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.

Apoptosis Following Photodynamic Tumor Therapy: Induction, Mechanisms and Detection

“…Photodynamic therapy (PDT) utilizes this effect to treat several types of early stage tumors and other diseases [4][5][6][7]. Typically, PDT involves a two step protocol; firstly, a lightabsorbing compound (the photosensitizer) is taken up (mostly) specifically by target cells [8][9][10][11][12], secondly, the sensitizer is activated by irradiation with visible light of the appropriate energy [13][14][15]. Since the light penetration depth in tissue increases with the wavelength, an absorption maximum at the highest possible wavelength (red / near infrared) is taken for activation of the sensitizer [16][17][18][19][20].…”

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

“…Significant delay in tumor regrowth was achieved following meta-tetrahydroxyphenylchlorin-mediated intraperitoneal PDT and a toxicity study has determined the maximum tolerable light dose of ALA-mediated intraperitoneal PDT. (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.…”

Nanostructural Hybrid Sensitizers for Photodynamic Therapy

“…Hornung et al have also studied the pegylated derivative of Foscan and proposed it as an efficient photodynamic agent [17,49]. The addition of four long PEG2000 side chains linked to mTHPC through a triazine group produced a tetrakis-(mmethoxypolyethylene glycol) derivative of 7,8-dihydro-5,10,15,20-tetrakis(3-hydroxyphenyl)-21-23-[H]-porphyrin (PEG-mTHPC).…”