Minimally-invasive debulking of ovarian cancer in the rat pelvis by means of photodynamic therapy using the pegylated photosensitizer PEG-m-THPC

Abstract

Summary Interstitial photodynamic therapy (PDT) using the pegylated photosensitizer PEG-m-THPC was evaluated as a minimally-invasive procedure to selectively debulk unrespectable pelvic ovarian cancer (NuTu-19) in immunocompetent rats. To assess tumour selectivity, PEGm-THPC at dosages of 0.3, 3.0 and 30 mg kg -1 body weight was administered intravenously to 30 rats 4 weeks following tumour induction. Eight days later laser light at 652 nm and optical doses ranging from 100 to 900 J cm -1 diffuser-length was delivered by an interstitial cylindrical diffusing fibre inserted blindly into the pelvis. Three days following light application, the volume of necrosis was measured and the damage to pelvic organs was assessed histologically on cross sections. For analysis of survival, 20 tumour-bearing rats received PDT using drug doses of 3 or 9 mg kg -1 body weight and an optical dose of 900 J cm -1 diffuser-length, whereas ten untreated tumour-bearing rats served as controls. The histological assessment of PDT induced necrosis showed a non-linear dose-response for both the photosensitizer dose and the optical dose. The lowest drug dose activated with the highest optical dose did not induce more necrosis than seen in tumour-bearing control animals. The same optical dose induced necrosis of 17 mm in diameter using 30 mg kg -1 and 11 mm using 3 mg kg -1 photosensitizer. The optical threshold for induction of significant necrosis was between 100 and 300 J cm -1 diffuser-length for 30 mg kg -1 and between 300 and 500 J cm -1 for 3 mg kg -1 PEG-m-THPC. Significant damage to normal pelvic organs was only seen if 30 mg kg -1 photosensitizer was activated with optical doses of 700 J cm -1 or more. In the survival study, all treated animals survived PDT for at least 2 weeks and the intestinal and urinary tract remained functional. No clinical signs of blood vessel or nerve injury were observed. Mean overall survival of untreated tumour-bearing rats was 25.0 ± 4.5 days compared to 38.4 ± 3.8 days and 40.0 ± 3.6 days for rats treated with 3 mg kg -1 or 9 mg kg -1 PEG-m-THPC mediated PDT respectively (P < 0.05). We conclude that PEG-m-THPC mediated PDT has a favourable therapeutic window and that this minimally-invasive procedure can reduce pelvic cancer bulks effectively and selectively.

PEG-m-THPC-mediated Photodynamic Effects on Normal Rat Tissues¶

“…Considering that this PDT dose induces maximal damage to all tissues, this steady temperature increase may be a sign of a systemic toxic reaction. This assumption can be supported by a previous finding where two of four tumor-bearing rats died during PDT with 30 mg/kg PEG-m-THPC activated with 900 J/cm diffuser length (2). Since the temperature never exceeded 39ЊC, damage to tissue was not induced by hyperthermia but by a PDTmediated phototoxic reaction.…”

“…uated (1,2). PDT is based on the preferential uptake and/or retention of a photosensitizer by malignant tissues (3)(4)(5).…”

“…Using the same tumor model, we developed a minimally invasive PEG-m-THPCmediated treatment modality for advanced stages of ovarian cancer. We demonstrated that 8 days following photosensitization PEG-m-THPC (9 mg/kg body weight)-mediated PDT has a favorable therapeutic window and that this minimally invasive procedure can selectively reduce pelvic cancer bulks, resulting in significant prolongation of survival (2). Tumors of various pelvic organs (rectum, anus, vulva, vagina, uterine cervix and endometrium, urinary bladder, ureter, prostate) may be treated by PDT.…”

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.…”

Intérêt et place de la thérapie photodynamique en gynécologie

“…De nombreuses études expérimentales animales rapportent l'efficacité de la PDT dans la carcinose péritonéale d'origine ovarienne [8,19,49,50]. Dans un modèle animal de carcinose péritonéale d'origine ovarienne, Hornung et al ont montré une efficacité significative en terme de survie, par rapport aux animaux témoins, de la PDT réalisée avec du Foscan W administré par voie intraveineuse, ou un de ses dérivés [49,50]. Une étude de Major en 2002 a permis de déterminer la dose thérapeutique maximale d'ALA (50 mg/kg) administrée par voie intrapéritonéale (IP) chez le rat.…”