^b ; ^{markkrym@buffalo.edu" class="auth_mail" title="E-mail the corresponding author} ; Young Choi^a ; ^{ychoi@wakehealth.edu" class="auth_mail" title="E-mail the corresponding author} ; Benjamin N. Coe^a ; ^{bncoe@wakehealth.edu" class="auth_mail" title="E-mail the corresponding author} ; Gregory A. Schamerhorn^b ; ^{gregorys@buffalo.edu" class="auth_mail" title="E-mail the corresponding author} ; Michelle K. Linder^b ; ^{mklinder@buffalo.edu" class="auth_mail" title="E-mail the corresponding author} ; Kellie S. Davies^b ; ^{kdavies@buffalo.edu" class="auth_mail" title="E-mail the corresponding author} ; Jacqueline E. Hill^b ; ^{jehill@buffalo.edu" class="auth_mail" title="E-mail the corresponding author} ; Geri A. Sawada^c ; ^{sawada_geri_a@lilly.com" class="auth_mail" title="E-mail the corresponding author} ; Jason M. Grayson^d ; ^{grayson@wakehealth.edu" class="auth_mail" title="E-mail the corresponding author} ; Michael R. Detty^b ; ^{mdetty@buffalo.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：T cell malignancy ; P-glycoprotein ; Photopheresis ; Phototherapy ; Selenorhodamines
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 September 2016
• 年：2016
• 卷：24
• 期：17
• 页码：3918-3931
• 全文大小：2520 K

文摘

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.