四氧化三铁纳米颗粒心肌毒性的体内实验研究
|
摘要
磁性纳米粒子不但具有普通纳米粒子所具有的效应(体积效应、表面效应、量子尺度效应和宏观量子隧道效应),还会随着磁性颗粒材料的组成变化而呈现异常的磁学性质。同时,在许多的生物体内存在以Fe_3O_4为主的强磁性矿物粒晶,所以磁性纳米粒子被认为具有良好的生物相容性,在医学领域的应用有着巨大的优势。但其安全性也受到广泛关注。
已有研究表明,磁性纳米粒子因粒径不同、表面包覆情况不同、进入机体的途径不同,显示的毒性不同,从体内排出的时间也不同。目前,超顺磁纳米粒子在临床应用前景主要是载药体系、MRI对比剂等,在这些用途中,纳米粒子进入机体的主要途径为静脉注射,虽然粒子表面包覆后,在较短时间内毒性很低,但其在体内代谢后可能还会在体内存留较长时间。这种状态的粒子对机体产生的作用深受人们关注。
本研究以化学共沉淀法制备的Fe_3O_4纳米粒子为材料,对其在不同溶液中的稳定性、静脉注射后的急性毒性和粒子的器官分布以及心肌毒性进行观察,为其安全应用提供基础数据。结果表明,注射用的Fe_3O_4纳米颗粒的平均粒径为9nm,反晶尖石结构。纳米粒子在盐溶液中的稳定性较差,而在高纯水中及含蛋白的溶液中稳定性良好。
在急性毒性实验中,小鼠尾静脉1次注射后,LD_(50)为163.60 mg/kg,LD_(50)的95%可信限为147.58 ~ 181.37 mg/kg。死亡鼠表现出明显的乏氧体征,可能因呼吸衰竭而死。纳米粒子可分布于全身各器官,主要分布在肺、肝、脾,并可能经肝脏排除。病理学观察表明,纳米粒子对心肌和肾脏产生损害作用,且出现心肌的损害作用较肾脏早。
心肌毒性实验中,纳米颗粒1次注射后的不同时间内,小鼠血清LDH、AST的活性下降, TIBC含量增高,心肌细胞的能量代谢酶ATPase活性下降,心肌产生脂质过氧化损伤,心肌细胞发生凋亡,与凋亡密切相关的蛋白表达增加。综上所述,在本实验条件下,未经包覆的Fe_3O_4纳米粒子经静脉注射后可对心肌产生损伤作用。
Nano-material as a new kind of material would be applied to a vast number of fields. Nano- biotechnology is highlighted and is a new frontier of the field of international biotechnology, with the specially significant direction of nano- technology advancement in the development of targeted medicine delivery containing nano-material and the implantation of artificial organ created by nano- material. The distinctive way of nano-material contacting human body while applying it in the field of medicine triggers the universal attention and dispute of its safety. This study focus on the stability of Fe_3O_4 nano-particles in different solutions, their acute toxicity to mice and their damage upon cardiac muscle and further to offer basis for the safety application of Fe_3O_4 nano-particles.
1. The characterization and stability of Fe_3O_4 nano-particles in different solutions
Utilize transmission electron microscope (TEM) to observe and XRD as well as infrared spectrometer to characterize Fe_3O_4 nano-particles that are synthesized by chemical co-precipitation. The result is that Fe_3O_4 nano-particles obtain cation antisite disorder with an average particle diameter of 9nm.
8 kinds of solutions were included, namely, high pure water, 0.1% NaCL, 0.5%NaCL, 0.9% NaCL, RPMI 1640 without blood serum, RPMI 1640 + 5% fetal bovine serum, RPMI 1640 +10% fetal bovine serum, RPMI 1640 + 20% fetal bovine serum, and formulate 5% (V/V) nano-particle solutions combining Fe_3O_4 nano-particles and the ten mentioned solutions. After 3 minutes of exposure to ultrasound, the changes of nano-particle diameter were measured via zeta potential apparatus within five minutes in each of the ten formulated solutions and made the particles in each solution into copper net, and observed the changs of their particle diameter under TEM. The result indicated that in solutions that contained different concentrations of salt, hydrated nano-particles diameter increased rapidly, and the increase rate were relatively unified. However, in the high pure water and fetal bovine serums of different densities, the nano-particles were stable, and no noticeable changes of their particle diameter were observed within five minutes. Moreover, in the solutions containing more than 10% protein, particle’s diameter was close to that with high pure water. The result of TEM observation suggested that despite the fact that hydrated particles’diameter achieved comparatively faster growth in salt solutions, the diameter of those particles themselves showed no changes at all. This was consistent with the situation in the medium with protein. These were all due to the particles aggregation.
Based on the discussion above, Fe_3O_4 nano-particles showed good dispersion and stability in high pure water, all of which were mainly associated with their stable electric double layer. Such phenomenon can also be observed in the medium containing blood serum where the reason might be related to the absorbed layer formed by protein on the surface of those particles. Moreover, the extent of dispersion was in accordance with protein density. In those salt solutions the stability of particles was relatively low, which has a possible relationship with the damage of surface electric double layer.
2. Acute toxicity of Fe_3O_4 nano-particles in mice and their distribution in its organs
Under bacteria free condition, Fe_3O_4 nano-particle suspension with density of 1.024 mg/ml,1.28 mg/ml,1.60 mg/ml,2.00 mg/ml,2.50 mg/ml respectively were prepared using high pure water. The solutions were subjected to ultrasound for 3 minutes before injecting to mice.
120 ICR mice, half male and half female, weighing 18±2g were chosen and divided into six groups, namely, groups with densities of Fe_3O_4 nano-particles of 102.4,128,160,200 and 250mg/kg respectively as well as control group(high pure water). 20 mouse in each group. Fe_3O_4 nano-particle solutions or high pure water were administered at 0.1 ml/10g via intravenous injection, with a speed of 3~4sec/0.1ml. The mouse death rate during the next 15 days after the injection were calculated.
Extract the survived mouse 20 minutes after the injection as well as 15 days after the injection in 102.4 mg/kg group and 160 mg/kg group, and after anesthetizing, acquire their brains, lungs, hearts, livers, spleens, kidneys and testicles, and fix those organs by 10% formaldehyde. Perform immediate dissection upon those dead mouse in 160 mg/kg group and 250 mg/kg group, and obtain and fix those organs mentioned above, which were then embed using paraffin and cut into slices, followed by dyeing utilizing Prussian blue to observe the distribution in each organ and HE to do pathological inspection on those tissues.
The consequence of intravenous injection to test acute toxcity of Fe_3O_4 nano-particles indicated that LD_(50) of Fe_3O_4 nano-particle was 163.60 mg/kg and the 95% credible line of LD_(50) was 147.58 ~181.37 mg/kg. The main behavior of those injected mouse were cramp, rolling, unstable stepping, dyspnoea, and death because of failure in breathing.
The result of Prussian coloration indicated that 20 minutes after the injection of nano-particles, the main distribution of those particles was in the liver, spleen, and lung, and considerable reduction of blue particles was seen in the lung and spleen, yet not so in the liver. Low portion of distribution was observed in other organs, say, brain, heart, kidney and testicle. Survived mouse in 160mg/kg group after the injection were seen identical distribution of blue iron particles in the lung, spleen, and liver to that of 102.4 mg/kg group, yet after the dissection of the dead mouse, more dense distribution of the blue particles were discovered on the alveolar wall in the lung, which was also the case in the liver using optical microscope. In contrast to the distribution of blue particles in the liver of the survived mouse, however, blue particles could be observed in the brain, heart and kidney in the dead mouse that were dissected immediately after death. The mouse in 250 mg/kg group immediately perished after the injection. Nano-particles in the lung appeared aggregated distribution, blue substances in the liver appeared the distribution in an even flocculating form, the quantity of particles in the spleen showed apparent reduction and that in the brain were seen obvious growth. Moreover, blue substances were more readily seen in the brain and liver.
The result of pathological observation suggested that 20 minutes after the injection, the particles in the cardiac muscle of the survived mouse were seen denaturalized, moreover, the scope of the denaturalized region expanded as the dose of the particles growed. 15 days later, local necrosis could be observed in the cardiac muscle, while such pathological changes did not exist in the dead mouse. Kidney of the mouse in 102.4 mg/kg group 20 minutes after the injection was not seen abnormal; however, brown particle-shaped substance was seen in the capillaries of glomerulus of the survived mouse of 160mg/kg group, yet not so in the rest mouse. 2 weeks later, protein cast could be observed in the glomerulus of the survived mouse of the two groups as well as edema in the carunculae papillaris; however, in the injected dead mouse, blood congestion in the carunculae papillaris and particle shaped substance in the blood vessels in the some of the glomerulutilizes could be seen.
Based on the presentation above, after the intravenous injection of 9 nm Fe_3O_4 nanoparticles, LD_(50) of mouse was 163.60 mg/kg, with 95% credible line of LD_(50) at 147.58 ~ 181.37 mg/kg. The main behavior before the death of mouse was typical breathing difficulty, and Prussian special coloration indicated full covering of blue iron particles on the base of the capillaries of the pulmonary of the dead mouse. On the contrary, the pathological observation (HE coloration) of the lung showed no sign of pathological changes, say, inflammation or bleeding, yet cardiac muscle that was sensitive to oxygen shortage appeared particle denaturalizing, and there was protein cast in the kidney; nano-particles, which was mainly excreted by liver and slow in excretion, performed a rapid distribution in the spleen and liver within a relatively short time (20 minutes), and the more the dose of the nano-particles, the wider of the scope of their distribution.
3. The impact of Fe_3O_4 nano-particles upon the blood serum enzymes and the cardiac muscles
Prepare suspension of Fe_3O_4 nano-particles with high pure water under the condition of bacteria free into three groups with the density of 0.1mg/ml,0.2mg/ml,and 0.8mg/ml respectively. Expose those suspensions to ultrasound for 3 minutes.
Choose 72 male ICR mouse with weight of 18±2g, then equally divide them into 4 groups, namely, group with Fe_3O_4 nano-particles 10 mg/kg, 20 mg/kg, 80 mg/kg and a control group (high pure water), and perform intravenous injection of the suspensions of nano-particles at 0.1ml/10g with the speed of 3 ~ 4 sec/0.1ml. After 1d, 3d and 7d respectively, randomly choose 6 mouse in each group, fetch blood from the eyes, and extract the blood serum, which would be utilized to measure LDH, AST activity, content of TIBC; fetch heart, liver, spleen to measure their weight and the heart was to be utilized to measure the content of water, oxidization damage, and the activity of enzymes in the cardiac muscle.
Divide equally another 20 mouse into 4 groups, and after 1d of injecting them with particles of the densities mentioned above anesthetize them by injecting 10% chloral hydrate of 0.03 mL/10g through abdominal cavity, followed by acquiring the whole heart, then fix it with 10% formaldehyde for 24 h, embedded by using paraffin and slice them into pieces, which were then utilized to examine the apoptosis of cardiac muscle and the related activities of protein and gene expressions.
The result was that apparent reduction of the activity of the blood serum LDH and AST occurred 1 day after the injection of nano-particles, moreover, the more the dose of the particles, the more the activity of the enzymes would reduce and no sign of recovery could be seen after 7 d; TIBC in the blood serum rose and groups of low dose were seen earlier rising while that of high dose later, after 7d, all test group were considerably higher than the control group.
The content of water in the cardiac muscle decreased tremendously.
The content of MDA in the cardiac muscle serum 1d after the injection plummeted, while 3d later that of each experimental group grew remarkably, and that of each experimental group was apparently higher than that of the control group till 7d later. The activity of SOD reduced vastly 1d after the injection, and that of every experimental group was continuously greater than that of the control group on the 3rd day after the injection, and such was also the case till the 7th day. The change of the activity of GSH-Px was similar with that of SOD, yet that of former was later than that of the latter.
1d after the injection, the activities of Na~+, K~+- ATPase and Ca~(2+), Mg~+- ATPase in each particle exposure group were considerably higher than that of the control group; 3d later, the activities decreasd obviously; 7 days later, 80mg/kg group was apparently lower than other groups, yet the activity of Na~+, K~+-ATPase in 10 mg/kg group and 20mg/kg group recovered to the level of the control group, and the activity of Ca~(2+), Mg~(2+)- ATPase in 20 mg/kg group remained lower than that of the control group.
1d after the injection, apoptosis of the myocardium cell was determined by means of TUNEL. The results demonstrated that apoptosis of myocardium cell occurred in the injected groups, and the more the amount of particle injected, the more severe the apoptosis emerged. The result of grayscale detection suggested that apparent dose dependence existed, in the meantime, the activities of Caspase-9 and Caspase-3 rose tremendously, and the expressions of Fas、FasL、p53 were much higher than that of the control group.
Based on the presentation above, after performing intravenous injection of Fe_3O_4 nano-particles on the mouse, it was likely that the releasing of the inflammation factors, which was caused by breathing difficulty and the nano-particles, resulted in the apoptosis of the cardiac muscle, the behavior of which is that the activity of LDH, AST enzymes that were intimately associated with the metabolism of the cardiac muscle decreased enormously, and the activity of Na~+, K~+- ATPase and Ca~(2+), Mg~+- ATPase on the cell membrane reduced greatly. The two reductions most likely gave rise to the increase of the density of Ca~(2+) in the cells. The amount of expressions of p53、Fas、FasL rose vastly, and rendered cardiac muscle apoptosis by activating Caspase through activating Caspase system.
已有研究表明,磁性纳米粒子因粒径不同、表面包覆情况不同、进入机体的途径不同,显示的毒性不同,从体内排出的时间也不同。目前,超顺磁纳米粒子在临床应用前景主要是载药体系、MRI对比剂等,在这些用途中,纳米粒子进入机体的主要途径为静脉注射,虽然粒子表面包覆后,在较短时间内毒性很低,但其在体内代谢后可能还会在体内存留较长时间。这种状态的粒子对机体产生的作用深受人们关注。
本研究以化学共沉淀法制备的Fe_3O_4纳米粒子为材料,对其在不同溶液中的稳定性、静脉注射后的急性毒性和粒子的器官分布以及心肌毒性进行观察,为其安全应用提供基础数据。结果表明,注射用的Fe_3O_4纳米颗粒的平均粒径为9nm,反晶尖石结构。纳米粒子在盐溶液中的稳定性较差,而在高纯水中及含蛋白的溶液中稳定性良好。
在急性毒性实验中,小鼠尾静脉1次注射后,LD_(50)为163.60 mg/kg,LD_(50)的95%可信限为147.58 ~ 181.37 mg/kg。死亡鼠表现出明显的乏氧体征,可能因呼吸衰竭而死。纳米粒子可分布于全身各器官,主要分布在肺、肝、脾,并可能经肝脏排除。病理学观察表明,纳米粒子对心肌和肾脏产生损害作用,且出现心肌的损害作用较肾脏早。
心肌毒性实验中,纳米颗粒1次注射后的不同时间内,小鼠血清LDH、AST的活性下降, TIBC含量增高,心肌细胞的能量代谢酶ATPase活性下降,心肌产生脂质过氧化损伤,心肌细胞发生凋亡,与凋亡密切相关的蛋白表达增加。综上所述,在本实验条件下,未经包覆的Fe_3O_4纳米粒子经静脉注射后可对心肌产生损伤作用。
Nano-material as a new kind of material would be applied to a vast number of fields. Nano- biotechnology is highlighted and is a new frontier of the field of international biotechnology, with the specially significant direction of nano- technology advancement in the development of targeted medicine delivery containing nano-material and the implantation of artificial organ created by nano- material. The distinctive way of nano-material contacting human body while applying it in the field of medicine triggers the universal attention and dispute of its safety. This study focus on the stability of Fe_3O_4 nano-particles in different solutions, their acute toxicity to mice and their damage upon cardiac muscle and further to offer basis for the safety application of Fe_3O_4 nano-particles.
1. The characterization and stability of Fe_3O_4 nano-particles in different solutions
Utilize transmission electron microscope (TEM) to observe and XRD as well as infrared spectrometer to characterize Fe_3O_4 nano-particles that are synthesized by chemical co-precipitation. The result is that Fe_3O_4 nano-particles obtain cation antisite disorder with an average particle diameter of 9nm.
8 kinds of solutions were included, namely, high pure water, 0.1% NaCL, 0.5%NaCL, 0.9% NaCL, RPMI 1640 without blood serum, RPMI 1640 + 5% fetal bovine serum, RPMI 1640 +10% fetal bovine serum, RPMI 1640 + 20% fetal bovine serum, and formulate 5% (V/V) nano-particle solutions combining Fe_3O_4 nano-particles and the ten mentioned solutions. After 3 minutes of exposure to ultrasound, the changes of nano-particle diameter were measured via zeta potential apparatus within five minutes in each of the ten formulated solutions and made the particles in each solution into copper net, and observed the changs of their particle diameter under TEM. The result indicated that in solutions that contained different concentrations of salt, hydrated nano-particles diameter increased rapidly, and the increase rate were relatively unified. However, in the high pure water and fetal bovine serums of different densities, the nano-particles were stable, and no noticeable changes of their particle diameter were observed within five minutes. Moreover, in the solutions containing more than 10% protein, particle’s diameter was close to that with high pure water. The result of TEM observation suggested that despite the fact that hydrated particles’diameter achieved comparatively faster growth in salt solutions, the diameter of those particles themselves showed no changes at all. This was consistent with the situation in the medium with protein. These were all due to the particles aggregation.
Based on the discussion above, Fe_3O_4 nano-particles showed good dispersion and stability in high pure water, all of which were mainly associated with their stable electric double layer. Such phenomenon can also be observed in the medium containing blood serum where the reason might be related to the absorbed layer formed by protein on the surface of those particles. Moreover, the extent of dispersion was in accordance with protein density. In those salt solutions the stability of particles was relatively low, which has a possible relationship with the damage of surface electric double layer.
2. Acute toxicity of Fe_3O_4 nano-particles in mice and their distribution in its organs
Under bacteria free condition, Fe_3O_4 nano-particle suspension with density of 1.024 mg/ml,1.28 mg/ml,1.60 mg/ml,2.00 mg/ml,2.50 mg/ml respectively were prepared using high pure water. The solutions were subjected to ultrasound for 3 minutes before injecting to mice.
120 ICR mice, half male and half female, weighing 18±2g were chosen and divided into six groups, namely, groups with densities of Fe_3O_4 nano-particles of 102.4,128,160,200 and 250mg/kg respectively as well as control group(high pure water). 20 mouse in each group. Fe_3O_4 nano-particle solutions or high pure water were administered at 0.1 ml/10g via intravenous injection, with a speed of 3~4sec/0.1ml. The mouse death rate during the next 15 days after the injection were calculated.
Extract the survived mouse 20 minutes after the injection as well as 15 days after the injection in 102.4 mg/kg group and 160 mg/kg group, and after anesthetizing, acquire their brains, lungs, hearts, livers, spleens, kidneys and testicles, and fix those organs by 10% formaldehyde. Perform immediate dissection upon those dead mouse in 160 mg/kg group and 250 mg/kg group, and obtain and fix those organs mentioned above, which were then embed using paraffin and cut into slices, followed by dyeing utilizing Prussian blue to observe the distribution in each organ and HE to do pathological inspection on those tissues.
The consequence of intravenous injection to test acute toxcity of Fe_3O_4 nano-particles indicated that LD_(50) of Fe_3O_4 nano-particle was 163.60 mg/kg and the 95% credible line of LD_(50) was 147.58 ~181.37 mg/kg. The main behavior of those injected mouse were cramp, rolling, unstable stepping, dyspnoea, and death because of failure in breathing.
The result of Prussian coloration indicated that 20 minutes after the injection of nano-particles, the main distribution of those particles was in the liver, spleen, and lung, and considerable reduction of blue particles was seen in the lung and spleen, yet not so in the liver. Low portion of distribution was observed in other organs, say, brain, heart, kidney and testicle. Survived mouse in 160mg/kg group after the injection were seen identical distribution of blue iron particles in the lung, spleen, and liver to that of 102.4 mg/kg group, yet after the dissection of the dead mouse, more dense distribution of the blue particles were discovered on the alveolar wall in the lung, which was also the case in the liver using optical microscope. In contrast to the distribution of blue particles in the liver of the survived mouse, however, blue particles could be observed in the brain, heart and kidney in the dead mouse that were dissected immediately after death. The mouse in 250 mg/kg group immediately perished after the injection. Nano-particles in the lung appeared aggregated distribution, blue substances in the liver appeared the distribution in an even flocculating form, the quantity of particles in the spleen showed apparent reduction and that in the brain were seen obvious growth. Moreover, blue substances were more readily seen in the brain and liver.
The result of pathological observation suggested that 20 minutes after the injection, the particles in the cardiac muscle of the survived mouse were seen denaturalized, moreover, the scope of the denaturalized region expanded as the dose of the particles growed. 15 days later, local necrosis could be observed in the cardiac muscle, while such pathological changes did not exist in the dead mouse. Kidney of the mouse in 102.4 mg/kg group 20 minutes after the injection was not seen abnormal; however, brown particle-shaped substance was seen in the capillaries of glomerulus of the survived mouse of 160mg/kg group, yet not so in the rest mouse. 2 weeks later, protein cast could be observed in the glomerulus of the survived mouse of the two groups as well as edema in the carunculae papillaris; however, in the injected dead mouse, blood congestion in the carunculae papillaris and particle shaped substance in the blood vessels in the some of the glomerulutilizes could be seen.
Based on the presentation above, after the intravenous injection of 9 nm Fe_3O_4 nanoparticles, LD_(50) of mouse was 163.60 mg/kg, with 95% credible line of LD_(50) at 147.58 ~ 181.37 mg/kg. The main behavior before the death of mouse was typical breathing difficulty, and Prussian special coloration indicated full covering of blue iron particles on the base of the capillaries of the pulmonary of the dead mouse. On the contrary, the pathological observation (HE coloration) of the lung showed no sign of pathological changes, say, inflammation or bleeding, yet cardiac muscle that was sensitive to oxygen shortage appeared particle denaturalizing, and there was protein cast in the kidney; nano-particles, which was mainly excreted by liver and slow in excretion, performed a rapid distribution in the spleen and liver within a relatively short time (20 minutes), and the more the dose of the nano-particles, the wider of the scope of their distribution.
3. The impact of Fe_3O_4 nano-particles upon the blood serum enzymes and the cardiac muscles
Prepare suspension of Fe_3O_4 nano-particles with high pure water under the condition of bacteria free into three groups with the density of 0.1mg/ml,0.2mg/ml,and 0.8mg/ml respectively. Expose those suspensions to ultrasound for 3 minutes.
Choose 72 male ICR mouse with weight of 18±2g, then equally divide them into 4 groups, namely, group with Fe_3O_4 nano-particles 10 mg/kg, 20 mg/kg, 80 mg/kg and a control group (high pure water), and perform intravenous injection of the suspensions of nano-particles at 0.1ml/10g with the speed of 3 ~ 4 sec/0.1ml. After 1d, 3d and 7d respectively, randomly choose 6 mouse in each group, fetch blood from the eyes, and extract the blood serum, which would be utilized to measure LDH, AST activity, content of TIBC; fetch heart, liver, spleen to measure their weight and the heart was to be utilized to measure the content of water, oxidization damage, and the activity of enzymes in the cardiac muscle.
Divide equally another 20 mouse into 4 groups, and after 1d of injecting them with particles of the densities mentioned above anesthetize them by injecting 10% chloral hydrate of 0.03 mL/10g through abdominal cavity, followed by acquiring the whole heart, then fix it with 10% formaldehyde for 24 h, embedded by using paraffin and slice them into pieces, which were then utilized to examine the apoptosis of cardiac muscle and the related activities of protein and gene expressions.
The result was that apparent reduction of the activity of the blood serum LDH and AST occurred 1 day after the injection of nano-particles, moreover, the more the dose of the particles, the more the activity of the enzymes would reduce and no sign of recovery could be seen after 7 d; TIBC in the blood serum rose and groups of low dose were seen earlier rising while that of high dose later, after 7d, all test group were considerably higher than the control group.
The content of water in the cardiac muscle decreased tremendously.
The content of MDA in the cardiac muscle serum 1d after the injection plummeted, while 3d later that of each experimental group grew remarkably, and that of each experimental group was apparently higher than that of the control group till 7d later. The activity of SOD reduced vastly 1d after the injection, and that of every experimental group was continuously greater than that of the control group on the 3rd day after the injection, and such was also the case till the 7th day. The change of the activity of GSH-Px was similar with that of SOD, yet that of former was later than that of the latter.
1d after the injection, the activities of Na~+, K~+- ATPase and Ca~(2+), Mg~+- ATPase in each particle exposure group were considerably higher than that of the control group; 3d later, the activities decreasd obviously; 7 days later, 80mg/kg group was apparently lower than other groups, yet the activity of Na~+, K~+-ATPase in 10 mg/kg group and 20mg/kg group recovered to the level of the control group, and the activity of Ca~(2+), Mg~(2+)- ATPase in 20 mg/kg group remained lower than that of the control group.
1d after the injection, apoptosis of the myocardium cell was determined by means of TUNEL. The results demonstrated that apoptosis of myocardium cell occurred in the injected groups, and the more the amount of particle injected, the more severe the apoptosis emerged. The result of grayscale detection suggested that apparent dose dependence existed, in the meantime, the activities of Caspase-9 and Caspase-3 rose tremendously, and the expressions of Fas、FasL、p53 were much higher than that of the control group.
Based on the presentation above, after performing intravenous injection of Fe_3O_4 nano-particles on the mouse, it was likely that the releasing of the inflammation factors, which was caused by breathing difficulty and the nano-particles, resulted in the apoptosis of the cardiac muscle, the behavior of which is that the activity of LDH, AST enzymes that were intimately associated with the metabolism of the cardiac muscle decreased enormously, and the activity of Na~+, K~+- ATPase and Ca~(2+), Mg~+- ATPase on the cell membrane reduced greatly. The two reductions most likely gave rise to the increase of the density of Ca~(2+) in the cells. The amount of expressions of p53、Fas、FasL rose vastly, and rendered cardiac muscle apoptosis by activating Caspase through activating Caspase system.
引文
[1]张立德,牟季美.纳米材料与纳米结构[M].北京:科学出版社, 2001:6.
[2]许海燕,孔桦.纳米材料的研究进展及其在生物医学中的应用[J].基础医学与临床, 2002, 22 (2):97-103.
[3]董晶莹,刘宁.纳米微粒在生物医学领域的应用研究.国外医学生物医学工程分册,2005,28(4):237-240
[4]孟磊,宋增瑛.量子点在生物医学中的应用[J].生物化学与生物物理进展, 2004, 31(2):185-187.
[5]林章碧,张皓,陈奇丹,等.利用水相合成的量子点标记木瓜蛋白酶的研究[J].高等学校化学学报, 2003, 24(4):609-611.
[6] Pathak S, Choi SK, Amhaeim N, et al. Hydroxylated quantum dots as lumi- nescent probes for in situ hybridization[J]. J Am Chem Soci, 2001, 123(17): 4103- 4104.
[7] Damge C, Michel C, AprahanianM, et al. New approach for oral administration of insulin with polyalky-cyanoacrylate nanoparticles as drug carrier[J]. Diabetes, 1988, 37:246.
[8]张磊,平其能,郭健新,等.口服胰岛素纳米脂质体的制备及其降血糖作用[J].中国药科大学学报, 2001, 32:25
[9] Sharma D, Chelvi TP, Kaur J , et al. Novel Taxol for mulation polyvinyp lyrro lidone nanoparticl-encap sulated Taxol for drug delivery in cancer therapy[J]. Oncol Res, 1996, 8: 281
[10]常津,魏民,姚康德.聚原酸酯抗癌药物毫微粒的制备及体外释药研究[J].中国生物医学工程学报, 1999, 18 (2):216.
[11] Jorg Keruter. Nanoparticulate systems for brain delivery of drugs[J]. Adv Drug Deliv Rev, 2001, 47(1):65-81.
[12] Aborl S, Terhan A, Katare OP. Formulation, characterization, and in vitor evaluation of silymarin -loaded lipid micorspheres[J]. Drug Deliver, 2004, 11 (3):185-191.
[13] Kreuater J. Nanoparticles and microparticles for drug and vaccine delivery[J]. JAnat, 1996, 189:503-509.
[14] O’Hagain DT. Theintestinal uptake of particles and the implications for drug and antugen delivery [J]. J Anat, 1996, 189:477-482.
[15] Kim YI, Fluckiger L, Hoffman M, et al. The antihypertensive effect of orally administered nifedip ineloaded nanopart icles in spontaneously by pertensiverats[J]. Br J Pharmacol, 1997, 120 (3):399-407.
[16] Zimmer A, M utschler E, Lambrecht G, et al. Pharmacokinetic and harmacodynamic aspects of an ophthalm ic pilocarpine nanoparticles delivery-system [J]. Pharm Res, 1994, 11 (10):1435-1441.
[17] Truong L, Vu L, Walsh, et al. Gene transfer by DNA-gelatin nano spheres[J]. Arch Biochem Biophys, 1999, 361 (1):47-54
[18] Lambert G, Fattal E, Pinto-Alphanadary H, et al. Polyisobutylcyanoacrylate nanocapsules containing an aqueous core as a novel colloidal carrier for the delivery of oligonucleo tides[J]. Pharm Res, 2000, 17:707-714.
[19] Radwan MA, Zaghloul IY, Aly ZH. In vivo performance of parenteral theophylline-loaded polyisobutyl-cyano-acrylate nanopart icles in rats[J]. Eur J Pharm Sci, 1999, 8 (2) :95-101.
[20]国立秋,梁吉.碳纳米管原子力显微镜探针对生物样品高分辨率成像的研究[J].中国生物医学工程学报, 2004, 23(3):243-246.
[21] Guobao W, Peter X. Structure and properties of nano-hydorxyapatite/polymer composite scaffolds for bone tissue engineering[J]. Biomaterial, 2004, 25: 4749-4757.
[22] Shin M, Yoshimoto H, Vacanti JP. In vivo bone tissue engineering using mesenchymal stem cells on a novel electrospun nanofibrous scaffold[J]. Tissue Eng, 2004, 10(1-2):33-39.
[23] Davda J, Labhasetwar V. Characterization of nanoparticle uptake by endothelial cell[J]. Int J Pharm, 2002, 233(1-2):51-59.
[24] Cognet L, Tardin C, Boyer D, et al. Single metallic nanoparticle imaging for protein detection in cells[J]. Biophysics, 2003, 100(20):11350-11355.
[25] Fan CY, Jiang L. Preparation of hydrophobic nanometer gold particle and theiroptic absorp- tion in chloroform[J]. Langmuir, 1997, 13(11):3059-3062.
[26]沈霞,郭薇. Fe304/葡聚糖/抗体磁性纳米生物探针的制备和层析检测[J].高等学校化学学报, 2004, 25(3):445-447.
[27] Lepek M, PittnerF. Novel transducers for nano-optical biosensorchips based on biological and synthetic polymers with analyte-dependent swelling/shrinking behavior[J]. J Nanosci Nanotechnol, 2004, 4(1-2):106-114.
[28] Bergemann C, Mueller-Schulute D, Oster J, et al. Magnetic ion-exchange nano- and micor-particles for medical, biochemical, and molecular biological applications[J]. J Magn Master, 1999, 194(l):45-52.
[29] Service RF. Nanomaterials show signs of toxicity[J]. Science, 2003, 300 (11) :243.
[30] Brumfiel G. A little known knowledge[J]. Nature, 2003, 424 (17) :246.
[31] Chiu WL, John TJ, Richard MC, et al. Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation[J]. Toxicol Sci, 2004, 77:126- 134.
[32] Borm PJ. Particle toxicology: from coalmining to nanotechnology[J]. Inhal Toxicol, 2002, 14 (3):311 - 324.
[33] Chiu-Wing Lam, James JT, Richard MC, et al. Pulmonary toxicity of single- wall carbon nano- tubes in Mice 7 and 90 days after intratracheal instillation[J]. Toxicological Sciences, 2004, 77(1):126-134.
[34] Warheit DB, Laurence BR, Reed KL, et al. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats[J]. Toxicological Sciences, 2004, 77(1):117-125.
[35] Edilberto B, James BM, Brian AW, et al. Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles[J]. Toxicol Sci, 2004, 77:347-357.
[36] Vincent C. From coal mine dust to quartz; mechanisms of pulmonary pathogenicity[J]. Inhal Toxicol, 2002, 12:7-14.
[37] Eva Oberdorster. Manufactured nanomaterials(fullerenes, C60) induce oxidative stress in the brain of juvenile largemouth bass[J]. Environmental HealthPerspectives, 2004, 112(10):1058-1062.
[38] Oberdorster G, Sharp Z, Atudorei V, et al. Translocation of inhaled ultrafine particles to the brain[J]. Inhalation Toxicology, 2004, 16(6/7):437-446.
[39] Donaldson K, Stone V, Tran CL, et al. Nanotoxicology[J]. Occup Environ Med, 2004, 61(9):727-728.
[40] Nemmar A, Hoet PH, Vanquickenborne B, et al. Passage of inhaled particles into the circulation in humans[J]. Circulation, 2002, 105(4):411-414.
[41] Harder B. Conduit to the brain: particles enter the nervous system via the nose [J]. Science News, 2004, 165(4):54
[42] Chen Z, Meng H, Xing GM, et al. Acute toxicological effects of copper nanoparticles in vivo[J]. Toxicol Lett, 2006, 163:109-120.
[43] Wang B, Feng WY, Wang TC, et al. Acute toxicity of nano- and micro-scale zinc powder in healthy adult mice[J].Toxicol Lett, 2006, 161:115-123.
[44]刘丽萍,肖雁冰,肖子文,等.家兔静脉注射经基磷灰石纳米粒子的反应研究[J].卫生研究, 2005, 34(4):474-476.
[45]刘涛,杨振中,张本界,等.纳米水镁石纤维的细胞毒性与致纤维化作用[J].工业卫生与职业病, 2005, 31(3):134-137.
[46] Laura LD, Dorothy MT, Cheng D, et al. Carboxy-fullerenes as neuroprortective agents[J]. Proc Natl Acad Sci USA, 1997, 94:9434-9439.
[47] Ye C, Chen CY, Chen Z, et al. In situ observation of C60 malonic acid derivative nanoparticles interacting with living cells by fluorescence microscopy[J]. Chinese Science Bulletin, 2006, 51(1):1-5.
[48] Jia G, Wang HF, Yan L, et al. Cytotoxicity of carbo nanomaterials: single-wall nanotube, multi-wall nanotube, and fulerene[J]. Enviorn Sci Technol, 2005, 39:1378- 1383.
[49]刘涛,杨振中,张本界.纳米级水镁石纤维粉尘的体外细胞毒性研究[J].中国职业学, 2005, 32(2):13-14.
[50] Cui DX, Tim FR, Ozkmr CS, et al. Effect of single wall carbon nanotuhes on human HEK293 cells[J]. Toxicol Lett, 2005, 155:73-85.
[51]范轶欧,张颖花,刘冰,等. TiO2、SiO2、Fe纳米及微米粉体对红细胞毒性作用的比较[J].中国工业医学杂志, 2005, 18(2):67-69.
[52] Zhang QW, KusakaY. Comparative injurious and proinflammatory effects of three ultrafine metalsin macrophages from young and old rats[J]. Inhal Toxicol, 2000, 12:267-273.
[53]李海丰,俞光荣,王德平.纳米羟基磷灰石对骨肉瘤U2-OS细胞生长的影响[J].同济大学学报(医学版), 2005, 26(1):35-38.
[54]许艳慧,李四群,李志安.纳米羟基磷灰石复合材料的研究——纳米羟基磷灰石的细胞毒性[J].实用口腔医学杂志, 2004, 20(2):147-150.
[55]何跃明.恶性肿瘤的磁靶向热疗[J].国外医学·物理医学与康复学分册, 2003, 23(2):96-101.
[56] Garret t Q , Chatelier C, Griesser HJ , et al. Effect of charged groups on the adsorption and penetration of proteins onto and into carboxymethylated poly- (HEMA)hydrogels[J]. Biomaterials, 1998, 19 (23):2175- 2186.
[57]贾秀鹏.磁流体在肿瘤学治疗领域的应用进展[J].国外医学(肿瘤学分册), 2002, 29 (3) :187-190.
[58]张阳德,张洋,潘一峰.磁性纳米颗粒靶向性肿瘤热疗的研究进展[J].中国医学工程, 2006, 14(2):148-152.
[59]徐雪青,沈辉,许家瑞,等.纳米水基磁性液体在肿瘤治疗领域的研究进展[J].化工进展, 2006, 25(4):488-493.
[60] Ito A, Kuga Y, Honda H, et al. Magnetite nanoparticle-loaded anti-HER2 immunoliposomes for combination of antibody therapy with hyperthermia [J]. Cancer Letters, 2004, 212:167-175.
[61]Wada S, Tazawa K, Furuta I, et al. Antitumor effect of new local hyperthermia using dextran magnetite complex in hamster tongue carcinoma[J]. Oral Dis, 2003, 9(4):218.
[62] Matsuoka F, Shinkai M, Honda H, et al. Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma[J]. Biomagn Res Techno1, 2004, 2:1-6.
[63]周伟家,何文,赵洪石,等.载药磁性纳米材料研究进展[J].山东轻工业学院学报, 2008, 22(2):5-8.
[64] Cordula C, Sandra R, Joachim T. Improved properties of magnetic particles by combination of different polymer materials particle matrix[J]. J Magn Magn Mater, 2001, (225) :1-7.
[65] Chen HT, Ebner AD, Rosengart AJ, et al . Analysis of magnetic drug carrier particle capture by a magnetizable intravascular stent :1. Parametric study with single wire correlation[J]. J Mag Mag Mater, 2004, 284:181-194.
[66]洪小平,彭图治.功能高分子磁性微球的制备及分析应用[J].分析化学, 2003, 31:789 - 793.
[67] Kubo T, Sugita T, Scimose S, et al. Targeted delivery of anticancer drugs with intravenously administered magnetic liposomes in osteosarcoma-bearing hamsters[J]. Int J Oncol, 2000, 17:309-315.
[68] Tartaj P, Morales MP, Gonzalez-Carrem T, et al . Advanced in magnetic nanoparticles for biotechnology applications[J]. J Mag Mag Mater, 2005, 290-291:28 -34.
[69] Bautista MC, Bomati-Miguel O, Zhang X, et al . Comparative study of ferro fluids based on dextran-coated iron oxide and metal nanoparticles for contrast agents in magnetic resonance imaging[J]. Nanotechnology, 2004, 15:S154-S159.
[70]王晶,徐玉清,王文秀.磁性纳米粒子及其在生物医学中的应用进展[J].药物生物技术, 2007, 14(5):386-390.
[71] Suzuki M, Honda H, Kobayashi T, et al. Development of a target-directed magnetic resonance contrast agent using mono-clonal antibody conjugated magnetic particles[J]. Brain Tumor Pathol, 1996, 13:127.
[72] Stark D. Superparamagnetic iron oxide: Clinical application as a contrast agent for MRI imaging of the liver[J]. Radiology, 1988, 168(2):297-301.
[73] Uchiyama T, Mohri K, Shinkai M, et al. Basic study for brain tumor pisition sensing using amorphous wire MI micro magnetic sensor[J]. Trans I E E J pn, 1999, 119-C:545.
[74] Matsunaga T, Nakayama H, Okochi M, et al . Fluorescent detection of cyanobacterial DNA using bacterial magnetic particles on a MAG-microarray[J].Biotechnol Bioeng, 2001, 73:400-405.
[75] Holschuh K, Schwammle A. Preparative purification of antibodies with protein A: a5n alterna- tive to conventional chromatograpy[J]. J Mag Mag Mater, 2005, 293:345-348.
[76] Demirel D, Ozdural A R, Mutlu M, et al. Preparation and characterization of magnetic duolite -polystyrene composite particles for enzyme immobilization[J]. J Food Engineering, 2004, 62:203-208.
[77]王秀利,聂立波.磁性纳米颗粒在生物医学领域中的应用[J].化学通报, 2009, 6:489-495.
[78] Schluep T, Cooney CL. Purification of plasmids by triplex affinity interaction[J]. Nucleic Acids Res, 1998, 26:4524.
[79] Rudi K, Kroken M, Dahlberg OJ, et al. Rapid, universal method to isolate PCR ready DNA using magnetic beads[J]. Biotechniques, 1997, 22:506.
[80] Oster J, Parker J, Brassard L. Polyvinyl-alcohol-based magnetic beads for rapid and efficient separation of specific or unspecific nucleic acid sequences[J]. Journal of magnetism and Magnetic Materials, 2001, 225:145.
[81] Xie Xin, Zhang Xu, Zhang Huan, et al. Preparation and application of surface -coated superparamagnetic nanobeads in the isolation of genomic DNA[J]. Journal of magnetism and magnetic materials, 2004, 277:16.
[82]谢欣,张旭,高华方,等.基于多功能纳米磁珠的DNA制备与基因分型[J].科学通报, 2004, 49 (6) :541.
[83] Spanova A, Rittich B, Horak D, et al. Immunomagnetic seperation and detection of Salmonella cells using newly designed carriers[J]. J Chromatography A, 2003, 1009:215-221.
[84] Scherer F, Anton M, Schilinger U, et al. Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo[J]. Gene Ther, 2002, 9:102.
[85] Krotz F, Wit C, Sohn HY, et al. Magnetofection a highly tool for antisense oligonucleotide delivery in vitro and in vivo[J]. Mol Ther, 2003, 7(5) :700
[86] Nagatani N, Shinkai M, Honda H, et al. Development of a new transformationmethod using magnetite cationic liposomes and magnetic selection of transformed cells[J]. Biotechnol Lett, 2000, 22:999.
[87] Zhou YM, Zhong CY, Kennedy IM, et al. Pulmonary responses of acute exposure to ultrafine iron particles in healthy adult rats[J]. Environ Toxicol, 2003, 18:227-235.
[88] Brown LM, Collings N, Harrison RM, et al. Ultrafine particles in the atmosphere: Introduction[J]. Philos Trans R Soc Lond A, 2000, 358:2563-2565.
[89]顾宁,张宇,马明,等.恶性肿瘤局部热疗用纳米磁性材料[J].新材料产业, 2004, 12:54-56.
[90]王国斌,肖勇,陶凯雄,等.纳米级四氧化三铁的药物动力学和组织分布研究[J].中南药学, 2005, 3(1):5-7.
[91]范我,杨凯,钱建华,等. 59Fe示踪法测定纳米级磁性氧化铁在小鼠体内的分布[J].同位素, 2001, 14(1):31- 35.
[92]施建华,吴信陶,樊明信,等.四氧化三铁超微粒子的毒性及其在小鼠体内的分布和排泄[J].中华物理医学杂志, 1995, 17(2):71-73.
[93] Tapan KJ, Maram KR, Marco AM, et al. Biodistribution, Clearance, and Biocompatibility of Iron Oxide Magnetic Nanoparticles in Rats[J]. Molecular Pharmaceutics, 2007, 5(2):316-327.
[94]刘岚,唐萌,刘璐,等. Fe2O3-Glu纳米颗粒在小鼠体内的代谢动力学研究[J].环境与职业医学, 2006, 23 (1):1-3.
[95]张景云,候慧茹,张何,等.新型磁共振对比剂超顺磁r-Fe纳米微粒脂质体毒理学研究[J].中国新药杂志, 2002, 11(3): 213- 215.
[96]庞小峰,张怀武,邓波,等.纳米尺度物质的生物效应和安全性[J].物理, 2006, 35(4):286-293.
[97] Moroz P, Jones SK, Metcalf C, et al. Hepatic clearance of arterially infused ferromagnetic particles[J]. Int J Hyperthermia, 2003, 19(1):23-34.
[98]刘岚,唐萌,顾宁,等. Nano-Fe2O3-Glu的急性和长期毒性研究[J].环境与职业医学, 2004, 2(6):430-433.
[99]王天成,贾光,沈惠麟,等.纳米铁材料对小鼠血清生化指标的影响[J].环境与职业医学, 2004, 21(6):434-436.
[100]刘岚,唐萌,何整,等. Fe3O4及Fe3O4-Glu纳米颗粒的毒性和致突变性研究[J].环境与职业医学, 2004, 21(1):14-17.
[101]李倩,唐萌,班婷婷,等.不同尺寸Fe2O3纳米粒子的细胞毒性及氧化作用研究[J].中国公共卫生, 2005, 21(5):589-591.
[102]居胜红,滕皋军,毛曦,等.脐血间充质干细胞磁探针标记和MR成像研究[J].中华放射学杂志, 2005, 39(1):101-105.
[103]何跃明,吕新生,艾中立,等.纳米及微米磁微粒磁性顺铂微球对肝癌细胞的影响及机理[J].中国普通外科杂志, 2004, 13(3):179-184.
[104] Arbab AS, BashawLA, Miller BR, et al. Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging[J]. Radiology, 2003, 229(3):838-846.
[105] Riviere C, Boudghene FP, Gazeau F, et al. Iron oxide nanoparticle-labeled rat smooth muscle cells: Cardiac MR imaging for cell graft monitoring and quantitation[J]. Radiology, 2005, 235(3):959-967.
[106] Hasegawa M, Hanaichi T, Shoji H, et al. Biological behavior of dextran-iron oxide magnetic fluid injected intravenously in rats[J]. Jpn J Appl Phys Part 1-Regular Papers Short Notes, 1998, 37(3A):1029-1032.
[107] Arbab AS, Yocum GT, Kalish H, et al. Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI[J]. Blood, 2004, 104(4):1217-1223.
[108]马勇杰,李红,许凯黎,等.人肺腺癌细胞SPC-A1与人胚肺细胞WI-38对纳米颗粒吞噬作用的研究[J].肿瘤, 2005, 25(1):7-9.
[109]马明,朱毅,张宇,等.四氧化三铁纳米粒子与癌细胞相互作用的初步研究[J].东南大学学报(自然科学版), 2003, 33 (2): 206-207.
[110]沈洪兴,王光毅,于宝军,等.严重烫伤大鼠心、肝、肾组织Na+,K+ -ATP酶、Ca2+ -ATP酶活性的变化.第二军医大学学报, 1998, 19(3):247-249.
[111]龚守良主编.实用医学实验技术[M].长春:吉林科学技术出版社, 1991,第一版, 238.
[112]汪冰,丰伟悦,赵宇亮,等.纳米材料生物效应及其毒理学研究进展[J].中国科学B辑化学, 2005, 35 (1):1-10.
[113] Service R F. Nanomaterials show signs of toxicity[J]. Science, 2003, 300 (11):243.
[114] Brumfiel G. A little knowledge. Nature, 2003, 424(17):246.
[115] Zhang Wei-xian. Environmental technologies at the nanoscale[J]. Environ Sci Technol, 2003, 37(5):103-108.
[116] Kelly K L. Nanotechno logy grows up[J]. Science, 2004, 304:1732-1734.
[117]张胜年主编.原文导读:纳米颗粒的危害评估[J].环境与健康展望, 2007, 115(4C):40.
[118] Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue[J]. Adv Drug Del Rev, 2003, 55:329-347.
[119]王煦漫,张彩宁,王晓亮,等.包覆双层表面活性剂Fe3O4纳米粒子的制备及性能研究[J].化工新型材料, 2007, 35:67-68.
[120] Markus Z. Magnetic fluid and nanoparticle applications to nanotechnology[J]. Journal of Nanoparticle Research, 2001, (3):73-78.
[121]李德才.磁性液体研磨技术[J].新技术新工艺,1998 , (5) :325.
[122]许孙曲,许菱.磁流体研究的若干新成果[J].新技术新工艺, 2001, (10):15 -18.
[123] Nakatsuka K. Trends of magnetic fluid applications in Japan[J]. Magn Mater, 1993, 122:387-394.
[124] Yu LQ, Zheng LJ, Yang JX. Study of preparation and properties on magnetization and stability for ferromagnetic fluids[J] .Materials Chemistry and Physics, 2000, 66:6-9.
[125]尧德中,熊茜桃.生物合成磁铁矿及其应用[J].大自然探索, 1995, 14 (52):63.
[126] Kim DK, Zang Y, Voit W, et al. Superparamagnetic iron oxide nano- particles for biomedical applications[J]. Scripta Mater, 2001, 44:1713-1717.
[127] Kim JS, Yoon T-J, Yu KN, et al. Toxicity and tissue distribution of magnetic nanoparticles in mice[J]. Toxicol Sci, 2006, 89(1):338-347.
[128] Lacava ZGM, Azevedo RB, Martins EV, et al. Biological effects of magnetic fluids: toxicity studies[J]. J Magn Magn Mater, 1999, 201(1-3):431-434.
[129]徐雪青,沈辉,许家瑞,等.纳米水基磁性液体在肿瘤治疗领域的研究进展[J].化工进展, 2006, 25(4):480-484.
[130] Lubbe AS, Bergemann C, Huhnt W, et al. Preclinical experience with magnetic drug targeting:Tolerance and efficiency[J]. Cancer Res, 1996, 56:4694 -4701.
[131] Lacava L, Garcia V, Kuckelhaus S, et al. Long-term retention of dextran- coated magnetite nanoparticles in the liver and spleen[J]. J Magnetism and Magnetic Mater, 2004, (272-276):2434-2435. 132] Hafeli U O, Gayle J P. In vit ro and in vivo toxicity of magnetic microspheres[J]. JMMM, 1999, 194:76-82.
[133] Wagner S , Schnorr J , Pilgrimm H, et al. Monomer-coated very small superpara- magnetic iron oxide particles as contrast medium for magnetic resonance imaging : preclinical in vivo characterization[J]. Invest Radiol, 2002, 37:167.
[134] Lawaczeck R , Bauer H , Frenzel T, et al. Magnetic iron oxide particles coated with carboxydextran for parenteral administration and liver contrasting[J]. Acta Radiol, 1997, 38:584.
[135]王国斌,夏泽锋,陶凯雄,等.医用纳米级Fe3O4磁流体的急性毒理学实验研究[J].华中科技大学学报(医学版), 2004, 33(4):452-456.
[136]孙秋艳,郭春丽.纳米粒子在润滑油中的分散稳定性研究[J].河北化工, 2008, 31(2):7-9.
[137]胡纪华,杨兆禧,郑忠.胶体与界面化学[M].广州:华南理工大学出版社, 1997.
[138] Patricia P.M, Daniela M.O, Karina F.R, et al. Studies of cell toxicity of complexes of magnetic fluids and biological macromolecules[J]. JMMM, 2005, 293:293-297.
[139] S.I.Park, J.H.Lim, J.H.Kim, et al. Toxicity estimation of magnetic fluids in biological test[J]. JMMM, 2006, 304:e406-e408.
[140] AkermanME, ChanWC, Laakkonen P, et al. Nanocrystal targeting in vivo [ J ]. Proc Natl Acad Sci USA, 2002, 99(20):12617-12621.
[141] Kreuter J. Influence of the surface p roperties on nanoparticle-mediated transport of drugs to the brain [J]. J Nanosci Nanotechnol, 2004, 4(5) :484–488.
[142] Neuberger T, Schopf B, Hofmann H, et al. Superparamagnetic nanoparticles for biomedical applications: Possibilities and limitations of a new drug deliverysystem [J]. J. Magn. Magn. Mater, 2005, 293:483-496.
[143] Briley-Saebo K, Bjornerud A, Grant D, et al. Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging[J]. Cell Tissue Res, 2004, 316:315-323.
[144] Okon E, Pouliquen D, Okon P, et al. Biodegradation of magnetite dextran nanoparticles in the rat. A histologic and biophysical study[J]. Lab. Invest, 1994, 71:895-903.
[145] Chouly C, Pouliquen D, Lucet I, et al.Development of superparamagnetic nanoparticles for MRI: effect of particle size, charge and surface nature on biodistribution[J]. J.Microencapsul, 1996, 13:245-255.
[146]龙玲,袁正,尹龙萍,等.纯磁性纳米四氧化三铁颗粒对肝癌和肺腺癌细胞活性的影响[J].毒理学杂志, 2009, 23(2):89-92.
[147] Chiuwing Lam, John J, Jam, et al. Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation[J]. Toxicology Sci, 2004, 77:126-133.
[148]范轶欧,张颖花,张晓芃,等.吸入二氧化硅纳米颗粒和微米颗粒对雄性大鼠精子及其功能的影响[J],卫生研究, 2006, 35(5) :549-553.
[149]梁戈玉,浦跃朴,尹立红,等.纳米二氧化钛经气管染毒对大鼠肝、肾的影响[J].癌变畸变突变, 2009, 21(2):81-84.
[150] Monica PG, Renata MP, Sacha BC, et al. Morphological analysis of mouse lungs after treatment with magnetite-based magnetic fluid stabilized with DMSA[J]. Journal of Magnetism and Magnetic Materials, 2005, 293:277-282.
[151] Hoshino A, Fujioka K, Oku T, et al. Physicochemical properties and cellular toxicity of nanocrystal quantum dots depend on their surface modification[J]. Nano Lett, 2004, 4(11):2163-2169.
[152] Thomas R.P, Jennifer D, Blackwella V I, et al. Nanotoxicity of iron oxide nanoparticle internalization in growing neurons[J]. Biomaterials, 2007, 28:2572- 2581.
[153]姚泰,吴博威.生理学(第6版)[M].北京:人民卫生出版社,2005, 8.
[154]金惠铭,王建枝.病理生理学(第6版)[M].北京:人民卫生出版社, 2006, 6.
[155]王天成,汪冰,丰伟悦,等.纳米锌对小鼠血清生化指标的影响[J].中国公共卫生, 2006, 22(8):934-935.
[156] Chen KZ, Hu YH. Cytotoxic Effects of Magnetic Iron Oxide Nanoparticles on HeLa and HEK 293 Cells[J]. Nanosci Nanotechnol, 2007, 4:8-11.
[157] Gupta AK, Gupta M. Cytotoxicity Suppression and Cellular Uptake Enhancement of Surface Modified Magnetic Nanoparticles[J]. Biomaterials, 2005, 26:1565-1573.
[158] Berry CC , Well S , Charles S, et al. Cell Response to Dextran-derivatised Iron xide Nanoparticles Post Internalization[J]. Biomaterials, 2004, 25:5405-5413.
[159]王天成,贾光,王翔,等.纳米氧化铁黄材料对小鼠血清生化指标的影响[J].实用预防医学, 2006, 13(3):486-487.
[160]张巧凤.新生儿缺氧缺血性脑病心肌酶活性变化及其临床意义[J].中国临床医生, 2006, 34 (3):46-47.
[161]刘金美.心肌酶同功酶检测在新生儿缺氧缺血性脑病中的诊断价值[J].现代医药卫生, 2006, 22(3):330.
[162]曾少勇,幸丽娅.急性心肌梗死患者血清肌钙蛋白、心肌酶谱和C-反应蛋白水平的诊断价值[J].国际医药卫生导报, 2006, 12(11): 67-68.
[163]赖永洪,翟莺莺,叶铁真.槲皮素对柔红霉素所致心肌损伤的保护作用[J].现代临床医学生物工程学杂志, 2005,11(1):15-18.
[164] Oberd?rster G, Finkelstein J N, Johnston C. Acute pulmonary effects of ultrafine particles in rats and mice[J]. Res Rep Health Eff Inst, 2000, 96:5-74.
[165]王天成,贾光,沈惠麟,等.纳米铁材料对小鼠血清生化指标的影响[J].环境与职业医学, 2004, 21(6):434-436.
[166]王天成,贾光,王翔,等.纳米铁、纳米氧化锌和纳米氧化镁对小鼠血清乳酸脱氢酶和α-羟丁酸脱氢酶活性的影响[J].实用预防医学, 2006, 13(5):1101 -1102.
[167]张豪,沈明山,方宏清,等.转铁蛋白/转铁蛋白受体介导的药物运输[J].中国生物工程杂志, 2004, 24(6):1-5.
[168]王赟,张云霞.转铁蛋白与总铁结合力的相关性研究[J].实用医技杂志, 2007, 14(30):4121-4122.
[169] Qian ZM, Tang PL , Wang Q. Iron crosses the endosomal membrane by a carrier-mediated process[J]. Prog Biophys Molec Biol, 1997, 67:12-15.
[170]王娜,关鹏,常彦忠,等.铁代谢与心血管损伤的研究进展[J].中国老年学杂志, 2008, 28(21):2167-2169.
[171]陈莹莹,钱忠明.心脏铁代谢及其相关疾病研究进展[J].中华心血管病杂志, 2002, 30(1):59-62.
[172]王迪浔,金惠铭.人体病理生理学[M].人民卫生出版社,第2版:520-524.
[173]汤新之,崔乃杰.临床生物化学[M].天津:天津科学技术出版社, 1999.
[174] Voogd A, Sluiter W, van Ei jk HG, et al. Low molecular weight iron and the oxygen paradox in isolated rat hearts [J]. J Clin Invest, 1992, 90:2050-2055.
[175] Bourrinet P, Bengele H, Bonnemain B, et al. Preclinical safety and pharmacokinetic profile of ferumoxtran-10 an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent[J]. Invest Radiol, 2006, 41:313-324.
[176]杨瑞华.自由基及其清除剂与细胞凋亡的关系[J].国外医学.卫生学分册, 1997, 24(4):202-206.
[177] Knight J A. The produce and theories of aging[J]. Ann Clin Lab sci, 1995, 25:1.
[178] HOGBERGJ , ORRENIUS S . Lipid peroxidation in isolated nepatocytes[J] . Eur J Biochem, 1975, 50:595-602.
[179]刘锦波,唐天驷,肖德生.游离铁在脊髓组织匀浆脂质过氧化中的作用[J].中国急救医学, 2002, 22(3):147-148.
[180]孙长颢,王朝旭.铁负荷对大鼠脂质过氧化作用影响及抗氧化维生素对其抑制作用[J].卫生研究, 2003, 32(3):209-211.
[181]王小雪,王朝旭,孙长颢,等.铁负荷大鼠肝脏及脑组织脂质过氧化相关研究[J].中国公共卫生, 2003, 19(8):932-934.
[182]王国斌,肖勇,陶凯雄等.纳米级四氧化三铁的药物动力学和组织分布研究[J].中南药学, 2005, 3(1):5-7.
[183]高娃.四氧化三铁的结构[J].化学教室, 2001, 13(8):68.
[184]刘岚,唐萌,顾宁,等. Nano-Fe2O3-Glu的急性和长期毒性研究[J].环境与职业医学, 2004, 21 (6):430-433.
[185]金惠铭,王建枝主编.缺氧.病理生理学[M].人民卫生出版社,第6版:85-86.
[186]魏登邦,张宝琛.缺氧引起的自由基增殖及其损伤[J].生物学通报, 2003, 38(1):7-10.
[187]芦晓磊.铁球铁质沉着症的研究进展[J].郧阳医学院学报, 2000, 19(1):62-64.
[188]崔萌萌,王江伟,曹毅,等.碳纳米管对小鼠心脏和肝脏组织SOD影响的研究[J].医学研究杂志, 2008, 37(2):21-23.
[189]朱航,张守华,雷蕾.不同剂量铁对小鼠肝脏损伤作用的实验研究[J].热带医学杂志, 2007, 7(2):129-131.
[190]韩玲,陈可冀.大鼠心肌整体缺血及离体再灌注致生物膜的损伤作用.中国应用生理学杂志2002,18(1):59-62
[191]包维民,郭永章,唐映梅,等.大鼠肝脏冷/热缺血再灌注损伤钠钾ATP酶、钙ATP酶及镁ATP酶与肝细胞死亡方式的研究[J].中国现代普通外科进展, 2004, 7(2) :343-346.
[192] Ostadal P, Elmoselhi AB, Zdobnicka I, et al. Ischemia-reperfusion alters gene expression of Na +-K+ ATPase isoforms in rat heart [J]. Biochem Biophys Res Commun, 2003, 306(2):457-464.
[193]郭曲练,潭秀娟,蔡宏伟,等.亚低温对完全性脑缺血再灌注后丙二醛含量和超氧化物歧化酶的影响[J].中华创伤杂志, 1997, 13(1) :10-13.
[194]唐益忠,陈侠英,汪昌荣,等.丹参对烫伤大鼠早期心肌组织ATP酶活性的影响[J].中华烧伤杂志, 2003, 19(4):242
[195]黄辉,陈建萍.心肌细胞凋亡机制的研究进展[J].西藏医药杂志, 2000, 21(2):30-32.
[196] Takeda K, Yu ZX, Nishikawa, et al. Immunohisto-chemical study of poptosis in the bulbus cordis of developing rat heart [J]. Circulation, 1995, 92:306-309
[197] James TNMD. Normal and abnormal consequence of apoptosis in the human heart from postnatal morphogenesis to paroxysmal arrhythmias[J]. Circulation, 1994, 90:556-573.
[198] Matsuzawa A, Ichijo H.Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signalregulating kinase 1[J]. J Biochem, 2001, 130:1-8.
[199] Tanaka M, Ito H, Adachi S, et al. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes[J]. Circ Res, 1994, 75:426- 433.
[200] Gottlieb RA, Burleson KO, Kloner RA, et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes[J]. J Clin Invest, 1994,94:1621-1628.
[201] Itoh G, Tamura J, Suzuki M, et al. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis[J]. Am J Pathol, 1995, 146:1325-1331.
[202] Kajstura J, Zhang X, Liu Y, et al. The cellular basis of pacing-induced dilated cardiomyopathy: myocyte cells loss and myocyte cellular reactive hypertrophy [J]. Circulation, 1995, 92:2306-2317.
[203] Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure[J]. Am J Pathol, 1996, 148:141-149.
[204] Teiger E, Than VD, Richard L, et al. Apoptosis in pressure overload-induced heart hypertrophy in the rat[J]. J Clin Invest, 1996, 97:2891-2897.
[205] Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart[J].N Engl J Med, 1997, 336:1131-1141.
[206] Saraste A, Pulkki K, Kallajoki M, et al.Apoptosis in human acute myocardial infarction[J]. Circulation, 1997, 95:320-323.
[207] Scarabellia TM, Stephanou A, Pasini E, et al. Different signalling pathways induce apoptosis in endothelial cells and cardiac myocytes during is chemia/reperfusion injury[J]. Cir Res, 2002, 90:745-748.
[208]张磊,张鳞.急性心肌梗死患者细胞凋亡水平影响因素的分析.中国医药, 2006, 1(6):325-326.
[209] Long X, Boluyt MO, Cirielli C, et al. Enhanceed expression of P53 in hypoxia induced apoptosis of cultured neonatal rat cardiomyocytes. Circulation, 1995, 92: 722-725.
[210] Orlinick JR, Vaishnaw AK, Elkon KB. Structure and function Fas/Fas ligand[J]. IntRev Immunol. 1999, 18(4):293-308.
[211]赵明中,陈运贞,李媛媛,等.大鼠心肌缺血/再灌注损伤心肌细胞凋亡与Fas、FasL基因表达的变化[J].中华心血管杂志, 2001, 29(10):605-608.
[212]潘越江,王铭辉,张华,等.穿孔素、粒酶B、Fas、Fas-L和Caspase3在心肌细胞凋亡中的作用和相互关系[J].广西医学, 2006, 28(7):967-971.
[213]李滨,童坦军. p53基因研究新进展[J].国外医学分子生物学分册, 1995, 17(3):106.
[214] Pierzchalski P, Reiss K, Cheng W,et al. p53 induces myocyte apoptosis via the activation of the renin-angiotensin system[J]. Exp Cell Res, 1997, 234(1):57-65.
[215]贾玉巧,赵晓红,郭新彪.大气PM10对两种不同细胞分泌炎性细胞因子的影响[J].卫生研究, 2006, 35(5):557-560.
[216] Pope CA, Burnett RT, Thurston GD, et al. Cardiovascular mortality and long- time exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease[J]. Circulation, 2004, 109:71-77.
[217] Ibald MA, Stieber J, Wichmann HE, et al. Effects of air pollution on blood pressure: a population-based approach[J]. Am J Pub Health, 2001, 91:571-577.
[218] Hong YC, Lee JT, Kim H, et al. Air pollution: a new risk factor in ischemic stroke mortality[J]. Stroke, 2002, 33:2165-2169.
[219] Tsai SS, Goggins WB, Chiu HF, et al. Evidence for an association between air pollution and daily stroke admissions in Kaohsiung Taiwan[J]. Stroke, 2003, 34:2612-2616.
[220] Morris RD. Airborne particulates and hospital admissions for cardiovascular disease: a quantitative review of the evidence[J]. Envieon Health Perspect, 2001,109:495-500.
[221] Van Eeden SF, Tan WC, Suwa T, et al. Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutions (PM10) [J]. Am J Respire Crit Care Med, 2001, 164:826-830.
[222] Lindmark E, Diderholm E, Wallentin L, et al. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive strategy[J]. JAMA, 2001, 286:2107-2113.
[223] Ramage L, Guy K. Expression of C-reactive protein and heat-shock protein-70 in the lung epithelial cell line A549, in response to PM10 exposure[J]. Inhal Toxicol, 2004,16:447-452.
[224] Gardner SY, Lehmann JR, Costa DL. Oil fly ash-induced elevation of plasma fibrinogen levels in rats[J]. Toxicol Sci, 2000, 56:175-180.
[225] Ghio AJ, Hall A, Bassett MA, et al. Exposure to concentrated ambient particles alters hematologic indices in humans[J]. Inhal Toxicol, 2003, 15:1465-1478.
[226]李玉林主编.病理学[M].北京:人民卫生出版社, 2004.
[2]许海燕,孔桦.纳米材料的研究进展及其在生物医学中的应用[J].基础医学与临床, 2002, 22 (2):97-103.
[3]董晶莹,刘宁.纳米微粒在生物医学领域的应用研究.国外医学生物医学工程分册,2005,28(4):237-240
[4]孟磊,宋增瑛.量子点在生物医学中的应用[J].生物化学与生物物理进展, 2004, 31(2):185-187.
[5]林章碧,张皓,陈奇丹,等.利用水相合成的量子点标记木瓜蛋白酶的研究[J].高等学校化学学报, 2003, 24(4):609-611.
[6] Pathak S, Choi SK, Amhaeim N, et al. Hydroxylated quantum dots as lumi- nescent probes for in situ hybridization[J]. J Am Chem Soci, 2001, 123(17): 4103- 4104.
[7] Damge C, Michel C, AprahanianM, et al. New approach for oral administration of insulin with polyalky-cyanoacrylate nanoparticles as drug carrier[J]. Diabetes, 1988, 37:246.
[8]张磊,平其能,郭健新,等.口服胰岛素纳米脂质体的制备及其降血糖作用[J].中国药科大学学报, 2001, 32:25
[9] Sharma D, Chelvi TP, Kaur J , et al. Novel Taxol for mulation polyvinyp lyrro lidone nanoparticl-encap sulated Taxol for drug delivery in cancer therapy[J]. Oncol Res, 1996, 8: 281
[10]常津,魏民,姚康德.聚原酸酯抗癌药物毫微粒的制备及体外释药研究[J].中国生物医学工程学报, 1999, 18 (2):216.
[11] Jorg Keruter. Nanoparticulate systems for brain delivery of drugs[J]. Adv Drug Deliv Rev, 2001, 47(1):65-81.
[12] Aborl S, Terhan A, Katare OP. Formulation, characterization, and in vitor evaluation of silymarin -loaded lipid micorspheres[J]. Drug Deliver, 2004, 11 (3):185-191.
[13] Kreuater J. Nanoparticles and microparticles for drug and vaccine delivery[J]. JAnat, 1996, 189:503-509.
[14] O’Hagain DT. Theintestinal uptake of particles and the implications for drug and antugen delivery [J]. J Anat, 1996, 189:477-482.
[15] Kim YI, Fluckiger L, Hoffman M, et al. The antihypertensive effect of orally administered nifedip ineloaded nanopart icles in spontaneously by pertensiverats[J]. Br J Pharmacol, 1997, 120 (3):399-407.
[16] Zimmer A, M utschler E, Lambrecht G, et al. Pharmacokinetic and harmacodynamic aspects of an ophthalm ic pilocarpine nanoparticles delivery-system [J]. Pharm Res, 1994, 11 (10):1435-1441.
[17] Truong L, Vu L, Walsh, et al. Gene transfer by DNA-gelatin nano spheres[J]. Arch Biochem Biophys, 1999, 361 (1):47-54
[18] Lambert G, Fattal E, Pinto-Alphanadary H, et al. Polyisobutylcyanoacrylate nanocapsules containing an aqueous core as a novel colloidal carrier for the delivery of oligonucleo tides[J]. Pharm Res, 2000, 17:707-714.
[19] Radwan MA, Zaghloul IY, Aly ZH. In vivo performance of parenteral theophylline-loaded polyisobutyl-cyano-acrylate nanopart icles in rats[J]. Eur J Pharm Sci, 1999, 8 (2) :95-101.
[20]国立秋,梁吉.碳纳米管原子力显微镜探针对生物样品高分辨率成像的研究[J].中国生物医学工程学报, 2004, 23(3):243-246.
[21] Guobao W, Peter X. Structure and properties of nano-hydorxyapatite/polymer composite scaffolds for bone tissue engineering[J]. Biomaterial, 2004, 25: 4749-4757.
[22] Shin M, Yoshimoto H, Vacanti JP. In vivo bone tissue engineering using mesenchymal stem cells on a novel electrospun nanofibrous scaffold[J]. Tissue Eng, 2004, 10(1-2):33-39.
[23] Davda J, Labhasetwar V. Characterization of nanoparticle uptake by endothelial cell[J]. Int J Pharm, 2002, 233(1-2):51-59.
[24] Cognet L, Tardin C, Boyer D, et al. Single metallic nanoparticle imaging for protein detection in cells[J]. Biophysics, 2003, 100(20):11350-11355.
[25] Fan CY, Jiang L. Preparation of hydrophobic nanometer gold particle and theiroptic absorp- tion in chloroform[J]. Langmuir, 1997, 13(11):3059-3062.
[26]沈霞,郭薇. Fe304/葡聚糖/抗体磁性纳米生物探针的制备和层析检测[J].高等学校化学学报, 2004, 25(3):445-447.
[27] Lepek M, PittnerF. Novel transducers for nano-optical biosensorchips based on biological and synthetic polymers with analyte-dependent swelling/shrinking behavior[J]. J Nanosci Nanotechnol, 2004, 4(1-2):106-114.
[28] Bergemann C, Mueller-Schulute D, Oster J, et al. Magnetic ion-exchange nano- and micor-particles for medical, biochemical, and molecular biological applications[J]. J Magn Master, 1999, 194(l):45-52.
[29] Service RF. Nanomaterials show signs of toxicity[J]. Science, 2003, 300 (11) :243.
[30] Brumfiel G. A little known knowledge[J]. Nature, 2003, 424 (17) :246.
[31] Chiu WL, John TJ, Richard MC, et al. Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation[J]. Toxicol Sci, 2004, 77:126- 134.
[32] Borm PJ. Particle toxicology: from coalmining to nanotechnology[J]. Inhal Toxicol, 2002, 14 (3):311 - 324.
[33] Chiu-Wing Lam, James JT, Richard MC, et al. Pulmonary toxicity of single- wall carbon nano- tubes in Mice 7 and 90 days after intratracheal instillation[J]. Toxicological Sciences, 2004, 77(1):126-134.
[34] Warheit DB, Laurence BR, Reed KL, et al. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats[J]. Toxicological Sciences, 2004, 77(1):117-125.
[35] Edilberto B, James BM, Brian AW, et al. Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles[J]. Toxicol Sci, 2004, 77:347-357.
[36] Vincent C. From coal mine dust to quartz; mechanisms of pulmonary pathogenicity[J]. Inhal Toxicol, 2002, 12:7-14.
[37] Eva Oberdorster. Manufactured nanomaterials(fullerenes, C60) induce oxidative stress in the brain of juvenile largemouth bass[J]. Environmental HealthPerspectives, 2004, 112(10):1058-1062.
[38] Oberdorster G, Sharp Z, Atudorei V, et al. Translocation of inhaled ultrafine particles to the brain[J]. Inhalation Toxicology, 2004, 16(6/7):437-446.
[39] Donaldson K, Stone V, Tran CL, et al. Nanotoxicology[J]. Occup Environ Med, 2004, 61(9):727-728.
[40] Nemmar A, Hoet PH, Vanquickenborne B, et al. Passage of inhaled particles into the circulation in humans[J]. Circulation, 2002, 105(4):411-414.
[41] Harder B. Conduit to the brain: particles enter the nervous system via the nose [J]. Science News, 2004, 165(4):54
[42] Chen Z, Meng H, Xing GM, et al. Acute toxicological effects of copper nanoparticles in vivo[J]. Toxicol Lett, 2006, 163:109-120.
[43] Wang B, Feng WY, Wang TC, et al. Acute toxicity of nano- and micro-scale zinc powder in healthy adult mice[J].Toxicol Lett, 2006, 161:115-123.
[44]刘丽萍,肖雁冰,肖子文,等.家兔静脉注射经基磷灰石纳米粒子的反应研究[J].卫生研究, 2005, 34(4):474-476.
[45]刘涛,杨振中,张本界,等.纳米水镁石纤维的细胞毒性与致纤维化作用[J].工业卫生与职业病, 2005, 31(3):134-137.
[46] Laura LD, Dorothy MT, Cheng D, et al. Carboxy-fullerenes as neuroprortective agents[J]. Proc Natl Acad Sci USA, 1997, 94:9434-9439.
[47] Ye C, Chen CY, Chen Z, et al. In situ observation of C60 malonic acid derivative nanoparticles interacting with living cells by fluorescence microscopy[J]. Chinese Science Bulletin, 2006, 51(1):1-5.
[48] Jia G, Wang HF, Yan L, et al. Cytotoxicity of carbo nanomaterials: single-wall nanotube, multi-wall nanotube, and fulerene[J]. Enviorn Sci Technol, 2005, 39:1378- 1383.
[49]刘涛,杨振中,张本界.纳米级水镁石纤维粉尘的体外细胞毒性研究[J].中国职业学, 2005, 32(2):13-14.
[50] Cui DX, Tim FR, Ozkmr CS, et al. Effect of single wall carbon nanotuhes on human HEK293 cells[J]. Toxicol Lett, 2005, 155:73-85.
[51]范轶欧,张颖花,刘冰,等. TiO2、SiO2、Fe纳米及微米粉体对红细胞毒性作用的比较[J].中国工业医学杂志, 2005, 18(2):67-69.
[52] Zhang QW, KusakaY. Comparative injurious and proinflammatory effects of three ultrafine metalsin macrophages from young and old rats[J]. Inhal Toxicol, 2000, 12:267-273.
[53]李海丰,俞光荣,王德平.纳米羟基磷灰石对骨肉瘤U2-OS细胞生长的影响[J].同济大学学报(医学版), 2005, 26(1):35-38.
[54]许艳慧,李四群,李志安.纳米羟基磷灰石复合材料的研究——纳米羟基磷灰石的细胞毒性[J].实用口腔医学杂志, 2004, 20(2):147-150.
[55]何跃明.恶性肿瘤的磁靶向热疗[J].国外医学·物理医学与康复学分册, 2003, 23(2):96-101.
[56] Garret t Q , Chatelier C, Griesser HJ , et al. Effect of charged groups on the adsorption and penetration of proteins onto and into carboxymethylated poly- (HEMA)hydrogels[J]. Biomaterials, 1998, 19 (23):2175- 2186.
[57]贾秀鹏.磁流体在肿瘤学治疗领域的应用进展[J].国外医学(肿瘤学分册), 2002, 29 (3) :187-190.
[58]张阳德,张洋,潘一峰.磁性纳米颗粒靶向性肿瘤热疗的研究进展[J].中国医学工程, 2006, 14(2):148-152.
[59]徐雪青,沈辉,许家瑞,等.纳米水基磁性液体在肿瘤治疗领域的研究进展[J].化工进展, 2006, 25(4):488-493.
[60] Ito A, Kuga Y, Honda H, et al. Magnetite nanoparticle-loaded anti-HER2 immunoliposomes for combination of antibody therapy with hyperthermia [J]. Cancer Letters, 2004, 212:167-175.
[61]Wada S, Tazawa K, Furuta I, et al. Antitumor effect of new local hyperthermia using dextran magnetite complex in hamster tongue carcinoma[J]. Oral Dis, 2003, 9(4):218.
[62] Matsuoka F, Shinkai M, Honda H, et al. Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma[J]. Biomagn Res Techno1, 2004, 2:1-6.
[63]周伟家,何文,赵洪石,等.载药磁性纳米材料研究进展[J].山东轻工业学院学报, 2008, 22(2):5-8.
[64] Cordula C, Sandra R, Joachim T. Improved properties of magnetic particles by combination of different polymer materials particle matrix[J]. J Magn Magn Mater, 2001, (225) :1-7.
[65] Chen HT, Ebner AD, Rosengart AJ, et al . Analysis of magnetic drug carrier particle capture by a magnetizable intravascular stent :1. Parametric study with single wire correlation[J]. J Mag Mag Mater, 2004, 284:181-194.
[66]洪小平,彭图治.功能高分子磁性微球的制备及分析应用[J].分析化学, 2003, 31:789 - 793.
[67] Kubo T, Sugita T, Scimose S, et al. Targeted delivery of anticancer drugs with intravenously administered magnetic liposomes in osteosarcoma-bearing hamsters[J]. Int J Oncol, 2000, 17:309-315.
[68] Tartaj P, Morales MP, Gonzalez-Carrem T, et al . Advanced in magnetic nanoparticles for biotechnology applications[J]. J Mag Mag Mater, 2005, 290-291:28 -34.
[69] Bautista MC, Bomati-Miguel O, Zhang X, et al . Comparative study of ferro fluids based on dextran-coated iron oxide and metal nanoparticles for contrast agents in magnetic resonance imaging[J]. Nanotechnology, 2004, 15:S154-S159.
[70]王晶,徐玉清,王文秀.磁性纳米粒子及其在生物医学中的应用进展[J].药物生物技术, 2007, 14(5):386-390.
[71] Suzuki M, Honda H, Kobayashi T, et al. Development of a target-directed magnetic resonance contrast agent using mono-clonal antibody conjugated magnetic particles[J]. Brain Tumor Pathol, 1996, 13:127.
[72] Stark D. Superparamagnetic iron oxide: Clinical application as a contrast agent for MRI imaging of the liver[J]. Radiology, 1988, 168(2):297-301.
[73] Uchiyama T, Mohri K, Shinkai M, et al. Basic study for brain tumor pisition sensing using amorphous wire MI micro magnetic sensor[J]. Trans I E E J pn, 1999, 119-C:545.
[74] Matsunaga T, Nakayama H, Okochi M, et al . Fluorescent detection of cyanobacterial DNA using bacterial magnetic particles on a MAG-microarray[J].Biotechnol Bioeng, 2001, 73:400-405.
[75] Holschuh K, Schwammle A. Preparative purification of antibodies with protein A: a5n alterna- tive to conventional chromatograpy[J]. J Mag Mag Mater, 2005, 293:345-348.
[76] Demirel D, Ozdural A R, Mutlu M, et al. Preparation and characterization of magnetic duolite -polystyrene composite particles for enzyme immobilization[J]. J Food Engineering, 2004, 62:203-208.
[77]王秀利,聂立波.磁性纳米颗粒在生物医学领域中的应用[J].化学通报, 2009, 6:489-495.
[78] Schluep T, Cooney CL. Purification of plasmids by triplex affinity interaction[J]. Nucleic Acids Res, 1998, 26:4524.
[79] Rudi K, Kroken M, Dahlberg OJ, et al. Rapid, universal method to isolate PCR ready DNA using magnetic beads[J]. Biotechniques, 1997, 22:506.
[80] Oster J, Parker J, Brassard L. Polyvinyl-alcohol-based magnetic beads for rapid and efficient separation of specific or unspecific nucleic acid sequences[J]. Journal of magnetism and Magnetic Materials, 2001, 225:145.
[81] Xie Xin, Zhang Xu, Zhang Huan, et al. Preparation and application of surface -coated superparamagnetic nanobeads in the isolation of genomic DNA[J]. Journal of magnetism and magnetic materials, 2004, 277:16.
[82]谢欣,张旭,高华方,等.基于多功能纳米磁珠的DNA制备与基因分型[J].科学通报, 2004, 49 (6) :541.
[83] Spanova A, Rittich B, Horak D, et al. Immunomagnetic seperation and detection of Salmonella cells using newly designed carriers[J]. J Chromatography A, 2003, 1009:215-221.
[84] Scherer F, Anton M, Schilinger U, et al. Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo[J]. Gene Ther, 2002, 9:102.
[85] Krotz F, Wit C, Sohn HY, et al. Magnetofection a highly tool for antisense oligonucleotide delivery in vitro and in vivo[J]. Mol Ther, 2003, 7(5) :700
[86] Nagatani N, Shinkai M, Honda H, et al. Development of a new transformationmethod using magnetite cationic liposomes and magnetic selection of transformed cells[J]. Biotechnol Lett, 2000, 22:999.
[87] Zhou YM, Zhong CY, Kennedy IM, et al. Pulmonary responses of acute exposure to ultrafine iron particles in healthy adult rats[J]. Environ Toxicol, 2003, 18:227-235.
[88] Brown LM, Collings N, Harrison RM, et al. Ultrafine particles in the atmosphere: Introduction[J]. Philos Trans R Soc Lond A, 2000, 358:2563-2565.
[89]顾宁,张宇,马明,等.恶性肿瘤局部热疗用纳米磁性材料[J].新材料产业, 2004, 12:54-56.
[90]王国斌,肖勇,陶凯雄,等.纳米级四氧化三铁的药物动力学和组织分布研究[J].中南药学, 2005, 3(1):5-7.
[91]范我,杨凯,钱建华,等. 59Fe示踪法测定纳米级磁性氧化铁在小鼠体内的分布[J].同位素, 2001, 14(1):31- 35.
[92]施建华,吴信陶,樊明信,等.四氧化三铁超微粒子的毒性及其在小鼠体内的分布和排泄[J].中华物理医学杂志, 1995, 17(2):71-73.
[93] Tapan KJ, Maram KR, Marco AM, et al. Biodistribution, Clearance, and Biocompatibility of Iron Oxide Magnetic Nanoparticles in Rats[J]. Molecular Pharmaceutics, 2007, 5(2):316-327.
[94]刘岚,唐萌,刘璐,等. Fe2O3-Glu纳米颗粒在小鼠体内的代谢动力学研究[J].环境与职业医学, 2006, 23 (1):1-3.
[95]张景云,候慧茹,张何,等.新型磁共振对比剂超顺磁r-Fe纳米微粒脂质体毒理学研究[J].中国新药杂志, 2002, 11(3): 213- 215.
[96]庞小峰,张怀武,邓波,等.纳米尺度物质的生物效应和安全性[J].物理, 2006, 35(4):286-293.
[97] Moroz P, Jones SK, Metcalf C, et al. Hepatic clearance of arterially infused ferromagnetic particles[J]. Int J Hyperthermia, 2003, 19(1):23-34.
[98]刘岚,唐萌,顾宁,等. Nano-Fe2O3-Glu的急性和长期毒性研究[J].环境与职业医学, 2004, 2(6):430-433.
[99]王天成,贾光,沈惠麟,等.纳米铁材料对小鼠血清生化指标的影响[J].环境与职业医学, 2004, 21(6):434-436.
[100]刘岚,唐萌,何整,等. Fe3O4及Fe3O4-Glu纳米颗粒的毒性和致突变性研究[J].环境与职业医学, 2004, 21(1):14-17.
[101]李倩,唐萌,班婷婷,等.不同尺寸Fe2O3纳米粒子的细胞毒性及氧化作用研究[J].中国公共卫生, 2005, 21(5):589-591.
[102]居胜红,滕皋军,毛曦,等.脐血间充质干细胞磁探针标记和MR成像研究[J].中华放射学杂志, 2005, 39(1):101-105.
[103]何跃明,吕新生,艾中立,等.纳米及微米磁微粒磁性顺铂微球对肝癌细胞的影响及机理[J].中国普通外科杂志, 2004, 13(3):179-184.
[104] Arbab AS, BashawLA, Miller BR, et al. Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging[J]. Radiology, 2003, 229(3):838-846.
[105] Riviere C, Boudghene FP, Gazeau F, et al. Iron oxide nanoparticle-labeled rat smooth muscle cells: Cardiac MR imaging for cell graft monitoring and quantitation[J]. Radiology, 2005, 235(3):959-967.
[106] Hasegawa M, Hanaichi T, Shoji H, et al. Biological behavior of dextran-iron oxide magnetic fluid injected intravenously in rats[J]. Jpn J Appl Phys Part 1-Regular Papers Short Notes, 1998, 37(3A):1029-1032.
[107] Arbab AS, Yocum GT, Kalish H, et al. Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI[J]. Blood, 2004, 104(4):1217-1223.
[108]马勇杰,李红,许凯黎,等.人肺腺癌细胞SPC-A1与人胚肺细胞WI-38对纳米颗粒吞噬作用的研究[J].肿瘤, 2005, 25(1):7-9.
[109]马明,朱毅,张宇,等.四氧化三铁纳米粒子与癌细胞相互作用的初步研究[J].东南大学学报(自然科学版), 2003, 33 (2): 206-207.
[110]沈洪兴,王光毅,于宝军,等.严重烫伤大鼠心、肝、肾组织Na+,K+ -ATP酶、Ca2+ -ATP酶活性的变化.第二军医大学学报, 1998, 19(3):247-249.
[111]龚守良主编.实用医学实验技术[M].长春:吉林科学技术出版社, 1991,第一版, 238.
[112]汪冰,丰伟悦,赵宇亮,等.纳米材料生物效应及其毒理学研究进展[J].中国科学B辑化学, 2005, 35 (1):1-10.
[113] Service R F. Nanomaterials show signs of toxicity[J]. Science, 2003, 300 (11):243.
[114] Brumfiel G. A little knowledge. Nature, 2003, 424(17):246.
[115] Zhang Wei-xian. Environmental technologies at the nanoscale[J]. Environ Sci Technol, 2003, 37(5):103-108.
[116] Kelly K L. Nanotechno logy grows up[J]. Science, 2004, 304:1732-1734.
[117]张胜年主编.原文导读:纳米颗粒的危害评估[J].环境与健康展望, 2007, 115(4C):40.
[118] Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue[J]. Adv Drug Del Rev, 2003, 55:329-347.
[119]王煦漫,张彩宁,王晓亮,等.包覆双层表面活性剂Fe3O4纳米粒子的制备及性能研究[J].化工新型材料, 2007, 35:67-68.
[120] Markus Z. Magnetic fluid and nanoparticle applications to nanotechnology[J]. Journal of Nanoparticle Research, 2001, (3):73-78.
[121]李德才.磁性液体研磨技术[J].新技术新工艺,1998 , (5) :325.
[122]许孙曲,许菱.磁流体研究的若干新成果[J].新技术新工艺, 2001, (10):15 -18.
[123] Nakatsuka K. Trends of magnetic fluid applications in Japan[J]. Magn Mater, 1993, 122:387-394.
[124] Yu LQ, Zheng LJ, Yang JX. Study of preparation and properties on magnetization and stability for ferromagnetic fluids[J] .Materials Chemistry and Physics, 2000, 66:6-9.
[125]尧德中,熊茜桃.生物合成磁铁矿及其应用[J].大自然探索, 1995, 14 (52):63.
[126] Kim DK, Zang Y, Voit W, et al. Superparamagnetic iron oxide nano- particles for biomedical applications[J]. Scripta Mater, 2001, 44:1713-1717.
[127] Kim JS, Yoon T-J, Yu KN, et al. Toxicity and tissue distribution of magnetic nanoparticles in mice[J]. Toxicol Sci, 2006, 89(1):338-347.
[128] Lacava ZGM, Azevedo RB, Martins EV, et al. Biological effects of magnetic fluids: toxicity studies[J]. J Magn Magn Mater, 1999, 201(1-3):431-434.
[129]徐雪青,沈辉,许家瑞,等.纳米水基磁性液体在肿瘤治疗领域的研究进展[J].化工进展, 2006, 25(4):480-484.
[130] Lubbe AS, Bergemann C, Huhnt W, et al. Preclinical experience with magnetic drug targeting:Tolerance and efficiency[J]. Cancer Res, 1996, 56:4694 -4701.
[131] Lacava L, Garcia V, Kuckelhaus S, et al. Long-term retention of dextran- coated magnetite nanoparticles in the liver and spleen[J]. J Magnetism and Magnetic Mater, 2004, (272-276):2434-2435. 132] Hafeli U O, Gayle J P. In vit ro and in vivo toxicity of magnetic microspheres[J]. JMMM, 1999, 194:76-82.
[133] Wagner S , Schnorr J , Pilgrimm H, et al. Monomer-coated very small superpara- magnetic iron oxide particles as contrast medium for magnetic resonance imaging : preclinical in vivo characterization[J]. Invest Radiol, 2002, 37:167.
[134] Lawaczeck R , Bauer H , Frenzel T, et al. Magnetic iron oxide particles coated with carboxydextran for parenteral administration and liver contrasting[J]. Acta Radiol, 1997, 38:584.
[135]王国斌,夏泽锋,陶凯雄,等.医用纳米级Fe3O4磁流体的急性毒理学实验研究[J].华中科技大学学报(医学版), 2004, 33(4):452-456.
[136]孙秋艳,郭春丽.纳米粒子在润滑油中的分散稳定性研究[J].河北化工, 2008, 31(2):7-9.
[137]胡纪华,杨兆禧,郑忠.胶体与界面化学[M].广州:华南理工大学出版社, 1997.
[138] Patricia P.M, Daniela M.O, Karina F.R, et al. Studies of cell toxicity of complexes of magnetic fluids and biological macromolecules[J]. JMMM, 2005, 293:293-297.
[139] S.I.Park, J.H.Lim, J.H.Kim, et al. Toxicity estimation of magnetic fluids in biological test[J]. JMMM, 2006, 304:e406-e408.
[140] AkermanME, ChanWC, Laakkonen P, et al. Nanocrystal targeting in vivo [ J ]. Proc Natl Acad Sci USA, 2002, 99(20):12617-12621.
[141] Kreuter J. Influence of the surface p roperties on nanoparticle-mediated transport of drugs to the brain [J]. J Nanosci Nanotechnol, 2004, 4(5) :484–488.
[142] Neuberger T, Schopf B, Hofmann H, et al. Superparamagnetic nanoparticles for biomedical applications: Possibilities and limitations of a new drug deliverysystem [J]. J. Magn. Magn. Mater, 2005, 293:483-496.
[143] Briley-Saebo K, Bjornerud A, Grant D, et al. Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging[J]. Cell Tissue Res, 2004, 316:315-323.
[144] Okon E, Pouliquen D, Okon P, et al. Biodegradation of magnetite dextran nanoparticles in the rat. A histologic and biophysical study[J]. Lab. Invest, 1994, 71:895-903.
[145] Chouly C, Pouliquen D, Lucet I, et al.Development of superparamagnetic nanoparticles for MRI: effect of particle size, charge and surface nature on biodistribution[J]. J.Microencapsul, 1996, 13:245-255.
[146]龙玲,袁正,尹龙萍,等.纯磁性纳米四氧化三铁颗粒对肝癌和肺腺癌细胞活性的影响[J].毒理学杂志, 2009, 23(2):89-92.
[147] Chiuwing Lam, John J, Jam, et al. Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation[J]. Toxicology Sci, 2004, 77:126-133.
[148]范轶欧,张颖花,张晓芃,等.吸入二氧化硅纳米颗粒和微米颗粒对雄性大鼠精子及其功能的影响[J],卫生研究, 2006, 35(5) :549-553.
[149]梁戈玉,浦跃朴,尹立红,等.纳米二氧化钛经气管染毒对大鼠肝、肾的影响[J].癌变畸变突变, 2009, 21(2):81-84.
[150] Monica PG, Renata MP, Sacha BC, et al. Morphological analysis of mouse lungs after treatment with magnetite-based magnetic fluid stabilized with DMSA[J]. Journal of Magnetism and Magnetic Materials, 2005, 293:277-282.
[151] Hoshino A, Fujioka K, Oku T, et al. Physicochemical properties and cellular toxicity of nanocrystal quantum dots depend on their surface modification[J]. Nano Lett, 2004, 4(11):2163-2169.
[152] Thomas R.P, Jennifer D, Blackwella V I, et al. Nanotoxicity of iron oxide nanoparticle internalization in growing neurons[J]. Biomaterials, 2007, 28:2572- 2581.
[153]姚泰,吴博威.生理学(第6版)[M].北京:人民卫生出版社,2005, 8.
[154]金惠铭,王建枝.病理生理学(第6版)[M].北京:人民卫生出版社, 2006, 6.
[155]王天成,汪冰,丰伟悦,等.纳米锌对小鼠血清生化指标的影响[J].中国公共卫生, 2006, 22(8):934-935.
[156] Chen KZ, Hu YH. Cytotoxic Effects of Magnetic Iron Oxide Nanoparticles on HeLa and HEK 293 Cells[J]. Nanosci Nanotechnol, 2007, 4:8-11.
[157] Gupta AK, Gupta M. Cytotoxicity Suppression and Cellular Uptake Enhancement of Surface Modified Magnetic Nanoparticles[J]. Biomaterials, 2005, 26:1565-1573.
[158] Berry CC , Well S , Charles S, et al. Cell Response to Dextran-derivatised Iron xide Nanoparticles Post Internalization[J]. Biomaterials, 2004, 25:5405-5413.
[159]王天成,贾光,王翔,等.纳米氧化铁黄材料对小鼠血清生化指标的影响[J].实用预防医学, 2006, 13(3):486-487.
[160]张巧凤.新生儿缺氧缺血性脑病心肌酶活性变化及其临床意义[J].中国临床医生, 2006, 34 (3):46-47.
[161]刘金美.心肌酶同功酶检测在新生儿缺氧缺血性脑病中的诊断价值[J].现代医药卫生, 2006, 22(3):330.
[162]曾少勇,幸丽娅.急性心肌梗死患者血清肌钙蛋白、心肌酶谱和C-反应蛋白水平的诊断价值[J].国际医药卫生导报, 2006, 12(11): 67-68.
[163]赖永洪,翟莺莺,叶铁真.槲皮素对柔红霉素所致心肌损伤的保护作用[J].现代临床医学生物工程学杂志, 2005,11(1):15-18.
[164] Oberd?rster G, Finkelstein J N, Johnston C. Acute pulmonary effects of ultrafine particles in rats and mice[J]. Res Rep Health Eff Inst, 2000, 96:5-74.
[165]王天成,贾光,沈惠麟,等.纳米铁材料对小鼠血清生化指标的影响[J].环境与职业医学, 2004, 21(6):434-436.
[166]王天成,贾光,王翔,等.纳米铁、纳米氧化锌和纳米氧化镁对小鼠血清乳酸脱氢酶和α-羟丁酸脱氢酶活性的影响[J].实用预防医学, 2006, 13(5):1101 -1102.
[167]张豪,沈明山,方宏清,等.转铁蛋白/转铁蛋白受体介导的药物运输[J].中国生物工程杂志, 2004, 24(6):1-5.
[168]王赟,张云霞.转铁蛋白与总铁结合力的相关性研究[J].实用医技杂志, 2007, 14(30):4121-4122.
[169] Qian ZM, Tang PL , Wang Q. Iron crosses the endosomal membrane by a carrier-mediated process[J]. Prog Biophys Molec Biol, 1997, 67:12-15.
[170]王娜,关鹏,常彦忠,等.铁代谢与心血管损伤的研究进展[J].中国老年学杂志, 2008, 28(21):2167-2169.
[171]陈莹莹,钱忠明.心脏铁代谢及其相关疾病研究进展[J].中华心血管病杂志, 2002, 30(1):59-62.
[172]王迪浔,金惠铭.人体病理生理学[M].人民卫生出版社,第2版:520-524.
[173]汤新之,崔乃杰.临床生物化学[M].天津:天津科学技术出版社, 1999.
[174] Voogd A, Sluiter W, van Ei jk HG, et al. Low molecular weight iron and the oxygen paradox in isolated rat hearts [J]. J Clin Invest, 1992, 90:2050-2055.
[175] Bourrinet P, Bengele H, Bonnemain B, et al. Preclinical safety and pharmacokinetic profile of ferumoxtran-10 an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent[J]. Invest Radiol, 2006, 41:313-324.
[176]杨瑞华.自由基及其清除剂与细胞凋亡的关系[J].国外医学.卫生学分册, 1997, 24(4):202-206.
[177] Knight J A. The produce and theories of aging[J]. Ann Clin Lab sci, 1995, 25:1.
[178] HOGBERGJ , ORRENIUS S . Lipid peroxidation in isolated nepatocytes[J] . Eur J Biochem, 1975, 50:595-602.
[179]刘锦波,唐天驷,肖德生.游离铁在脊髓组织匀浆脂质过氧化中的作用[J].中国急救医学, 2002, 22(3):147-148.
[180]孙长颢,王朝旭.铁负荷对大鼠脂质过氧化作用影响及抗氧化维生素对其抑制作用[J].卫生研究, 2003, 32(3):209-211.
[181]王小雪,王朝旭,孙长颢,等.铁负荷大鼠肝脏及脑组织脂质过氧化相关研究[J].中国公共卫生, 2003, 19(8):932-934.
[182]王国斌,肖勇,陶凯雄等.纳米级四氧化三铁的药物动力学和组织分布研究[J].中南药学, 2005, 3(1):5-7.
[183]高娃.四氧化三铁的结构[J].化学教室, 2001, 13(8):68.
[184]刘岚,唐萌,顾宁,等. Nano-Fe2O3-Glu的急性和长期毒性研究[J].环境与职业医学, 2004, 21 (6):430-433.
[185]金惠铭,王建枝主编.缺氧.病理生理学[M].人民卫生出版社,第6版:85-86.
[186]魏登邦,张宝琛.缺氧引起的自由基增殖及其损伤[J].生物学通报, 2003, 38(1):7-10.
[187]芦晓磊.铁球铁质沉着症的研究进展[J].郧阳医学院学报, 2000, 19(1):62-64.
[188]崔萌萌,王江伟,曹毅,等.碳纳米管对小鼠心脏和肝脏组织SOD影响的研究[J].医学研究杂志, 2008, 37(2):21-23.
[189]朱航,张守华,雷蕾.不同剂量铁对小鼠肝脏损伤作用的实验研究[J].热带医学杂志, 2007, 7(2):129-131.
[190]韩玲,陈可冀.大鼠心肌整体缺血及离体再灌注致生物膜的损伤作用.中国应用生理学杂志2002,18(1):59-62
[191]包维民,郭永章,唐映梅,等.大鼠肝脏冷/热缺血再灌注损伤钠钾ATP酶、钙ATP酶及镁ATP酶与肝细胞死亡方式的研究[J].中国现代普通外科进展, 2004, 7(2) :343-346.
[192] Ostadal P, Elmoselhi AB, Zdobnicka I, et al. Ischemia-reperfusion alters gene expression of Na +-K+ ATPase isoforms in rat heart [J]. Biochem Biophys Res Commun, 2003, 306(2):457-464.
[193]郭曲练,潭秀娟,蔡宏伟,等.亚低温对完全性脑缺血再灌注后丙二醛含量和超氧化物歧化酶的影响[J].中华创伤杂志, 1997, 13(1) :10-13.
[194]唐益忠,陈侠英,汪昌荣,等.丹参对烫伤大鼠早期心肌组织ATP酶活性的影响[J].中华烧伤杂志, 2003, 19(4):242
[195]黄辉,陈建萍.心肌细胞凋亡机制的研究进展[J].西藏医药杂志, 2000, 21(2):30-32.
[196] Takeda K, Yu ZX, Nishikawa, et al. Immunohisto-chemical study of poptosis in the bulbus cordis of developing rat heart [J]. Circulation, 1995, 92:306-309
[197] James TNMD. Normal and abnormal consequence of apoptosis in the human heart from postnatal morphogenesis to paroxysmal arrhythmias[J]. Circulation, 1994, 90:556-573.
[198] Matsuzawa A, Ichijo H.Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signalregulating kinase 1[J]. J Biochem, 2001, 130:1-8.
[199] Tanaka M, Ito H, Adachi S, et al. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes[J]. Circ Res, 1994, 75:426- 433.
[200] Gottlieb RA, Burleson KO, Kloner RA, et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes[J]. J Clin Invest, 1994,94:1621-1628.
[201] Itoh G, Tamura J, Suzuki M, et al. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis[J]. Am J Pathol, 1995, 146:1325-1331.
[202] Kajstura J, Zhang X, Liu Y, et al. The cellular basis of pacing-induced dilated cardiomyopathy: myocyte cells loss and myocyte cellular reactive hypertrophy [J]. Circulation, 1995, 92:2306-2317.
[203] Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure[J]. Am J Pathol, 1996, 148:141-149.
[204] Teiger E, Than VD, Richard L, et al. Apoptosis in pressure overload-induced heart hypertrophy in the rat[J]. J Clin Invest, 1996, 97:2891-2897.
[205] Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart[J].N Engl J Med, 1997, 336:1131-1141.
[206] Saraste A, Pulkki K, Kallajoki M, et al.Apoptosis in human acute myocardial infarction[J]. Circulation, 1997, 95:320-323.
[207] Scarabellia TM, Stephanou A, Pasini E, et al. Different signalling pathways induce apoptosis in endothelial cells and cardiac myocytes during is chemia/reperfusion injury[J]. Cir Res, 2002, 90:745-748.
[208]张磊,张鳞.急性心肌梗死患者细胞凋亡水平影响因素的分析.中国医药, 2006, 1(6):325-326.
[209] Long X, Boluyt MO, Cirielli C, et al. Enhanceed expression of P53 in hypoxia induced apoptosis of cultured neonatal rat cardiomyocytes. Circulation, 1995, 92: 722-725.
[210] Orlinick JR, Vaishnaw AK, Elkon KB. Structure and function Fas/Fas ligand[J]. IntRev Immunol. 1999, 18(4):293-308.
[211]赵明中,陈运贞,李媛媛,等.大鼠心肌缺血/再灌注损伤心肌细胞凋亡与Fas、FasL基因表达的变化[J].中华心血管杂志, 2001, 29(10):605-608.
[212]潘越江,王铭辉,张华,等.穿孔素、粒酶B、Fas、Fas-L和Caspase3在心肌细胞凋亡中的作用和相互关系[J].广西医学, 2006, 28(7):967-971.
[213]李滨,童坦军. p53基因研究新进展[J].国外医学分子生物学分册, 1995, 17(3):106.
[214] Pierzchalski P, Reiss K, Cheng W,et al. p53 induces myocyte apoptosis via the activation of the renin-angiotensin system[J]. Exp Cell Res, 1997, 234(1):57-65.
[215]贾玉巧,赵晓红,郭新彪.大气PM10对两种不同细胞分泌炎性细胞因子的影响[J].卫生研究, 2006, 35(5):557-560.
[216] Pope CA, Burnett RT, Thurston GD, et al. Cardiovascular mortality and long- time exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease[J]. Circulation, 2004, 109:71-77.
[217] Ibald MA, Stieber J, Wichmann HE, et al. Effects of air pollution on blood pressure: a population-based approach[J]. Am J Pub Health, 2001, 91:571-577.
[218] Hong YC, Lee JT, Kim H, et al. Air pollution: a new risk factor in ischemic stroke mortality[J]. Stroke, 2002, 33:2165-2169.
[219] Tsai SS, Goggins WB, Chiu HF, et al. Evidence for an association between air pollution and daily stroke admissions in Kaohsiung Taiwan[J]. Stroke, 2003, 34:2612-2616.
[220] Morris RD. Airborne particulates and hospital admissions for cardiovascular disease: a quantitative review of the evidence[J]. Envieon Health Perspect, 2001,109:495-500.
[221] Van Eeden SF, Tan WC, Suwa T, et al. Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutions (PM10) [J]. Am J Respire Crit Care Med, 2001, 164:826-830.
[222] Lindmark E, Diderholm E, Wallentin L, et al. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive strategy[J]. JAMA, 2001, 286:2107-2113.
[223] Ramage L, Guy K. Expression of C-reactive protein and heat-shock protein-70 in the lung epithelial cell line A549, in response to PM10 exposure[J]. Inhal Toxicol, 2004,16:447-452.
[224] Gardner SY, Lehmann JR, Costa DL. Oil fly ash-induced elevation of plasma fibrinogen levels in rats[J]. Toxicol Sci, 2000, 56:175-180.
[225] Ghio AJ, Hall A, Bassett MA, et al. Exposure to concentrated ambient particles alters hematologic indices in humans[J]. Inhal Toxicol, 2003, 15:1465-1478.
[226]李玉林主编.病理学[M].北京:人民卫生出版社, 2004.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |