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Metronomic photodynamic therapy (mPDT) is a new type of photodynamic therapy (PDT) that has received much attention in recent years. It has a similar therapeutic mechanism to traditional PDT, i.e. the photosensitizer is irradiated by visible light irradiation with a specific wavelength, and tissue oxygen photochemical reactions produce cytotoxic reactive oxygen species (ROS) that selectively kill rapidly proliferating tumor cells. Unlike traditional PDT, the photosensitizer and light in mPDT are continuously transmitted at a low time and at a low rate, and the specificity of tumor treatment is enhanced by apoptosis. In this paper, the current researches on the in vitro and in vivo effects and mechanisms of mPDT, as well as the research status of photosensitizers and light sources for in vivo research, were reviewed, with a view to understanding the existing mPDT technology and providing reference for the further studies. This review paper can provide a basic for promoting the clinical research and application of mPDT.
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Objective To explore the effects of 3-mercaptopropionic acid (3-MPA) coated CdSe-CdS/ZnS quantum dots (3-MPA-QDs) on the uptake , proliferation and migration of human umbilical vein endothelial cells (HUVEC), and to study the biotoxicity of 3-MPA-QDs, so as to provide the theoretical basis for the development of quantum dot photosensitizers . Methods The short-term ( 6 h ) uptakes of 3-MPA-QDs and the small molecule photosensitizer protoporphyrin IX (PpIX) in HUVEC cells were real-time observed and compared by a laser confocal scanning microscope. Besides, the uptakes within 48 h as well as the effects of the uptake on morphology and proliferation of HUVEC were also observed. The effect of 3-MPA-QDs on the migration of HUVEC cells within 24 h was observed using a grid dish. LysoTrackerTM Deep Red was used to label lysosomes, and the endocytosis mechanism of 3-MPA-QDs was observed by fluorescence co-localization. Results The fluorescence of 3-MPA-QDs in the HUVEC showed a continuous rising trend within 6 h, weakened after 24 h, and then turned weaker after 48h of the uptake, which is different from the"up-saturation"absorption pattern of PpIX. However, the fluorescence signal was still clear and bright which indicate 3-MPA-QDs were passaged into newborn cells. Migration experiments showed that the target cells carrying 3-MPA-QDs migrated 50 μm grids within 24 h, indicating the cell migration ability was not significantly affected. Co-localization results showed that 3-MPA-QDs localized in lysosomes. Conclusions The 3-MPA-QDs localized in lysosome, and they were easy to be absorbed and hard to be excreted by HUVEC. However, no obvious effects of 3-MPA-QDs were observed on cell proliferation and migration.
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Objective To evaluate the influence of dosage,operation method,adverse reaction of endoscopic photodynamic therapy (EPDT) on its therapeutic efficacy in rabbit models of in-situ rectal cancer,so as to provide preclinical basis of photodynamic therapy for rectal cancer.Methods 20 rabbits with in-situ VX2 rectal cancer were randomly divided into control group,PDT low dose group,intermediate dose group,and high dose group.At 24 h before PDT,photosensitizer (hermimether) was intravenously injected into rabbits.630 nm semiconductor laser was used as light source.The growth of the tumor was observed by conventional endoscopy and endoscopic ultrasonography,and the survival time,general conditions and adverse reactions were recorded.The histopathological changes were observed by hematoxylin-eosin staining.Results At 7 d after PDT,the total response rates of low dose,intermediate dose and high dose group respectively were 40％ (slight),80％ (60％ remarkable and 20％ slight),100％ (20％ remarkable and 80％ slight).The average survival times of the three groups were 14 d,10 d and 5 d,respectively.The main adverse reactions were inflammation,intestinal obstruction,intestinal peristalsis loss and death.Conclusions The dosage of PDT is an important factor to influence the curative effect.The appropriate dose of PDT will have a better effect on the treatment of rectal cancer.A thorough study of these problems is helpful to the clinical application of PDT in the treatment of rectal cancer.
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Objective To explore the killing effect of dielectric barrier discharge (DBD) plasma on tumor cells and to analyze the DBD-induced apoptosis mechanism.Methods Thiazolyl blue tetrazolium bromide (MTT) assay method was used to detect the killing effect of low temperature plasma on the cytotoxicity of normal spleen leukocytes and acute promyelocytic leukemia cells (LT-12) at different doses.The changes of reactive oxygen species (ROS) level were measured after plasma treatment.The cell apoptosis rate was detected by Annexin V/PI double staining at different doses.The expression of apoptosis-related genes and proteins was detected by qRT-PCR and Western Blot.Results MTT results showed that the killing effect of plasma treatment was dose-dependent and time-dependent.The cell survival rate after 8 hours of treatment decreased from 98％ to 63％ with the dose increasing from 30 s to 240 s.The survival rate decreased from 78％ (2 h) to 39％ (24 h) after the treatment with a same dose (e.g.240 s).Annexin V/PI double staining results demonstrated that the plasma effect can induce apoptosis,and the apoptosis rate was not only positively correlated with the plasma dose,but also with the post-plasma time.The longer the post-plasma time,the higher was the apoptosis rate.The apoptotic rate of the 60 s dose treatment after 12 h was 48％ that increased to 55.3％ with the dose of 120 s.The production of reactive oxygen species (ROS) detected by flow cytometry also showed a time correlation of the plasma treatment.After the plasma treatment,the ROS level immediately increased to 1.24 times,and sharply increased to 5.39 times after 20 h post-plasma.The experimental results of qRT-PCR and Western blot showed that the expression of the genes and proteins of Caspase family and Bcl-2 family was very active at 8 to 12 h post-plasma treatment.Conclusions Low-temperature plasma can effectively kill tumor cells,and apoptosis is the main mechanism of death.The molecular mechanism of apoptosis of tumor cells induced by low temperature plasma was preliminary confirmed.
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Objective To prepare 5-aminolevulinic acid (ALA) and hematoporphyrin monomethyl ether (HMME) hydrogel suppositories and to evaluate their photosensitizer transfer efficiencies in rectal tumor tissue.Methods The BALB/c mice implanted SW837 rectal cancer cells subcutaneously were randomly divided into four groups:intrarectal suppository administration group,cutaneous administration group,intratumoral injection group and intravenous injection group.Fluorescence spectrophotometry was used to measure the concentration of protoporphyrin Ⅸ (PpⅨ) and HMME in rectal wall,skin and tumor tissue.The distribution of photosensitizer was determined by a fluorescence spectroscopy system.Results The concentration of PpⅨ in the ALA suppository administration group was 9.76 times (1 h) and 5.80 times (3 h) higher than that in the cutaneous administration group,and the differences were statistically significant (all P＜0.05).The maximal penetration depth of ALA in tumor tissue was about 3-6 mm at 2 h after the cutaneous administration.After the HMME suppository administration,the concentration of HMME in the rectal wall was very low.The maximal penetration depth of HMME in tumor tissue was less than 2 mm after the cutaneous administration.Conclusions ALA is more likely to penetrate mucosal barrier compared to skin tissue.The hydrogel suppository based rectal administration is expected to be a new administration method for the rectal cancer photodynamic therapy using ALA.
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Objective To evaluate the efficacy of the systemic photodynamic therapy (SPDT)for treating leukemia using a Brown Norway myeloid leukemia (BNML) rat model.Methods The BNML rat model was established by injecting green fluorescent protein (GFP)-LT12 cells into the tail vein.After GFP-LT12 injection,the early-SPDT group,mid-SPDT group and late-SPDT group were treated with SPDT at 5,10 and 15 days,the negative control group was fed as usually,and the Ara-c positive control group was treated with Ara-c at 7 days.The GFP-LT12 cells were traced by a fluorescence imaging system.The GFP-LT12 cells in the tissues and organs were detected by flow cytometry.The levels of IFN-γ,IL-1α,IL-1β,IL-2,IL-4,IL-6,IL-10 and TNF-α in serum were detected by milliplex rat cytokine 9 kits.Results Compared with the negative control group,the survival times of the rats in the earlySPDT group,mid-SPDT group and the late-SPDT group were prolonged (all P＜0.05).The ratios of GFP-LT12 cells in pulp and liver were decreased in the late-SPDT group.The levels of IL-1β,IL-10,TNF-α and IFN-γin serum of the late-SPDT group were decreased (all P＜0.05).Conclusion The SPDT is an effective method for the treatment of leukemia,and the anti-tumor immune effect may play a key role in this process.
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Objective To study the effects of umbilical cord mesenchymal stem cells (UCMSCs) on the apoptosis of human breast cancer cell line MCF-7.Methods MCF-7 cells were co-cultured with different concentrations of UCMSCs.The apoptosis of MCF-7 cells was detected by in situ apoptosis and flow cytometry.Nude mouse subcutaneous tumor model was established by inoculating MCF-7 and MSCs cells subcutaneously on the right side of the back of a mouse.The MCF-7 cells were inoculated on the left side of the mouse as control.The tumor volume was measured every week to compare the difference between the two groups.On the 17th day after inoculation,the tumor tissue was harvested and the apoptosis of tumor cells was observed by a transmission electron microscopy.Results In situ apoptosis and flow cytometry showed that the early and late apoptosis rates of MCF-7 cells increased first and then decreased with the increase of UCMSCs concentration.The differences between the control and the MCF-7+UCMSCs group were statistically significant for early (F=39.80,P＜0.001) and late apoptosis rates (F=5.68,P＜0.01).The tumor volume of MCF-7+UCMSCs group was significantly lower than that of control group in 17 days after inoculation (F=9.81,P＜0.01).The representative apoptotic cells were observed by the transmission electron microscopyin the MCF-7 +UCMSCs group.Conclusion The UCMSCs with a certain concentration can effectively promote the apoptosis of MCF-7 cells.This study provides a certain experimental basis for the clinical treatment of breast cancer.