Biodistribution of hypericin in orthotopic transitional cell carcinoma bladder tumors: Implication for whole bladder wall photodynamic therapy

Abstract

In a recent clinical study, we reported a selective uptake of hypericin in superficial bladder tumors. The results suggested that hypericin, a potent photosensitizer, could be used not only for diagnosis but also for photodynamic therapy (PDT) of superficial bladder tumors. In the present study, we investigated the biodistribution of hypericin in an orthotopic rat bladder tumor model by assessing the extent of hypericin penetration and the kinetics of accumulation into rat bladder tumors and normal bladder wall. Hypericin (8 or 30 M) was instilled into the bladder via the catheter for 1, 2 or 4 hr. The fluorescence of hypericin in the bladder tumors and normal bladder was documented using fluorescence microscopy. In situ quantification of hypericin fluorescence in the tumor or normal bladder was performed using the laserinduced fluorescence technique. There was much more hypericin fluorescence in the tumor than in the normal bladder, with the tumor-to-normal-bladder ratio mounting to 12:1 after 4 hr of hypericin (30 M) instillation. Moreover, hypericin was retained in the tumor for at least 1 hr before it was gradually lost from the tissue. Microscopically, the fluorescence of hypericin was restricted to the urothelial tumor and normal urothelium without fluorescence in the submucosa and the muscle layers. Subsequently no hypericin was detected in plasma, indicating that under these conditions systemic side effects should not be expected. Because the conditions used in this study were similar to those used in our previous clinical study, it is therefore likely that whole bladder wall PDT in the clinic under these conditions will produce selective urothelial tumor destruction without causing damage to the underlying muscle layers.

Cellular Mechanisms and Prospective Applications of Hypericin in Photodynamic Therapy

“…For Hyp, several studies report a tumor-cell specific accumulation; for example, Kamuhabwa et al found a 12:1 ratio of fluorescence for specific tumor accumulation in superficial bladder tumors after 4 hr of instillation with 30 µM Hyp implicating the possibility of whole bladder wall PDT for superficial bladder tumors [89]. A tumor-specific retention was demonstrated by Xie et al in a human prostate model system.…”

Selective enrichment of hypericin in malignant glioma: Pioneering in vivo results

“…In vitro and in vivo photodynamic effects inducing apoptosis and/or necrosis of various malignant cells, such as human glioblastoma cell lines (22), human HL-60 promyelocytic leukaemia cells and CD4 + T-cells (23), rat bladder transitional cell carcinoma (24), human colon carcinoma and hepatoma cell lines (25) as well as human pancreatic cancer (26), were demonstrated. In vitro hypericin accumulates in glioma cells significantly higher than in neurones (27,28).…”

PDT of bladder carcinoma: the old and the new

“…10,11 . Following bladder instillation, hypericin remains limited to malignant or benign urothelium, but the ratio tumor to normal urothelium seems rather low in animal studies (0.6 -1.5, depending of the instillation conditions), by opposition to clinical observations in human 12,13 . According to hypericin sub-cellular localization in mitochondria and lysosomes, apoptosis as cell death mechanism may be involved in hypericin induced PDT 14 .…”