ABSTRACT
This study attempted the liposomalization of coproporphyrin I (CPI) with hydrophobic properties. Liposomalization of CPI was not successful at any pH when using lactate buffer. In contrast, when using 9% sucrose/10mM phosphate buffer (pH 7.8), CPI liposomes (Lipo-CPI) and polyethyleneglycol (PEG) modified liposomes (PEG-CPI) were prepared with a high entrapment ratio of CPI and small particle size. Plasma CPI concentration at 6h after PEG-CPI injection were 6.5-fold greater than that after the injection of Lipo-CPI. In tumors, the CPI concentration was higher after PEG-CPI injection than after Lipo-CPI or CPI solution. Therefore, PEG-CPI was likely to increase blood circulation and achieve greater accumulation of CPI in the tumor. When loaded into tumor cells, photosensitizers generate singlet oxygen during laser irradiation, resulting in the induction of necrosis in the cells. The order of magnitude of CPI tumor cells uptake was PEG-CPI>Lipo-CPI>CPI solution. Thus, the PEG modification of CPI liposomes improved its tumor cell uptake. Furthermore, it is likely that the order of the ability to produce singlet oxygen was PEG-CPI [symbol: see text] Lipo-CPI>CPI solution. The cytotoxicity of PEG-CPI was significantly greater than the other formulations, suggesting that the cytotoxicity reflected the CPI concentration in tumor cells. In conclusion, PEG-CPI was confirmed to show effective tissue distribution, elevated CPI concentration in the tumor cells, to produce singlet oxygen, and cytotoxicity by PDT.
Subject(s)
Coproporphyrins/pharmacology , Coproporphyrins/toxicity , Dermatitis, Phototoxic , Liposomes/chemistry , Animals , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/therapy , Cell Survival/drug effects , Cell Survival/radiation effects , Coproporphyrins/chemistry , Drug Carriers , Electrochemistry , Light , Male , Mice , Neoplasm Transplantation , Particle Size , Photochemotherapy , Photons , Reactive Oxygen Species/chemistry , Tissue Distribution , Zinc/chemistryABSTRACT
We studied the antitumor effects of photodynamic therapy (PDT) with Zincphyrin, coproporphyrin III with zinc, derived from Streptomyces sp. AC8007, in vitro and in vivo. The photokilling effect of Zincphyrin in the presence of 0.78-100 microg/ml with visible light of 27.2 mW x min/cm2 for 10 min was lower than the hematoporphyrin (Hp) used as a control with L5178Y or sarcoma-180 cells. On the other hand, Zincphyrin apparently reduced tumor growth after intraperitoneal injection at doses of 12.5-50 mg/kg with light irradiation of 75.48 mW x min/cm2 for 10 min in sarcoma-180-bearing mice. Although no mice treated with Zincphyrin died, Hp did cause the death of mice. In B-16 melanoma-bearing mice, both Zincphyrin and Hp had a similar phototherapic effect. Further improvement of the phototherapic effect was observed with the continuous administration of Zincphyrin at 12.5 mg/kg per day for 3 days. The concentration of Zincphyrin in the serum reached a maximum level of 16 microg/ml within 20 min, and the concentration remained at 4.2 microg/ml at 1 hour after the onset of treatment, indicating its rapid action in the body. No animals died after the intraperitoneal administration of Zincphyrin at 100 mg/kg plus exposure to light of 10 mW x min/cm2 for 2 hours, and the body weight of the mice did not decrease. In contrast, all animals receiving 100 mg/kg of Hp under the same conditions died. These results indicate that Zincphyrin would be a useful photosensitizer with low phototoxicity.