Enhanced permeation and retention（EPR） targeting effect of rhodamine B labeled PEG-b-P（LA-co-DHP） [PEG：poly（ethylene glycol）;LA：L-lactide;DHP：2,2-dihydroxylmethyl-propylene carbonate] micelles（RhB-micelles）...Enhanced permeation and retention（EPR） targeting effect of rhodamine B labeled PEG-b-P（LA-co-DHP） [PEG：poly（ethylene glycol）;LA：L-lactide;DHP：2,2-dihydroxylmethyl-propylene carbonate] micelles（RhB-micelles） was observed in H22 liver cancer bearing mice.The RhB-micelles were prepared by conjugating rhodamine B with the DHP units of amphiphilic block copolymer PEG-b-P（LA-co-DHP） followed by subsequent self-assembling of the conjugate.The parent copolymer PEG-b-P（LA-co-DHP） was synthesized by ring-opening copolymerization of LA and DHP with PEG as macroinitiator and diethyl zinc（ZnEt2） as catalyst.The micelles have a spherical shape and the average diameter is ca.50 nm by TEM（transmission electron microscope） or 80 nm by DLS（dynamic light scattering）.Their in vitro cell uptake experiment by CLSM（confocal laser scanning microscopy） and flow cytometry showed preferential internalization of micelles by MCF-7 human breast cancer cells to free RhB.The in vivo tests by live animal imaging and ex vivo excised organ imaging showed that after vena tail injection,free RhB molecules were distributed in the whole body through the circulation system and then gradually metabolized and excreted and there was no preferential partition in tumor bed from the beginning to the end.But the RhB-micelles were preferentially distributed to the tumor bed so that their concentration（fluorescent intensity） in tumor bed got the level of the liver at a certain time point between 1 and 6 h and reached a maximum relative intensity at around 12 h,indicating an obvious EPR effect of RhB-micelles in H22 liver cancer.展开更多
The EPR parameters of trivalent Er（3＋） ions doped in hexagonal Ga N crystal have been studied by diagonalizing the 364×364 complete energy matrices. The results indicate that the resonance ground states may be...The EPR parameters of trivalent Er（3＋） ions doped in hexagonal Ga N crystal have been studied by diagonalizing the 364×364 complete energy matrices. The results indicate that the resonance ground states may be derived from the Kramers doublet Γ6. The EPR g-factors may be ascribed to the stronger covalent bonding and nephelauxetic effects compared with other rare-earth doped complexes, as a result of the mismatch of ionic radii of the impurity Er（3＋）ion and the replaced Ga（3＋） ion apart from the intrinsic covalency of host Ga N. Furthermore, the J–J mixing effects on the EPR parameters from the high-lying manifolds have been evaluated. It is found that the dominant J–J mixing contribution is from the manifold 2K（15/2）, which accounts for about 2.5%. The next important J–J contribution arises from the crystal–field mixture between the ground state 4I（15/2） and the first excited state4I（13/2）, and is usually less than 0.2%. The contributions from the rest states may be ignored.展开更多
Objective:The introduction of therapeutic antibodies(tAbs)into clinical practice has revolutionized tumor treatment strategies,but their tumor therapy efficiency is still far below expectations because of the rapid de...Objective:The introduction of therapeutic antibodies(tAbs)into clinical practice has revolutionized tumor treatment strategies,but their tumor therapy efficiency is still far below expectations because of the rapid degradation and limited tumor accumulation of tAbs.Methods:We developed a nanocapsule-based delivery system to induce the self-augmentation of the enhanced permeability and retention(EPR)effect.This system constantly penetrated across the blood-tumor barrier into the tumor while avoiding the attack of tAbs by the immune system.The biodistribution and therapeutic effect were tested with single dose administration of nanocapsule-tAbs in vivo.Results:The accumulation of Nano(cetuximab)within subcutaneous PC9 tumors was gradually enhanced over 6 days after single dose administration,which was contrary to the biodistribution of native cetuximab.Nano(cetuximab)accumulated in tumor tissues via the EPR effect and released cetuximab.The released cetuximab acted on vascular endothelial cells to destroy the blood-tumor barrier and induce self-augmentation of the EPR effect,which in turn contributed to further tumor accumulation of long-circulating Nano(cetuximab).Compared with single dose administration of native cetuximab,Nano(cetuximab)showed an effective tumor suppressive effect for 3 weeks.Conclusions:The nanocapsule-based delivery system efficiently delivered tAbs to tum or tissues and released them to boost the EPR effect,which facilitated further tumor accumulation of the tAbs.This novel self-augmentation of the EPR effect facilitated by the biological characteristics of tAbs and nanotechnology contributed to the improvement of the therapeutic effect of tAbs,and stimulated new ideas for antibody-based tumor therapy.展开更多
通过对角化364×364完全能量矩阵的理论方法,对掺杂在Bi_(4)Ge_(3)O_(12)晶体中的Er^(3+)的Stark能级和EPR参数进行了研究,同时,定量分析了高阶晶体场混合效应和J-J混合效应对EPR g因子的影响。研究结果表明:对Er^(3+)来说,最主要的...通过对角化364×364完全能量矩阵的理论方法,对掺杂在Bi_(4)Ge_(3)O_(12)晶体中的Er^(3+)的Stark能级和EPR参数进行了研究,同时,定量分析了高阶晶体场混合效应和J-J混合效应对EPR g因子的影响。研究结果表明:对Er^(3+)来说,最主要的J-J混合效应来源于多重态谱项2 K 15/2,其对EPR g因子的贡献约占2.5%,而最主要的高阶晶体场混合效应来源于第一激发多重态^(4)I_(13/2)和基态多重态^(4)I_(15/2)之间的晶体场混合,其对各向异性g因子中g⊥的贡献大致是g//的两倍(即g⊥约占0.21%,g//约占0.092%),其他更高阶的晶体场混合和J-J混合效应可以忽略不计。因此,对于Er^(3+)掺杂的络合物系统来说,只考虑基态多重态4 I 15/2对EPR g因子的贡献应该是一个很好的近似。展开更多
在过去的几十年里,高渗透强滞留效应(enhanced permeability and retention effect,EPR)成为抗肿瘤药物靶向递送的主要理论基础。由于EPR效应的问世,纳米技术在抗肿瘤研究领域引起了更多的关注。然而,由于复杂的肿瘤微环境、肿瘤异质性...在过去的几十年里,高渗透强滞留效应(enhanced permeability and retention effect,EPR)成为抗肿瘤药物靶向递送的主要理论基础。由于EPR效应的问世,纳米技术在抗肿瘤研究领域引起了更多的关注。然而,由于复杂的肿瘤微环境、肿瘤异质性、小鼠肿瘤模型与临床肿瘤模型的差异,基于EPR效应的新药研究在临床试验中表现远低于预期。因此,研究者们从不同角度进行了很多探索,笔者从改善肿瘤微环境、纳米粒子的设计和修饰、物理辅助等方面综述了近年来提高EPR效应的策略,以及不依赖EPR效应的抗肿瘤药物递送技术,为抗肿瘤纳米药物的设计和临床转化提供新视角。展开更多
This work is investigating Mexidol (2-ethyl-6-methyl-3-hydroxy pyridine succinate) effect on the formation of nitric oxide (NO) in animal liver tissues, which is a regulator of many physiological processes and plays a...This work is investigating Mexidol (2-ethyl-6-methyl-3-hydroxy pyridine succinate) effect on the formation of nitric oxide (NO) in animal liver tissues, which is a regulator of many physiological processes and plays an important role in the vascular relaxation, neurotransmission and immune system functioning. Analyses performed by EPR spectroscopy revealed Hem-NO complex signals from paramagnetic centers in arbitrary units;produced nitrogen oxide amount in liver tissues was determined by method of double integration signals from nitrosyl complexes.展开更多
The effects of pressure and solvent on the intramolecular spin exchange of biradicals having two nitroxide fragments linked by a long flexible chain were studied by means of highpressure EPR technique.It was found tha...The effects of pressure and solvent on the intramolecular spin exchange of biradicals having two nitroxide fragments linked by a long flexible chain were studied by means of highpressure EPR technique.It was found that the intramolecular exchange interaction between nitroxides of biradical took place through the direct contact between them.By analyzing the observed EPR spectra,we have estimated the ratio(in/out)value of the average lifetime of the radical fragments inside a cage(in)to that outside the cage(out).The in/out values decreased with decreasing temperature and increasing pressure.The results suggest that the nearly cyclic conformation in a cage is favorable in solution.Further,the rotational correlation time of individual nitroxide was estimated from the anisotropic EPR signal,and the information on the segmental motion of the nitroxide group in biradical was obtained.展开更多
目的综述高渗透长滞留效应(enhanced permeability and retention effect,简称EPR效应)的发现历史、影响因素及其在大分子药物肿瘤传递中的广泛应用。方法查阅近年来国内外相关文献50篇,对其进行归纳、总结和分析。结果大分子理化性质...目的综述高渗透长滞留效应(enhanced permeability and retention effect,简称EPR效应)的发现历史、影响因素及其在大分子药物肿瘤传递中的广泛应用。方法查阅近年来国内外相关文献50篇,对其进行归纳、总结和分析。结果大分子理化性质、肿瘤血管结构及血管调节因子对EPR效应有重要影响,临床上使用硝酸甘油、血管紧张肽转化酶抑制剂等外源性物质来提升EPR效应,以加强微粒给药系统的肿瘤靶向效果。结论 EPR效应作为大分子抗癌药物设计的"金标准",为肿瘤靶向药物传递系统设计的研究与开发提供了重要参考。展开更多
基金Supported by the National Basic Research Program of China(No.2009CB930102)the National High Technology Research and Development Program of China(No.2007AA03Z535)+3 种基金the National Natural Science Foundation of China(No.21004062)the China-Japan-Korea Foresight Program(No.20621140369)"100 Talents Program" of the Chinese Academy of Sciences(No.KGCX2- YW-802) the Project of Jilin Provincial Science & Technology Department,China(No.200705110)
文摘Enhanced permeation and retention（EPR） targeting effect of rhodamine B labeled PEG-b-P（LA-co-DHP） [PEG：poly（ethylene glycol）;LA：L-lactide;DHP：2,2-dihydroxylmethyl-propylene carbonate] micelles（RhB-micelles） was observed in H22 liver cancer bearing mice.The RhB-micelles were prepared by conjugating rhodamine B with the DHP units of amphiphilic block copolymer PEG-b-P（LA-co-DHP） followed by subsequent self-assembling of the conjugate.The parent copolymer PEG-b-P（LA-co-DHP） was synthesized by ring-opening copolymerization of LA and DHP with PEG as macroinitiator and diethyl zinc（ZnEt2） as catalyst.The micelles have a spherical shape and the average diameter is ca.50 nm by TEM（transmission electron microscope） or 80 nm by DLS（dynamic light scattering）.Their in vitro cell uptake experiment by CLSM（confocal laser scanning microscopy） and flow cytometry showed preferential internalization of micelles by MCF-7 human breast cancer cells to free RhB.The in vivo tests by live animal imaging and ex vivo excised organ imaging showed that after vena tail injection,free RhB molecules were distributed in the whole body through the circulation system and then gradually metabolized and excreted and there was no preferential partition in tumor bed from the beginning to the end.But the RhB-micelles were preferentially distributed to the tumor bed so that their concentration（fluorescent intensity） in tumor bed got the level of the liver at a certain time point between 1 and 6 h and reached a maximum relative intensity at around 12 h,indicating an obvious EPR effect of RhB-micelles in H22 liver cancer.
基金Project supported by the Foundation of Education Department of Shaanxi Province,China(Grant No.16JK1402)
文摘The EPR parameters of trivalent Er（3＋） ions doped in hexagonal Ga N crystal have been studied by diagonalizing the 364×364 complete energy matrices. The results indicate that the resonance ground states may be derived from the Kramers doublet Γ6. The EPR g-factors may be ascribed to the stronger covalent bonding and nephelauxetic effects compared with other rare-earth doped complexes, as a result of the mismatch of ionic radii of the impurity Er（3＋）ion and the replaced Ga（3＋） ion apart from the intrinsic covalency of host Ga N. Furthermore, the J–J mixing effects on the EPR parameters from the high-lying manifolds have been evaluated. It is found that the dominant J–J mixing contribution is from the manifold 2K（15/2）, which accounts for about 2.5%. The next important J–J contribution arises from the crystal–field mixture between the ground state 4I（15/2） and the first excited state4I（13/2）, and is usually less than 0.2%. The contributions from the rest states may be ignored.
基金the National Key Research and Development Program(Grant Nos.2016YFC0902502 and 2018YFA0209700)the National Natural Science Foundation of China(Grant Nos.81772667 and 51773151)the Special Construction Innovation Funded Project for Community in Beijing,Tianjin and Hebei of China(Grant No.18247792D).
文摘Objective:The introduction of therapeutic antibodies(tAbs)into clinical practice has revolutionized tumor treatment strategies,but their tumor therapy efficiency is still far below expectations because of the rapid degradation and limited tumor accumulation of tAbs.Methods:We developed a nanocapsule-based delivery system to induce the self-augmentation of the enhanced permeability and retention(EPR)effect.This system constantly penetrated across the blood-tumor barrier into the tumor while avoiding the attack of tAbs by the immune system.The biodistribution and therapeutic effect were tested with single dose administration of nanocapsule-tAbs in vivo.Results:The accumulation of Nano(cetuximab)within subcutaneous PC9 tumors was gradually enhanced over 6 days after single dose administration,which was contrary to the biodistribution of native cetuximab.Nano(cetuximab)accumulated in tumor tissues via the EPR effect and released cetuximab.The released cetuximab acted on vascular endothelial cells to destroy the blood-tumor barrier and induce self-augmentation of the EPR effect,which in turn contributed to further tumor accumulation of long-circulating Nano(cetuximab).Compared with single dose administration of native cetuximab,Nano(cetuximab)showed an effective tumor suppressive effect for 3 weeks.Conclusions:The nanocapsule-based delivery system efficiently delivered tAbs to tum or tissues and released them to boost the EPR effect,which facilitated further tumor accumulation of the tAbs.This novel self-augmentation of the EPR effect facilitated by the biological characteristics of tAbs and nanotechnology contributed to the improvement of the therapeutic effect of tAbs,and stimulated new ideas for antibody-based tumor therapy.
文摘通过对角化364×364完全能量矩阵的理论方法,对掺杂在Bi_(4)Ge_(3)O_(12)晶体中的Er^(3+)的Stark能级和EPR参数进行了研究,同时,定量分析了高阶晶体场混合效应和J-J混合效应对EPR g因子的影响。研究结果表明:对Er^(3+)来说,最主要的J-J混合效应来源于多重态谱项2 K 15/2,其对EPR g因子的贡献约占2.5%,而最主要的高阶晶体场混合效应来源于第一激发多重态^(4)I_(13/2)和基态多重态^(4)I_(15/2)之间的晶体场混合,其对各向异性g因子中g⊥的贡献大致是g//的两倍(即g⊥约占0.21%,g//约占0.092%),其他更高阶的晶体场混合和J-J混合效应可以忽略不计。因此,对于Er^(3+)掺杂的络合物系统来说,只考虑基态多重态4 I 15/2对EPR g因子的贡献应该是一个很好的近似。
文摘在过去的几十年里,高渗透强滞留效应(enhanced permeability and retention effect,EPR)成为抗肿瘤药物靶向递送的主要理论基础。由于EPR效应的问世,纳米技术在抗肿瘤研究领域引起了更多的关注。然而,由于复杂的肿瘤微环境、肿瘤异质性、小鼠肿瘤模型与临床肿瘤模型的差异,基于EPR效应的新药研究在临床试验中表现远低于预期。因此,研究者们从不同角度进行了很多探索,笔者从改善肿瘤微环境、纳米粒子的设计和修饰、物理辅助等方面综述了近年来提高EPR效应的策略,以及不依赖EPR效应的抗肿瘤药物递送技术,为抗肿瘤纳米药物的设计和临床转化提供新视角。
文摘This work is investigating Mexidol (2-ethyl-6-methyl-3-hydroxy pyridine succinate) effect on the formation of nitric oxide (NO) in animal liver tissues, which is a regulator of many physiological processes and plays an important role in the vascular relaxation, neurotransmission and immune system functioning. Analyses performed by EPR spectroscopy revealed Hem-NO complex signals from paramagnetic centers in arbitrary units;produced nitrogen oxide amount in liver tissues was determined by method of double integration signals from nitrosyl complexes.
文摘The effects of pressure and solvent on the intramolecular spin exchange of biradicals having two nitroxide fragments linked by a long flexible chain were studied by means of highpressure EPR technique.It was found that the intramolecular exchange interaction between nitroxides of biradical took place through the direct contact between them.By analyzing the observed EPR spectra,we have estimated the ratio(in/out)value of the average lifetime of the radical fragments inside a cage(in)to that outside the cage(out).The in/out values decreased with decreasing temperature and increasing pressure.The results suggest that the nearly cyclic conformation in a cage is favorable in solution.Further,the rotational correlation time of individual nitroxide was estimated from the anisotropic EPR signal,and the information on the segmental motion of the nitroxide group in biradical was obtained.
