A safety study of a novel photosensitizer, sinoporphyrin sodium, for photodynamic therapy in Beagle dogs

Abstract

Sinoporphyrin sodium (DVDMS) is a novel hematoporphyrin-like photosensitizer developed for photodynamic therapy (PDT), an effective therapeutic modality for tumor treatment; however, the safety of photosensitizer-based PDT is always of great concern. The purpose of the current study was to investigate the potential repeated-dose toxicity and describe the toxicokinetic process of DVDMS-based PDT in Beagle dogs. The dogs were randomly allocated to six groups, and then were administrated a DVDMS preparation intravenously at dose levels of 0, 1, 3, 9, 1 and 9 mg per kg body weight, respectively; then, the latter two groups were illuminated 24 h later with a 630 nm laser for 10 min, once every seven days for 5 weeks. During the study period, clinical signs, mortality, body weight, food consumption, body temperature, ophthalmoscopy, hematology, serum biochemistry, urinalysis, electrocardiograms, toxicokinetics, organ weights, gross anatomy and histopathology were examined. After the administration, no deaths were observed; however, the dogs that received PDT showed skin swelling and ulceration, indicating that DVDMS-PDT induced a phototoxic effect. DVDMS led to an increase in blood coagulation in dogs in the 9 mg kg(-1) group and in the two PDT groups on Day 35, whereas it induced a decrease in dogs in the 3 mg kg(-1) group and in the two PDT groups on Day 49. The toxicokinetic study showed that the systematic exposure of DVDMS in dogs occurred in a dose-dependent manner, and DVDMS did not accumulate in blood plasma. The DVDMS-based PDT group showed no obvious treatment-related pathological changes; however, slight or mild brown-and-yellow pigmentation of DVDMS (or its metabolite) was observed to deposit in the liver, spleen, local lymph nodes and marrow of dogs in the mid- and high-dose groups, as well as the high-dose PDT group. In females, the absolute and relative spleen weights increased in dogs in the 9 mg kg(-1) DVDMS groups with and without PDT during the treatment and recovery period, respectively. The target organs are presumed to be the liver and immune organs (spleen, bone marrow and lymph nodes), while all of the responses were slight. Based on the results above, the no-observed-adverse-effect level (NOAEL) was considered to be 1 mg kg(-1), and DVDMS-PDT appeared to be a safe and promising anti-tumor therapy in the clinic.

Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents

“…PS for PDT may elicit intrinsic adverse reactions, may employ drug formulations with some toxicity, or may show toxicity as a consequence of the illumination protocol. This last concern is specific of PDT and requires the design of safety evaluation strategies that take into consideration the combination of drug and light [ 6 , 7 ].…”

Sinoporphyrin sodium is a promising sensitizer for photodynamic and sonodynamic therapy in glioma

“…The death of mice was verified as follows: The breath, heartbeat and circulation were permanently stopped and the onset of rigor mortis was confirmed. According to previous studies, the maximum concentration of DVDMS in tumors occurs at 24 h after intravenous injection through the tail vein (10,11). Therefore, PDT and SDT were performed at this time in the present study (Fig.…”

“…Previous studies have revealed that DVDMS has good water solubility and stability, is widely applicable in PDT and SDT, and shows good therapeutic effects against tumors, bacteria and skin diseases (11,39). Preclinical safety evaluation showed that DVDMS as a good safety profile in SD rats and beagles (10,40). Furthermore, there are two registered phase I clinical trials investigating DVDMS for the treatment of esophageal cancer and advanced solid tumors (no.…”

“…DVDMS has good water and lipid solubility, and can be activated by both laser and ultrasound. Preliminary studies have demonstrated that DVDMS is an effective and safe photosensitizer for PDT and inhibits antitumor effects both in vitro and in vivo (10,11). Furthermore, previous studies revealed that DVDMS can achieve therapeutic effects following ultrasound activation (12,13).…”

Fighting Cancer with Corroles

“…32 It is quite surprising, however, that very little is known about the systemic toxicities of the parent metal complexes (metalloporphyrins). 33–34 One likely explanation is that many of them undergo demetallation under biological conditions. 35–36…”