Experimental study of antiangiogenic and photodynamic therapies combination for treatment of peritoneal carcinomatosis: preliminary results

Aim: To create adequate orthotopic model of peritoneal carcinomatosis in rats using a transplantable rat tumor M-1 sarcoma, to assess the early tumor response after intraperitoneal photodynamic and/or antiangiogenic therapy for peritoneal carcinomatosis. Methods: In 14–18 days after intraperitoneal inoculation, eighteen tumor-bearing animals were divided into three groups and undergone intraperitoneal photodynamic therapy and/or antiangiogenic therapy. Assessment of the tumor posttreatment changes was performed using a method of vital staining with Evans blue, MRI-monitoring and morphologic investigation. Results: Percentage of necrosis in disseminated tumors of animals undergone combination therapy significantly higher then after each of the methods alone and achieved 89.46% vs 41.47% after antiangiogenic therapy and 69.73% after photodynamic therapy. Contrast-enhanced MRI showed entirely necrotic tumor nodes in rats undergone the combination therapy. Morphologic study confirmed that tumor response after combination therapy was characterized by maximal spread of necrotic and inflammatory changes in tumor. Conclusion: Preliminary results demonstrate enhance of the treatment outcome after combination of antiangiogenic and intraperitoneal photodynamic therapies for peritoneal carcinomatosis in rats

Photodynamic efficacy of topical application of chlorin e6 — polyvinyl pyrrolidone complex in tumor-bearing rats

Aim: To evaluate the antitumor efficacy of photodynamic therapy with ointment form of chlorin e6 — polyvinyl pyrrolidone complex. Methods: 2 or 5% chlorin e6 ointment was applied on the surface of rat SM-1 tumor for 15 min — 5 h, and then tumors were scored for photosensitizer accumulation and tissue damage induced by laser irradiation. Results: Selectivity of chlorin e6 accumulation in tumor tissues considerably increases when photosensitizer was applied topically compared with intravenous administration. Antitumor efficacy of photodynamic therapy using topical application of chlorin e6 — polyvinyl pyrrolidone complex is just as high as upon intravenous administration of the preparation. Conclusion: The level of tissue accumulation of chlorin e6 — polyvinyl pyrrolidone complex administered in ointment form allows to carry out fluorescence diagnosis and PDT of superficially localized malignant tumors.Цель: исследовать противоопухолевую эффективность фотодинамической терапии с аппликационной формой комплекса хлорин е6 — поливинилпирролидон. Методы: мазь, содержащую 2 или 5% хлорина е6, наносили на поверхность опухоли Са М-1 крыс на 15 мин–5 ч, а затем определяли накопление фотосенсибилизатора и повреждение опухоли лазерным излучением. Результаты: при местном введении фотосенсибилизатора избирательность накопления хлорина е6 в опухолевых тканях значительно возрастала, по сравнению с внутривенным введением. По противоопухолевой эффективности фотодинамической терапии местное применение комплекса хлорин е6 — поливинилпирролидон не уступало внутривенному введению препарата. Выводы: уровень накопления фотосенсибилизатора в тканях крыс при использовании мазевой формы комплекса хлорин е6 — поливинилпирролидон позволяет проводить как флуоресцентную диагностику, так и фотодинамическую терапию поверхностно расположенных злокачественных опухолей

Fluorescent diagnosis and photodynamic therapy for C6 glioma in combination with antiangiogenic therapy in subcutaneous and intracranial tumor models

Objective: Investigating the distinctions pharmacokinetics of chlorin e6 conjugated with polyvinyl pyrrolidone photosensitizer (Ce6CPPPS)in healthy and tumor tissues of rat brain and evaluating the antitumor efficacy of combination treatment for C6 rat glioma including photodynamic (PDT) and antiangiogenic therapy (AAT). Materials and Methods: The study was performed on 50 white random-bred rats in subcutaneous and intracranial models of C6 glioma. Photosensitizer (PS) Ce6CPPPS single injection at a dose of 2.5 mg/kg was made into the animal’s caudal vein. The PS accumulation level in brain tissues and C6 rat glioma was measured with spectral fluorescence technique using LESA-01-Biospek spectrum analyser (Russian Federation, Moscow; λ = 632.8 nm). Photoirradiation of intracranial and subcutaneous C6 glioma was carried out with a light exposure dose of 50 J/cm2 (IMAF-Axicon, Republic of Belarus; λ = 661 nm). AAT drug bevacizumab, single injection was made intravenously at a dose of 10 mg/kg 24 h after tumor photoirradiation. The criteria for efficacy evaluation were mean survival time (MST) and median survival of the animals in the study group vs the control and the ­percentage of tumor necrosis areas induced by the above-mentioned treatment. Results: The optimal time for photoirradiation of intracranial C6 glioma is 0.5 h after Ce6CPPPS injection. The combination therapy group demonstrated a statistically significant MST increase (38.4 ± 4.39 days) compared with the PDT group (29.2 ± 3.5 days) (p = 0.02) and the AAT group (27.1 ± 2.74 days) (p = 0.02). Necrosis areas in tumor tissue were as follows: the intact control — 10.0 ± 2.55%, PDT — 54.87 ± 6.95% (p = 0.003), AAT — 57.83 ± 6.53% (p = 0.003) and combination therapy — 89.43 ± 5.57% (p = 0.001). Conclusions: This paper is the first report about feasibility of efficient use of PDT with a PS of chlorin series and AAT with bevacizumab for the treatment of brain tumors in experimental models. Key Words: Ce6CPPPS, bevacizumab, glioma C6, photodynamic therapy, antiangiogenic therapy

The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro

Aim: To evaluate the effect of cell oxygenation on photocytotoxicity of a novel tricarbocyanine indolenine dye covalently bound to glucose (TICS). Methods: HeLa cells were incubated with 5 µM TICS, 2 h later irradiated by laser at 740 nm with a light dose of 10 J/cm2, delivered at a power density of 10, 20, 25 or 30 mW/cm2, in air or in argon atmosphere, and then scored for viability. Results: The photocytotoxicity of TICS increased dramatically as the power density was reduced. Under hypoxia TICS-photosensitized cell death was determined but its value was lowered, compared to photoirradiation in the air. Conclusion: Photosensitizing effect of TICS is only partially dependent on the oxygenation of tumor cells.Цель: исследование влияния оксигенации клеток на фотоцитотоксичность нового трикарбоцианинового индоленинового красителя, ковалентно связанного с глюкозой (ТИКС). Методы: клетки HeLa инкубировали в среде, содержащей 5 мкМ ТИКС, а через 2 ч на воздухе или в атмосфере аргона облучили светом лазера с длиной волны 740 нм в дозе 10 Дж/см2 при плотности мощности 10, 20, 25 или 30 мВт/см2 . Затем была определена их жизнеспособность. Результаты: фотоцитотоксичность ТИКС значительно возрастала при уменьшении плотности мощности облучения. В условиях гипоксии гибель клеток, фотосенсибилизированная ТИКС, сохранялась, но несколько уменьшалась в сравнении с результатами фотооблучения на воздухе. Выводы: фотосенсибилизирующий эффект ТИКС только частично зависит от оксигенации опухолевых клеток