胆固醇衍生物脂质体作为药物载体的研究
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摘要
脂质体是磷脂分散在水中而形成的由一层或多层脂质构成的囊泡结构，具有良好的生物相容性和可降解性，不仅能够降低药物的毒副作用，而且能增强疗效。但是脂质体在长期保存过程中容易出现聚集、药物渗漏等现象，并且容易受到生物环境，特别是血清蛋白的影响而导致载药能力降低。胆固醇作为生物膜的重要组成部分，能调节生物膜的流动性，增加机械强度并降低生物膜的渗透性。本研究利用实验室合成的两种新型胆固醇衍生物，组入到脂质体中，考察了这些脂质体在体外的长期稳定性，并着重评价了胆固醇衍生物脂质体作为小分子药物阿霉素（DOX）载体和大分子模型药物聚乙二醇6000-罗丹明B（PEG-RhB）载体在血清存在下的细胞内输送能力。初步研究了载有阿霉素的胆固醇衍生物脂质体静脉给药后大鼠体内的药代动力学以及玻璃体注射给药后阿霉素在视网膜上的分布及滞留情况。
合成的新型胆固醇衍生物包括：4-cholesterocarbonyl-4'-(N,N,N-triethylamine butyloxylbromide) azobenzene（CTBBA），及与其结构类似的4-cholesterocarbonyl-4'-(N,N-diethylamine butyloxyl)azobenzene（CDBA），两者结构上的差异是CTBBA的头部基团为三乙胺，而CDBA的头部基团为二乙胺，这就使得CTBBA带有正电荷而CDBA显示为中性，基于此我们研究了电荷及血清对脂质体稳定性的影响。超声法制备的脂质体粒径大小在100-150nm之间，且在中性缓冲液体系（pH7.0）下，PC脂质体和CDBA脂质体的ζ电位为中性（0.7mV和-3.6mV），而CTBBA脂质体带正电荷（+25.4mV）。以阿霉素作为渗漏标记物，我们考察了长期保存过程中脂质体粒径和包封率的变化，以及在不同浓度血清存在下的稳定性。结果表明，在长达48周的时间内，组有胆固醇衍生物的阿霉素脂质体，粒径变化比PC阿霉素脂质体小，药物保存能力（包封率）更高；血清存在下，组有胆固醇衍生物的脂质体比PC脂质体在短时间内（3h）保留的阿霉素更多。
药物载体本身的生物相容性是其能否真正得到应用的关键因素之一。一般而言正电荷脂质体本身会对细胞产生一定的毒性，因此以常用的正电荷脂质N-(1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammoniummesylate(DOTAP)作为对照，评价了CTBBA脂质体对两种细胞株Bel7402和NIH3T3的毒性。结果显示CTBBA脂质体的细胞毒性明显低于DOTAP脂质体，说明我们的脂质体具有良好的生物相容性。
作为药物载体，除了上述优点外，还必须具有高效的细胞内输送能力，特别是在血清共存的模拟体内环境中。因此，我们制备了包封小分子药物阿霉素和大分子药物模型聚乙二醇-罗丹明B（PEG-RhB）的脂质体，运用荧光显微镜技术分析了胆固醇衍生物脂质体输送药物至细胞的能力以及输送机制，同时也评价了药物载体包封阿霉素后的细胞毒性。结果表明与PC脂质体和CDBA脂质体相比，CTBBA脂质体输送阿霉素/PEG-RhB进入细胞的能力最强；同时这些脂质体载体能改善大分子药物模型不能进入细胞的缺陷。共聚焦显微镜结果还显示PEG-RhB进入细胞后会聚集在细胞核周围但不能进入细胞核。虽然血清会减弱脂质体和细胞之间的作用，并降低脂质体所载药物进入细胞的量，但正电荷脂质体CTBBA仍然比CDBA具有高的细胞导入效率。我们运用共聚焦显微镜观测了阿霉素脂质体的细胞摄入动态过程。发现偏中性的PC脂质体和CDBA脂质体与Bel7402细胞作用1h后，由于细胞内吞作用其阿霉素荧光主要分布在细胞核内，而正电荷CTBBA脂质体由于和带负电的细胞膜强烈作用，其阿霉素荧光主要分布在细胞膜上，并随着培养时间的增加，阿霉素荧光逐渐扩散到细胞核中,且其最终强度高于CDBA脂质体和PC脂质体。这种强烈的静电作用使得正电荷CTBBA脂质体具有更高的药物输送能力以及细胞杀伤能力。
我们通过尾部静脉给药评价了阿霉素脂质体在Sprague-Dawley（SD）大鼠体内的药代动力学。结果显示CDBA和CTBBA脂质体能延长裸药阿霉素的AUC（药浓度和时间曲线下的面积）值和T1/2(半衰期)；同时降低了Ke（消除常数）和CL（清除率）。相比以往报道的正电荷脂质体在药物动力学上的不适宜性（如容易被体液清除，半衰期短），CTBBA脂质体在Ke,T1/2和CL上的参数值和PC脂质体无显著差异（P>0.05）。
最后，我们通过玻璃体注射给药和共聚焦显微镜技术研究了阿霉素脂质体在SD大鼠视网膜上的分布及滞留情况。结果表明正电荷的CTBBA脂质体能增加阿霉素进入视网膜节细胞层（GLC）上的量并延长阿霉素的滞留时间，甚至能载药到内核细胞层（INL）。这个结果表明我们的正电荷脂质体CTBBA能将阿霉素高效导入到视网膜，且滞留时间长，具有眼部药物新剂型的潜力。
综上所述，我们的胆固醇衍生物脂质体能有效抑制药物的自然渗漏，并增加脂质体悬液的长期稳定性。即使在血清存在下，正电荷脂质体无论对小分子药物阿霉素还是大分子药物模型PEG-RhB，均能保持高的细胞内导入效率。载有阿霉素的正电荷脂质体在高效杀死癌细胞的同时，自身所具有的毒性也比常用的正电荷脂质DOTAP弱。此外正电荷脂质体CTBBA还能高效的将阿霉素输送到视网膜内。大鼠药代实验结果表明胆固醇衍生物脂质体能改善药物的动力学参数，且可以克服其他已报道的正电荷脂质体容易被体液清除、药物半衰期缩短、AUC降低等缺陷。我们希望通过这些体外体内的综合评价，为新型胆固醇衍生物脂质体的实际应用可行性提供全面数据。
Liposomes are formed when thin phospholipids films are hydrated, withcomposite structures of one or multiple layers of lipid vesicles. Liposomes have goodbiocompatibility and biodegradability and have been used as good drug deliverycarriers. But liposomes trend to aggregate together in long-term preservation,accompany with drugs leakage. Cholesterol is an important part of the biomembraneand it can increase the mechanical strength and reduce the permeability ofbiomembrane. This research is based on newly synthesized cholesterol derivatives,which are combined into the liposomes. We have investigated the long-term stabilityof the liposome in vitro, and focused on the evaluation of the cholesterol derivativescombined liposome as small molecule drug (doxorubicin, DOX) carrier andmacromolecule model (polyethylene glycol6000-rohadamine B, PEG-RhB) carrier inthe presence of serum. We have also studied the pharmacokinetic parameters ofDOX-liposomes and the distribution of DOX-liposomes in rats’ retina.
The newly synthesized cholesterol derivatives include4-cholesterocarbonyl-4'-(N,N,N-triethylamine butyloxyl bromide) azobenzene(CTBBA) and its structural analog4-cholesterocarbonyl-4'-(N,N-diethylaminebutyloxyl) azobenzene (CDBA). CTBBA has a triethylamine while CDBA has adiethylamine in the head group, which makes CTBBA positive and CDBA neutral.We studied the influence of charge and serum on the stability of liposomes. Thesecholesterol derivatives combined liposomes dispersed well with a size distribution between100to150nm. CTBBA-liposome showed a positive ζ-potential in PBS,while PC-liposome and CDBA-liposome were near neutral. We evaluated the changesin particle size and encapsulation efficiency during long-term preservation and foundthat CDBA-liposome/CTBBA-liposome were more stable than PC-liposome.CDBA-liposome/CTBBA-liposome had higher drug retention (within3h) than PCliposome in the presence of serum.
As a drug carrier, CTBBA-liposome showed lower cytotoxicity in Bel7402cellsand NIH3T3cells, compared to N-(1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium mesylate (DOTAP) liposome, a common usedpositive liposome. Then the drug delivery capacity of CDBA/CTBBA liposomes wasevaluated in Bel7402cells. Small molecule drug DOX and macromolecule modelPEG-RhB were chosen as the contents. The results showed that CTBBA-liposomehad higher DOX/PEG-RhB delivery than CDBA-liposome or PC-liposome in Bel7402cells. Meanwhile the serum could reduce the interaction betweenDOX-liposomes or PEG-RhB-liposomes and the cells, which led to decreasedintracellular uptake. The interesting thing was that DOX-CTBBA had a stronginteraction with the cell membrane after1hour incubation because the fluorescence ofDOX was mainly distributed on the cell membrane. On the contrary the fluorescencewas almost in the nuclear after treatment with DOX-PC or DOX-CDBA, which wasdue to the endocytosis after liposome-cell interaction. After continuous incubation,the fluorescence on the cell membrane gradually receded while the fluorescence in thenucleus was enhanced, with a higher intensity than DOX-PC or DOX-CDBA. Thisstrong electrostatics interaction between CTBBA-liposome and cells madeCTBBA-liposome have higher capacity to deliver drug and to kill cancer cells.
Then we evaluated the pharmacokinetic parameters of DOX-liposomes inSprague Dawley (SD) rats after tail intravenous injection. The results showed thatDOX-CDBA and DOX-CTBBA increased the values of AUC (area under curve) andT1/2, while reduced Ke(constant of elimination) and CL (clearance). In addition,compared to those previous reported positively charged liposomes, which were easilycleared from the blood with shorten T1/2, the value of Ke, T1/2and CL of DOX-CTBBA was not significantly different from those of DOX-PC (P>0.05).
Finally we investigated the retention and distribution of DOX-liposomes in rat’sretina after intravitreous injection. The results showed that DOX-CTBBA had higherfluorescence intensity than DOX-PC or DOX-CDBA in the ganglion cell layer (GCL)even after36hours. Moreover, DOX was even delivered to the inner cell layer (INL)by DOX-CTBBA. This indicated that CTBBA-liposome could efficiently transportdrug into the retina with longer retention, and it could be developed as a new drugformulation for ocular therapy.
In conclusion, our cholesterol derivatives combined liposomes could efficientlyinhibit drug leakage from the liposomes, with improved long-term physical stability insuspension. Even in the present of serum, the positively charged CTBBA-liposomecould maintain high drug delivery efficiency for both encapsulated small moleculeDOX and macromolecule PEG-RhB. The positive DOX-CTBBA could efficiently killthe tumor cells with lower cytotoxicity than that of DOTAP-liposome. The resultsfrom retina also indicated that the positive CTBBA-liposome could deliver drug intothe tissue with high efficiency. Finally the pharmacokinetic study showed thatcholesterol derivatives combined liposomes could improve the pharmacokineticparameters of DOX. We hope that these comprehensive assessments, including invitro and in vivo, could provide comprehensive data for application of these newcholesterol derivatives liposomes.
合成的新型胆固醇衍生物包括：4-cholesterocarbonyl-4'-(N,N,N-triethylamine butyloxylbromide) azobenzene（CTBBA），及与其结构类似的4-cholesterocarbonyl-4'-(N,N-diethylamine butyloxyl)azobenzene（CDBA），两者结构上的差异是CTBBA的头部基团为三乙胺，而CDBA的头部基团为二乙胺，这就使得CTBBA带有正电荷而CDBA显示为中性，基于此我们研究了电荷及血清对脂质体稳定性的影响。超声法制备的脂质体粒径大小在100-150nm之间，且在中性缓冲液体系（pH7.0）下，PC脂质体和CDBA脂质体的ζ电位为中性（0.7mV和-3.6mV），而CTBBA脂质体带正电荷（+25.4mV）。以阿霉素作为渗漏标记物，我们考察了长期保存过程中脂质体粒径和包封率的变化，以及在不同浓度血清存在下的稳定性。结果表明，在长达48周的时间内，组有胆固醇衍生物的阿霉素脂质体，粒径变化比PC阿霉素脂质体小，药物保存能力（包封率）更高；血清存在下，组有胆固醇衍生物的脂质体比PC脂质体在短时间内（3h）保留的阿霉素更多。
药物载体本身的生物相容性是其能否真正得到应用的关键因素之一。一般而言正电荷脂质体本身会对细胞产生一定的毒性，因此以常用的正电荷脂质N-(1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammoniummesylate(DOTAP)作为对照，评价了CTBBA脂质体对两种细胞株Bel7402和NIH3T3的毒性。结果显示CTBBA脂质体的细胞毒性明显低于DOTAP脂质体，说明我们的脂质体具有良好的生物相容性。
作为药物载体，除了上述优点外，还必须具有高效的细胞内输送能力，特别是在血清共存的模拟体内环境中。因此，我们制备了包封小分子药物阿霉素和大分子药物模型聚乙二醇-罗丹明B（PEG-RhB）的脂质体，运用荧光显微镜技术分析了胆固醇衍生物脂质体输送药物至细胞的能力以及输送机制，同时也评价了药物载体包封阿霉素后的细胞毒性。结果表明与PC脂质体和CDBA脂质体相比，CTBBA脂质体输送阿霉素/PEG-RhB进入细胞的能力最强；同时这些脂质体载体能改善大分子药物模型不能进入细胞的缺陷。共聚焦显微镜结果还显示PEG-RhB进入细胞后会聚集在细胞核周围但不能进入细胞核。虽然血清会减弱脂质体和细胞之间的作用，并降低脂质体所载药物进入细胞的量，但正电荷脂质体CTBBA仍然比CDBA具有高的细胞导入效率。我们运用共聚焦显微镜观测了阿霉素脂质体的细胞摄入动态过程。发现偏中性的PC脂质体和CDBA脂质体与Bel7402细胞作用1h后，由于细胞内吞作用其阿霉素荧光主要分布在细胞核内，而正电荷CTBBA脂质体由于和带负电的细胞膜强烈作用，其阿霉素荧光主要分布在细胞膜上，并随着培养时间的增加，阿霉素荧光逐渐扩散到细胞核中,且其最终强度高于CDBA脂质体和PC脂质体。这种强烈的静电作用使得正电荷CTBBA脂质体具有更高的药物输送能力以及细胞杀伤能力。
我们通过尾部静脉给药评价了阿霉素脂质体在Sprague-Dawley（SD）大鼠体内的药代动力学。结果显示CDBA和CTBBA脂质体能延长裸药阿霉素的AUC（药浓度和时间曲线下的面积）值和T1/2(半衰期)；同时降低了Ke（消除常数）和CL（清除率）。相比以往报道的正电荷脂质体在药物动力学上的不适宜性（如容易被体液清除，半衰期短），CTBBA脂质体在Ke,T1/2和CL上的参数值和PC脂质体无显著差异（P>0.05）。
最后，我们通过玻璃体注射给药和共聚焦显微镜技术研究了阿霉素脂质体在SD大鼠视网膜上的分布及滞留情况。结果表明正电荷的CTBBA脂质体能增加阿霉素进入视网膜节细胞层（GLC）上的量并延长阿霉素的滞留时间，甚至能载药到内核细胞层（INL）。这个结果表明我们的正电荷脂质体CTBBA能将阿霉素高效导入到视网膜，且滞留时间长，具有眼部药物新剂型的潜力。
综上所述，我们的胆固醇衍生物脂质体能有效抑制药物的自然渗漏，并增加脂质体悬液的长期稳定性。即使在血清存在下，正电荷脂质体无论对小分子药物阿霉素还是大分子药物模型PEG-RhB，均能保持高的细胞内导入效率。载有阿霉素的正电荷脂质体在高效杀死癌细胞的同时，自身所具有的毒性也比常用的正电荷脂质DOTAP弱。此外正电荷脂质体CTBBA还能高效的将阿霉素输送到视网膜内。大鼠药代实验结果表明胆固醇衍生物脂质体能改善药物的动力学参数，且可以克服其他已报道的正电荷脂质体容易被体液清除、药物半衰期缩短、AUC降低等缺陷。我们希望通过这些体外体内的综合评价，为新型胆固醇衍生物脂质体的实际应用可行性提供全面数据。
Liposomes are formed when thin phospholipids films are hydrated, withcomposite structures of one or multiple layers of lipid vesicles. Liposomes have goodbiocompatibility and biodegradability and have been used as good drug deliverycarriers. But liposomes trend to aggregate together in long-term preservation,accompany with drugs leakage. Cholesterol is an important part of the biomembraneand it can increase the mechanical strength and reduce the permeability ofbiomembrane. This research is based on newly synthesized cholesterol derivatives,which are combined into the liposomes. We have investigated the long-term stabilityof the liposome in vitro, and focused on the evaluation of the cholesterol derivativescombined liposome as small molecule drug (doxorubicin, DOX) carrier andmacromolecule model (polyethylene glycol6000-rohadamine B, PEG-RhB) carrier inthe presence of serum. We have also studied the pharmacokinetic parameters ofDOX-liposomes and the distribution of DOX-liposomes in rats’ retina.
The newly synthesized cholesterol derivatives include4-cholesterocarbonyl-4'-(N,N,N-triethylamine butyloxyl bromide) azobenzene(CTBBA) and its structural analog4-cholesterocarbonyl-4'-(N,N-diethylaminebutyloxyl) azobenzene (CDBA). CTBBA has a triethylamine while CDBA has adiethylamine in the head group, which makes CTBBA positive and CDBA neutral.We studied the influence of charge and serum on the stability of liposomes. Thesecholesterol derivatives combined liposomes dispersed well with a size distribution between100to150nm. CTBBA-liposome showed a positive ζ-potential in PBS,while PC-liposome and CDBA-liposome were near neutral. We evaluated the changesin particle size and encapsulation efficiency during long-term preservation and foundthat CDBA-liposome/CTBBA-liposome were more stable than PC-liposome.CDBA-liposome/CTBBA-liposome had higher drug retention (within3h) than PCliposome in the presence of serum.
As a drug carrier, CTBBA-liposome showed lower cytotoxicity in Bel7402cellsand NIH3T3cells, compared to N-(1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium mesylate (DOTAP) liposome, a common usedpositive liposome. Then the drug delivery capacity of CDBA/CTBBA liposomes wasevaluated in Bel7402cells. Small molecule drug DOX and macromolecule modelPEG-RhB were chosen as the contents. The results showed that CTBBA-liposomehad higher DOX/PEG-RhB delivery than CDBA-liposome or PC-liposome in Bel7402cells. Meanwhile the serum could reduce the interaction betweenDOX-liposomes or PEG-RhB-liposomes and the cells, which led to decreasedintracellular uptake. The interesting thing was that DOX-CTBBA had a stronginteraction with the cell membrane after1hour incubation because the fluorescence ofDOX was mainly distributed on the cell membrane. On the contrary the fluorescencewas almost in the nuclear after treatment with DOX-PC or DOX-CDBA, which wasdue to the endocytosis after liposome-cell interaction. After continuous incubation,the fluorescence on the cell membrane gradually receded while the fluorescence in thenucleus was enhanced, with a higher intensity than DOX-PC or DOX-CDBA. Thisstrong electrostatics interaction between CTBBA-liposome and cells madeCTBBA-liposome have higher capacity to deliver drug and to kill cancer cells.
Then we evaluated the pharmacokinetic parameters of DOX-liposomes inSprague Dawley (SD) rats after tail intravenous injection. The results showed thatDOX-CDBA and DOX-CTBBA increased the values of AUC (area under curve) andT1/2, while reduced Ke(constant of elimination) and CL (clearance). In addition,compared to those previous reported positively charged liposomes, which were easilycleared from the blood with shorten T1/2, the value of Ke, T1/2and CL of DOX-CTBBA was not significantly different from those of DOX-PC (P>0.05).
Finally we investigated the retention and distribution of DOX-liposomes in rat’sretina after intravitreous injection. The results showed that DOX-CTBBA had higherfluorescence intensity than DOX-PC or DOX-CDBA in the ganglion cell layer (GCL)even after36hours. Moreover, DOX was even delivered to the inner cell layer (INL)by DOX-CTBBA. This indicated that CTBBA-liposome could efficiently transportdrug into the retina with longer retention, and it could be developed as a new drugformulation for ocular therapy.
In conclusion, our cholesterol derivatives combined liposomes could efficientlyinhibit drug leakage from the liposomes, with improved long-term physical stability insuspension. Even in the present of serum, the positively charged CTBBA-liposomecould maintain high drug delivery efficiency for both encapsulated small moleculeDOX and macromolecule PEG-RhB. The positive DOX-CTBBA could efficiently killthe tumor cells with lower cytotoxicity than that of DOTAP-liposome. The resultsfrom retina also indicated that the positive CTBBA-liposome could deliver drug intothe tissue with high efficiency. Finally the pharmacokinetic study showed thatcholesterol derivatives combined liposomes could improve the pharmacokineticparameters of DOX. We hope that these comprehensive assessments, including invitro and in vivo, could provide comprehensive data for application of these newcholesterol derivatives liposomes.
引文
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