Highly Selective Targeting of Ovarian Cancer with the Photosensitizer PEG‐m‐THPC in a Rat Model

Abstract

Photodynamic therapy (PDT) uses light to activate a photosensitizer that has been absorbed or retained preferentially by cancer cells after systemic administration. The first pegylated photosensitizer, tetrakis-(m-methoxypolyethylene glycol) derivative of 7,8-dihydro-5,10,15,20-tetrakis(3-hydroxyphenyl)-21,23-[H]-porphyrin (PEG-m-THPC), was evaluated to target selectively unresectable pelvic ovarian cancer bulks. Our goals were two-fold: (1) to establish an ovarian cancer model suitable for the development of debulking techniques and (2) to characterize the pharmacokinetics and tumor selectivity of PEG-m-THPC by fluorescence microscopy. NuTu-19 ovarian cancer cells were injected into the caudal part of the right psoas muscle of Fisher rats. Five weeks later, 30 mg/kg body weight of PEG-m-THPC was injected intravenously. Necropsy was performed between 4 and 10 days following drug application, and fluorescence of the tumor and various abdominal organs was measured. All rats developed bulky pelvic tumors with an average diameter of 2.6 cm (+/- 0.6 SD). Tumor masses were encompassing and infiltrating pelvic organs in a similar manner to ovarian cancers in humans. Fluorescence of cancer tissue was maximal 8-10 days following drug application. At 8 days, the tumor-to-tissue ratio was 40:1 (+/- 12 SE) for most abdominal organs. We conclude that this tumor model may be used for the study of new pelvic debulking techniques, and that the tumor selectivity of PEG-m-THPC is exceptionally high 8 days after drug application. Based on these data, we are currently developing a PDT-based minimally invasive debulking technique for advanced ovarian cancer.

Temoporfin (Foscan®, 5,10,15,20‐Tetra(m‐hydroxyphenyl)chlorin)—A Second‐generation Photosensitizer†,‡

“…Chinese hamster lung fibroblasts (223), human colorectal carcinoma cells (470) and xenografts (467) and murine leukemic cells L1210 (470). Other examples were studies on ovarian cancer cells (474) with very high tumor/tissue ratios (280) and liver tumor models (478), which showed no significant advantage. For example, m THPC‐MD 2000 in a rat colon adenocarcinoma resulted in an increase of PS concentration in the liver with time, thus resulting in a loss of tumor selectivity (478).…”

“…A NuTu‐19 ovarian cancer rat model was developed and used for testing debulking techniques. Use of m THPC‐PEG gave a very high (40 ± 12) tumor/tissue ratio after 8 days (280).…”

Mechanisms of porphyrinoid localization in tumors

“…These systems tend to increase plasma lifetimes and tumor uptake, by decreasing the drug accumulation in liver and other organs of the reticuloendothelial system [138][139][140]. A hydrophilic derivative of m-THPC bearing four polyethylene glycol side chains (6-PEG) was found to be highly selective for NuTu-19 ovarian tumors in rats [141], although no specificity was found in a rat liver tumor model, as a consequence of concomitant uptake by normal liver tissue [142]. Water-soluble Al(III)-phthalocyanine derivatives bearing a polyethylene glycol or a polyvinylalcohol chain coordinated to the aluminum ion were shown to be as efficient as Al(III)-phthalocyanine in CRM emulsion for the PDT treatment of EMT-6 tumors in mice [143].…”

Intraperitoneal photodynamic therapy for an ovarian cancer ascite model in Fischer 344 rat using hematoporphyrin monomethyl ether

“…( 7,8 ) Hornung et al . ( 9,10 ) showed that intraperitoneal PDT, as a minimally invasive procedure, could selectively debulk unresectable pelvic ovarian cancer in immunocompetent rats using the pegylated photosensitizer PEG‐m‐THPC, which was confirmed to be highly targeted to ovarian cancer in a rat model. Several clinical trials using first‐generation photosensitizer dihematoporphyrin ether and porfimer sodium showed the therapeutic effects of PDT in treating peritoneal malignancy including ovarian cancer.…”