Selective photodepletion of malignant T cells in extracorporeal photopheresis with selenorhodamine photosensitizers.
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.
Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States. Electronic address: zmciver@wakehealth.edu.
Zachariah A
ZA
McIver
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States. Electronic address: markkrym@buffalo.edu.
Mark W
MW
Kryman
Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States. Electronic address: ychoi@wakehealth.edu.
Young
Y
Choi
Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States. Electronic address: bncoe@wakehealth.edu.
Benjamin N
BN
Coe
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States. Electronic address: gregorys@buffalo.edu.
Gregory A
GA
Schamerhorn
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States. Electronic address: mklinder@buffalo.edu.
Michelle K
MK
Linder
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States. Electronic address: kdavies@buffalo.edu.
Kellie S
KS
Davies
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States. Electronic address: jehill@buffalo.edu.
Jacqueline E
JE
Hill
Drug Disposition, Eli Lilly and Company, Indianapolis, IN 46285, United States. Electronic address: sawada_geri_a@lilly.com.
Geri A
GA
Sawada
Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States. Electronic address: grayson@wakehealth.edu.
Jason M
JM
Grayson
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States. Electronic address: mdetty@buffalo.edu.
Michael R
MR
Detty
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008027:Light; D008223:Lymphoma; D008928:Mitochondria / Q000378:metabolism; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D017893:Photopheresis; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D012235:Rhodamines / Q000138:chemical synthesis / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016566:Organoselenium Compounds; D017319:Photosensitizing Agents; D012235:Rhodamines; D014700:Verapamil
P-glycoprotein; Photopheresis; Phototherapy; Selenorhodamines; T cell malignancy