PEG修饰对PAMAM树状大分子导致细胞损伤的保护作用及其机理
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摘要
聚酰胺-胺树状大分子(PAMAM)是一类由中心向外对称发散且高度分枝的纳米级高分子化合物，分子内部的空腔可以用来包裹药物分子，而末端得基团可以通过修饰连接配体、抗体等生物活性物质，分子所带的高密度正电荷可以压缩DNA。PAMAM树状大分子现已广泛应用于生物医药领域，如基因载体、药物载体、磁共振成像对比剂等。虽然PAMAM树状大分子的应用研究已取得了快速发展，但整代PAMAM树状大分子表面有大量氨基基团，在生理pH条件下易质子化而带正电，因此不可避免的具有一定的细胞毒性。利用无毒、水溶性好的免疫惰性大分子聚合物对PAMAM进行修饰是降低毒性、提高生物相容性的有效方法之一。本实验采用不同相对分子质量(MW)的聚乙二醇(PEG)对五代(generation 5，G5)PAMAM进行不同程度的修饰。考察PAMAM的细胞毒性和PEG修饰的保护作用及其机理，探讨PEG的相对分子质量和修饰度对保护作用的影响，并研究PEG修饰对树状大分子的细胞摄取和转染能力的影响。完成的主要工作有：
(1)分别用相对分子质量为2 k和5 k的mPEG-SC对G5 PAMAM进行两种氨基取代度修饰，低取代度偶联的PEG数为13、高取代度偶联数为51，分别为G5PAMAM表面氨基数的10％和40％。得到四种PEG-PAMAM化合物，分别为13PEG-2k-PAMAM、51PEG-2k-PAMAM、13PEG-5k-PAMAM和51PEG-5k-PAMAM。用相对分子质量为20 k的mPEG-SC对G5 PAMAM进行修饰，偶联的PEG数为13，得到13PEG-20k-PAMAM。用核磁波谱和红外光谱进行结构表征。
(2)应用噻唑蓝法(MTT)考察PAMAM对鼠成纤维细胞(NIH 3T3)的细胞毒作用，结果表明PAMAM的细胞毒性有浓度和时间依赖性。比较PAMAM与PEG-PAMAM的细胞毒性，发现PEG修饰后树状大分子细胞毒性显著降低，13PEG-2k-PAMAM、51PEG-2k-PAMAM和13PEG-5k-PAMAM分别降低1 2、37和34倍，毒性最小的51PEG-5k-PAMAM可以降低105倍。
(3)用FITC标记PAMAM和PEG-PAMAM，考察细胞对树状大分子的摄取情况。结果表明，PAMAM可以被细胞快速摄取，PEG-2k修饰对摄取过程没有显著影响，PAMAM、13PEG-2k-PAMAM和51PEG-2k-PAMAM与细胞孵育2 h后阳性细胞率接近100％。相对分子质量较大PEG修饰的13PEG-5k-PAMAM和51PEG-5k-PAMAM的摄取率虽然略低，但也达到了80％。此外，树状大分子细胞摄取过程有温度依赖性，在低温环境条件下摄取率明显降低，说明细胞对树状大分子的摄取是一个耗能过程。PAMAM和PEG-PAMAM有核靶向力，与细胞孵育15 min后即开始在核聚集。进一步用绿色荧光蛋白(GFP)作为报告基因考察PAMAM和PEG-PAMAM的转染能力。PAMAM和PEG-PAMAM均能将GFP转运至NIH 3T3细胞并成功表达。调整13PEG-2k-PAMAM和51PEG-2k-PAMAM复合物中的电荷比，可以得到与PAMAM相似的转染效果。
(4)通过流式细胞术、荧光分光光度法考察细胞凋亡、胞内ROS含量和线粒体膜电位的变化，发现PAMAM诱发细胞内ROS的增加，损伤细胞膜及线粒体膜，引起线粒体跨膜电位的降低，诱导细胞凋亡。与PAMAM相比，PEG修饰的树状大分子在较高浓度时才会引致细胞凋亡，而且凋亡率明显下降。此外，PEG化可明显抑制胞内ROS的产生和蓄积，维持线粒体膜电位稳定，保护线粒体。说明PEG化是通过拮抗胞内氧化应激损伤而降低PAMAM的细胞毒性的。偶联的PEG链越多、偶联的PEG相对分子质量越大，毒性下降的越明显。
(5)以人红细胞考察PAMAM、13PEG-2k-PAMAM、13PEG-5k-PAMAM和13PEG-20k-PAMAM的血液相容性。红细胞溶血实验结果发现5 mg／mL PAMAM的平均溶血率达到7．67±2．25％，13PEG-2k-PAMAM、13PEG-5k-PAMAM和13PEG-20k-PAMAM的平均溶血率在实验浓度范围内均小于5％，低于PAMAM组溶血率(P＜0．05)。用光学显微镜观察细胞形态，结果发现PAMAM和13PEG-2k-PAMAM能够引起红细胞聚集，而13PEG-5k-PAMAM和13PEG-20k-PAMAM与红细胞作用后细胞仍维持正常形态，保持良好的悬浮性。用原子力显微镜(AFM)观察红细胞表面超微结构变化，发现PAMAM和13PEG-2k-PAMAM处理后红细胞变形，红细胞膜被严重破坏，而13PEG-5k-PAMAM和13PEG-20k-PAMAM处理的红细胞膜表面结构与正常红细胞接近，膜表面粗糙度远低于PAMAM处理红细胞。说明PEG的相对分子质量会对树状大分子的血液相容性产生较大影响，相对分子质量较大的PEG修饰的树状大分子血液相容性较好。
综上所述，PAMAM细胞毒性的产生主要是通过诱发细胞内ROS的过量产生和蓄积，损伤细胞膜及线粒体膜，引起线粒体损伤，从而诱导细胞凋亡。而PEG化可以通过拮抗胞内氧化应激损伤而降低PAMAM的细胞毒性。偶联的PEG链越多、偶联的PEG相对分子质量越大，毒性下降的越明显。PEG修饰的树状大分子在提高安全性的同时仍具备转染能力，在基因治疗方面有更广阔的应用前景。可以通过热活化、偶联核定位信号等手段来进一步提高PEG-PAMAM的转染效率。
Dendrimers are highly branched macromolecules which have specific size,shape andchemical functions.Poly (amidoamine) (PAMAM) dendrimers are a specific family ofdendritic polymers,which are based on an ethylene diamine core and an amidoaminerepeat branching structure.Dendrimers have recently been successfully used in the field ofbiomedicine,such as drug delivery,gene delivery,cancer diagnosis,etc.Despite theextensive interests in pharmaceutical applications of dendrimers,PAMAM dendrimersbearing amino terminals show certain cytotoxicity.In order to improve theirbiocompatibility,generation 5 (G5) PAMAM dendrimers were modified by conjugation ofpoly (ethylene glycol) (PEG) of two different molecular weights and different number ofchains.To investigate the influence of PEGylation on PAMAM-induced cytotoxicty,theintracellular responses including reactive oxygen species (ROS) content,mitochondrialmembrane potential (△ψm) and apoptosis were examined.Meanwhile,the protectiveeffect of PEGylation against PAMAM dendrimers induced hemolysis of human red bloodcells (RBCs) was studied.Furthermore,the uptake rate of PEGylated dendrimers wasquantified by using FITC labeled PAMAM and PEG-PAMAM.Moreover,the ability oftransfection for PEGylated dendrimers was investigated.The main results are asfollowings:
(1) G5 PAMAM were conjugated with PEG-2k or PEG-5k of 13 or 51 PEG chains,which meant 10% and 40% of the total amino terminals of G5 PAMAM were PEGylated,respectively.Thus,four conjugates 13PEG-2k-PAMAM,51PEG-2k-PAMAM,13PEG-5k-PAMAM and 51PEG-5k-PAMAM were prepared.The conjugates werecharacterized by ~1H NMR and FT-IR spectra.
(2) The IC_(50) values (concentration at which 50% of mitochondrial dehydrogenaseactivity was inhibited) were determined to compare the cytotoxicity of differentdendrimers.The cytotoxicity of PAMAM was concentration- and time-dependent.Theorder of IC_(50) of those conjugates on NIH 3T3 cells was 51PEG-5k-PAMAM,51PEG-2k-PAMAM,13PEG-5k-PAMAM,13PEG-2k-PAMAM,PAMAM.The IC_(50) valueof 13PEG-2k-PAMAM dendrimers was 12 fold more than that of PAMAM.Moreover,the value of 51PEG-5k-PAMAM was about 100 fold more than that of PAMAM.As a result,dendrimers conjugated with more PEG chains of higher molecular weight were much lesscytotoxic.
(3) The cellular internalization of PAMAM and PEG-PAMAM grew steadily over theincubation time.The total rates of cell accumulation of PAMAM,13PEG-2k-PAMAM and51PEG-2k-PAMAM were almost 100%.The rates of the dendrimers modified by PEG-5kwere little less,about 80%.The uptake rate of PAMAM and PEG-PAMAM were alsotemperature dependent,which was inhibited at 4℃.PAMAM and PEG-PAMAM couldenter the nucleus in 15 min.Moreover,the PEGylated dendrimers maintained the ability oftransfection.The transfection effects of 13PEG-2k-PAMAM and 51PEG-2k-PAMAMwere similar to that of PAMAM at appropriate charge ratio.
(4) The intracellular responses including ROS contents,mitochondrial membranepotential and apoptosis were examined to elucidate the mechanism of decreasingPAMAM-induced cytotoxicity by PEGylation.The results showed PAMAM inducedapoptosis in a concentration dependent manner.The PEGylation protected remarkablyagainst the PAMAM induced apoptosis.DCFH-DA and Rhodamine-123 were used todetect the levels of intracellular ROS and△ψm,respectively.The results showed PAMAMinduced the burst of intracellular ROS and the dissipation of△ψm,then triggered the cellsa start-up of apoptosis program.These results suggested that cell apoptosis induced byPAMAM was mediated by mitochondrial pathway.PEGylation could effectively reducethe PAMAM-induced cell apoptosis by attenuating ROS production and inhibitingPAMAM-induced△ψm collapse.PAMAM conjugated with more PEG chains of highermolecular weight were much less cytotoxic.
(5) The protective effect of PEGylation against PAMAM induced hemolysis of RBCswas studied.PAMAM were PEGylated with three molecular weights (2k,5k and 20k).The RBCs morphology and surface structure were analyzed by optical microscopy (OM)and atomic force microscopy (AFM).PAMAM dendrimers induced obvious hemolysiswhile PEGylated ones exhibited good haemocompatibility.The hemolysis resulting fromPEGylated dendrimers was much lower compared to the parent dendrimers.Moreover,RBCs treated with PEG-5k and PEG-20k modified dendrimers kept their normalmorphology.This study demonstrated that haemocompatibility of PAMAM dendrimers could be greatly enhanced by PEGylation.Dendrimers conjugated with higher molecularweight PEG showed much lower haemotoxicity.The results of hemolysis test andmorphology investigation for PEG-5k and PEG-20k modified groups were closer to thoseof control RBCs.
In conclusion,PEGylated dendrimers were more suitable and valuable for practicalapplication in which they presented a much lower cytotoxicity and higherhaemocompatibility.We suggested that PAMAM dendrimers would stimulateoverproduction of ROS in cells,which could disturb the function of mitochondrial andeventually lead to cell death.However,modified with PEG was able to inhibitPAMAM-induced cell death.Meanwhile,dendrimers conjugated with fewer PEG of lowermolecular weight did not significantly change the endocytic properties.Moreover,thePEGylated dendrimers maintained the ability of transfection.The transfection effect ofPEGylated dendrimers would be enhanced by heating activation or conjugation totargeting ligands.
(1)分别用相对分子质量为2 k和5 k的mPEG-SC对G5 PAMAM进行两种氨基取代度修饰，低取代度偶联的PEG数为13、高取代度偶联数为51，分别为G5PAMAM表面氨基数的10％和40％。得到四种PEG-PAMAM化合物，分别为13PEG-2k-PAMAM、51PEG-2k-PAMAM、13PEG-5k-PAMAM和51PEG-5k-PAMAM。用相对分子质量为20 k的mPEG-SC对G5 PAMAM进行修饰，偶联的PEG数为13，得到13PEG-20k-PAMAM。用核磁波谱和红外光谱进行结构表征。
(2)应用噻唑蓝法(MTT)考察PAMAM对鼠成纤维细胞(NIH 3T3)的细胞毒作用，结果表明PAMAM的细胞毒性有浓度和时间依赖性。比较PAMAM与PEG-PAMAM的细胞毒性，发现PEG修饰后树状大分子细胞毒性显著降低，13PEG-2k-PAMAM、51PEG-2k-PAMAM和13PEG-5k-PAMAM分别降低1 2、37和34倍，毒性最小的51PEG-5k-PAMAM可以降低105倍。
(3)用FITC标记PAMAM和PEG-PAMAM，考察细胞对树状大分子的摄取情况。结果表明，PAMAM可以被细胞快速摄取，PEG-2k修饰对摄取过程没有显著影响，PAMAM、13PEG-2k-PAMAM和51PEG-2k-PAMAM与细胞孵育2 h后阳性细胞率接近100％。相对分子质量较大PEG修饰的13PEG-5k-PAMAM和51PEG-5k-PAMAM的摄取率虽然略低，但也达到了80％。此外，树状大分子细胞摄取过程有温度依赖性，在低温环境条件下摄取率明显降低，说明细胞对树状大分子的摄取是一个耗能过程。PAMAM和PEG-PAMAM有核靶向力，与细胞孵育15 min后即开始在核聚集。进一步用绿色荧光蛋白(GFP)作为报告基因考察PAMAM和PEG-PAMAM的转染能力。PAMAM和PEG-PAMAM均能将GFP转运至NIH 3T3细胞并成功表达。调整13PEG-2k-PAMAM和51PEG-2k-PAMAM复合物中的电荷比，可以得到与PAMAM相似的转染效果。
(4)通过流式细胞术、荧光分光光度法考察细胞凋亡、胞内ROS含量和线粒体膜电位的变化，发现PAMAM诱发细胞内ROS的增加，损伤细胞膜及线粒体膜，引起线粒体跨膜电位的降低，诱导细胞凋亡。与PAMAM相比，PEG修饰的树状大分子在较高浓度时才会引致细胞凋亡，而且凋亡率明显下降。此外，PEG化可明显抑制胞内ROS的产生和蓄积，维持线粒体膜电位稳定，保护线粒体。说明PEG化是通过拮抗胞内氧化应激损伤而降低PAMAM的细胞毒性的。偶联的PEG链越多、偶联的PEG相对分子质量越大，毒性下降的越明显。
(5)以人红细胞考察PAMAM、13PEG-2k-PAMAM、13PEG-5k-PAMAM和13PEG-20k-PAMAM的血液相容性。红细胞溶血实验结果发现5 mg／mL PAMAM的平均溶血率达到7．67±2．25％，13PEG-2k-PAMAM、13PEG-5k-PAMAM和13PEG-20k-PAMAM的平均溶血率在实验浓度范围内均小于5％，低于PAMAM组溶血率(P＜0．05)。用光学显微镜观察细胞形态，结果发现PAMAM和13PEG-2k-PAMAM能够引起红细胞聚集，而13PEG-5k-PAMAM和13PEG-20k-PAMAM与红细胞作用后细胞仍维持正常形态，保持良好的悬浮性。用原子力显微镜(AFM)观察红细胞表面超微结构变化，发现PAMAM和13PEG-2k-PAMAM处理后红细胞变形，红细胞膜被严重破坏，而13PEG-5k-PAMAM和13PEG-20k-PAMAM处理的红细胞膜表面结构与正常红细胞接近，膜表面粗糙度远低于PAMAM处理红细胞。说明PEG的相对分子质量会对树状大分子的血液相容性产生较大影响，相对分子质量较大的PEG修饰的树状大分子血液相容性较好。
综上所述，PAMAM细胞毒性的产生主要是通过诱发细胞内ROS的过量产生和蓄积，损伤细胞膜及线粒体膜，引起线粒体损伤，从而诱导细胞凋亡。而PEG化可以通过拮抗胞内氧化应激损伤而降低PAMAM的细胞毒性。偶联的PEG链越多、偶联的PEG相对分子质量越大，毒性下降的越明显。PEG修饰的树状大分子在提高安全性的同时仍具备转染能力，在基因治疗方面有更广阔的应用前景。可以通过热活化、偶联核定位信号等手段来进一步提高PEG-PAMAM的转染效率。
Dendrimers are highly branched macromolecules which have specific size,shape andchemical functions.Poly (amidoamine) (PAMAM) dendrimers are a specific family ofdendritic polymers,which are based on an ethylene diamine core and an amidoaminerepeat branching structure.Dendrimers have recently been successfully used in the field ofbiomedicine,such as drug delivery,gene delivery,cancer diagnosis,etc.Despite theextensive interests in pharmaceutical applications of dendrimers,PAMAM dendrimersbearing amino terminals show certain cytotoxicity.In order to improve theirbiocompatibility,generation 5 (G5) PAMAM dendrimers were modified by conjugation ofpoly (ethylene glycol) (PEG) of two different molecular weights and different number ofchains.To investigate the influence of PEGylation on PAMAM-induced cytotoxicty,theintracellular responses including reactive oxygen species (ROS) content,mitochondrialmembrane potential (△ψm) and apoptosis were examined.Meanwhile,the protectiveeffect of PEGylation against PAMAM dendrimers induced hemolysis of human red bloodcells (RBCs) was studied.Furthermore,the uptake rate of PEGylated dendrimers wasquantified by using FITC labeled PAMAM and PEG-PAMAM.Moreover,the ability oftransfection for PEGylated dendrimers was investigated.The main results are asfollowings:
(1) G5 PAMAM were conjugated with PEG-2k or PEG-5k of 13 or 51 PEG chains,which meant 10% and 40% of the total amino terminals of G5 PAMAM were PEGylated,respectively.Thus,four conjugates 13PEG-2k-PAMAM,51PEG-2k-PAMAM,13PEG-5k-PAMAM and 51PEG-5k-PAMAM were prepared.The conjugates werecharacterized by ~1H NMR and FT-IR spectra.
(2) The IC_(50) values (concentration at which 50% of mitochondrial dehydrogenaseactivity was inhibited) were determined to compare the cytotoxicity of differentdendrimers.The cytotoxicity of PAMAM was concentration- and time-dependent.Theorder of IC_(50) of those conjugates on NIH 3T3 cells was 51PEG-5k-PAMAM,51PEG-2k-PAMAM,13PEG-5k-PAMAM,13PEG-2k-PAMAM,PAMAM.The IC_(50) valueof 13PEG-2k-PAMAM dendrimers was 12 fold more than that of PAMAM.Moreover,the value of 51PEG-5k-PAMAM was about 100 fold more than that of PAMAM.As a result,dendrimers conjugated with more PEG chains of higher molecular weight were much lesscytotoxic.
(3) The cellular internalization of PAMAM and PEG-PAMAM grew steadily over theincubation time.The total rates of cell accumulation of PAMAM,13PEG-2k-PAMAM and51PEG-2k-PAMAM were almost 100%.The rates of the dendrimers modified by PEG-5kwere little less,about 80%.The uptake rate of PAMAM and PEG-PAMAM were alsotemperature dependent,which was inhibited at 4℃.PAMAM and PEG-PAMAM couldenter the nucleus in 15 min.Moreover,the PEGylated dendrimers maintained the ability oftransfection.The transfection effects of 13PEG-2k-PAMAM and 51PEG-2k-PAMAMwere similar to that of PAMAM at appropriate charge ratio.
(4) The intracellular responses including ROS contents,mitochondrial membranepotential and apoptosis were examined to elucidate the mechanism of decreasingPAMAM-induced cytotoxicity by PEGylation.The results showed PAMAM inducedapoptosis in a concentration dependent manner.The PEGylation protected remarkablyagainst the PAMAM induced apoptosis.DCFH-DA and Rhodamine-123 were used todetect the levels of intracellular ROS and△ψm,respectively.The results showed PAMAMinduced the burst of intracellular ROS and the dissipation of△ψm,then triggered the cellsa start-up of apoptosis program.These results suggested that cell apoptosis induced byPAMAM was mediated by mitochondrial pathway.PEGylation could effectively reducethe PAMAM-induced cell apoptosis by attenuating ROS production and inhibitingPAMAM-induced△ψm collapse.PAMAM conjugated with more PEG chains of highermolecular weight were much less cytotoxic.
(5) The protective effect of PEGylation against PAMAM induced hemolysis of RBCswas studied.PAMAM were PEGylated with three molecular weights (2k,5k and 20k).The RBCs morphology and surface structure were analyzed by optical microscopy (OM)and atomic force microscopy (AFM).PAMAM dendrimers induced obvious hemolysiswhile PEGylated ones exhibited good haemocompatibility.The hemolysis resulting fromPEGylated dendrimers was much lower compared to the parent dendrimers.Moreover,RBCs treated with PEG-5k and PEG-20k modified dendrimers kept their normalmorphology.This study demonstrated that haemocompatibility of PAMAM dendrimers could be greatly enhanced by PEGylation.Dendrimers conjugated with higher molecularweight PEG showed much lower haemotoxicity.The results of hemolysis test andmorphology investigation for PEG-5k and PEG-20k modified groups were closer to thoseof control RBCs.
In conclusion,PEGylated dendrimers were more suitable and valuable for practicalapplication in which they presented a much lower cytotoxicity and higherhaemocompatibility.We suggested that PAMAM dendrimers would stimulateoverproduction of ROS in cells,which could disturb the function of mitochondrial andeventually lead to cell death.However,modified with PEG was able to inhibitPAMAM-induced cell death.Meanwhile,dendrimers conjugated with fewer PEG of lowermolecular weight did not significantly change the endocytic properties.Moreover,thePEGylated dendrimers maintained the ability of transfection.The transfection effect ofPEGylated dendrimers would be enhanced by heating activation or conjugation totargeting ligands.
引文
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