硬化治疗血管瘤用平阳霉素原位凝胶的研究
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摘要
血管瘤的药物治疗主要是硬化剂注射治疗，其中平阳霉素(Pingyangmycin，PYM)是目前临床上应用最为广泛的一种硬化剂。但从文献报道中可以发现，平阳霉素作为硬化剂治疗海绵状血管瘤(临床上最为常见的血管畸形)时，治愈率并不高。本课题以平阳霉素作为模型药物，以原位凝胶作为药物的载体，对一种用于硬化治疗血管瘤的新型药物传递系统进行了研究。
经单因素考察和正交实验，确定了原位凝胶的主要基质——玉米醇溶蛋白(Zein)的精制工艺。十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)结果表明，精制所得的产品仅含有19 kDa和22 kDa两个分子量的条带。通过对有机溶剂、活性炭以及超临界萃取等脱色工艺的研究，确定了玉米醇溶蛋白的脱色工艺。
考察了该制剂体外栓塞效果的影响因素，将240.0 mg·mL~(-1)定为该制剂的玉米醇溶蛋白浓度；将拟栓塞血管瘤的最大引流血管口径定为2 mm；最为有效的栓塞部位是引流管口附近；适量的蔗糖醋酸异丁酯(sucrose acetate isobutyrate，SAIB)或PEG6000的加入对该制剂的栓塞效果无显著影响。
凝胶相转变过程的流变学研究表明，在与生理盐水接触之后的几十秒内，原位凝胶溶液的G′、G″、η急剧增加(约两个数量级)，而δ则急剧减小直至48-57°之间。说明在注入生理盐水之后，原位凝胶溶液与之接触的部分发生了从溶液向凝胶的相转变。SAIB的加入使平阳霉素原位凝胶的相角增大，从而调整其相转变行为，获得理想的栓塞和缓释效果。
体外释放的研究表明，释放面积、凝胶量、震荡速度、温度等因素的均会影响平阳霉素原位凝胶的释放行为。PEG6000的加入可使药物释放加快，适当量的SAIB的加入会减小药物的突释，延长药物释放的时间；载药量加大可使药物释放加快，突释加大，释放时间缩短，释放得更加完全；释放介质中加入胰蛋白酶，可使药物的释放加快。
应用小角X射线衍射(Small Angle X-ray Scattering，SAXS)技术对玉米醇溶蛋白在甲醛缩甘油中的三维结构进行了研究，测得其Rg和Rc分别为4.15±0.04 nm和1.78±0.03 nm，从而推断它在甲醛缩甘油中是以三维为13.0 nm×5.4 nm×3.0 nm的五聚体形式存在的。分别通过光学显微镜、扫描电镜和原子力显微镜(Atomic Force Microscope，AFM)对平阳霉素原位凝胶的结构进行观察，对平阳霉素原位凝胶形成及药物释放的机理进行了深入的探讨。
采用微渗析取样技术测定了平阳霉素在家兔和家犬体外的血浆蛋白结合率，并应用一般血样取样法和微渗析取样法同时监测了平阳霉素在家兔体内的经时过程，计算得到了平阳霉素在家兔体内的血浆蛋白结合率为31.96±7.51％，与体外测得结果无显著性差异(P＞0.05)。
平阳霉素原位凝胶在血管瘤模型中释放的研究表明，平阳霉素原位凝胶可明显的延长平阳霉素在局部的滞留时间，SAIB可以明显减少平阳霉素原位凝胶早期的突释，并使其后期的释放保持一定速度，使药物释放时间长达4天，局部药物浓度保持在10μg·mL~(-1)左右。
通过观察细胞形态学变化、绘制细胞生长曲线以及MTT法，研究了平阳霉素及其原位凝胶对人脐静脉内皮细胞ECV304的抑制作用，结果表明平阳霉素对ECV304细胞的抑制作用具有明显的时间和浓度依赖性，作用24、48、72h后的IC_(50)分别为16.05±1.21、1.99±0.56和0.29±0.18μg·mL~(-1)。应用分子生物学技术，研究了平阳霉素作用后的ECV304细胞DNA含量变化，对平阳霉素抑制ECV304细胞生长的机理进行初步探讨，发现此作用是通过诱导细胞凋亡和造成细胞坏死两条途径实现的。平阳霉素原位凝胶对ECV304细胞抑制作用的研究表明，该原位凝胶有明显的缓释作用。
以家兔耳缘静脉系统为血管畸形模型，研究了应用平阳霉素溶液、空白原位凝胶、PYM-Zein原位凝胶及PYM-Zein-SAIB原位凝胶后耳缘静脉的形态学及组织学的变化，结果表明，PYM-Zein-SAIB原位凝胶能有效地栓塞家兔的耳缘静脉并使之闭锁，且炎性反应较PYM-Zein原位凝胶小，疗效明显优于平阳霉素溶液、空白原位凝胶和PYM-Zein原位凝胶。PYM-Zein-SAIB原位凝胶是较为理想的治疗血管瘤的药物传递系统。
Sclerotherapy was frequently used for complicated haemangioma, and Pingyangmycin (PYM) was the most promising sclerosing agent. However, according to the reports, the cure rate of PYM to cavernous hemangioma, the most epidemic vascular malformation, was not satisfying. A new drug delivery system, Pingyangmycin in situ gel, was designed in this study to get better curative effect of haemangioma and vascular malformation.
The refining process of zein, the main matrix of Pingyangmycin in situ gel, was decided according to orthogonal experiment. The result of SDS-PAGE showed that the refined zein contained two compositions, and their molecular weight were 19 kDa and 22 kDa, respectively. The decolorized zein was produced with optimized decolorizing process.
Factors which could influence the in vitro embolizing effect of Pingyangmycin in situ gel were studied, and the proper concentration of zein was 240.0 mg·mL~(-1). The maximum caliber of the draining blood vessel for treated haemangioma and vascular malformation was 2 mm., and moreover the most effective embolizing site was around the orifice of the draining blood vessel. A certain amount of sucrose acetate isobutyrate or PEG 6000 would not influence obviously the embolizing effect.
Rheology study of in situ gel showed that G′, G″,ηincreased andδdecreased sharply when it contacted with normal sodium. These phenomena indicated that in situ gel solution contacting with NS changed into gel. SAIB could increaseδof PYM in situ gel, modulate its phase transition and improve the embolizing effect and delayed release.
In vitro release study revealed that release area, in situ get amount, shake rate and temperature would affect drug release; PEG 6000 would quicken drug release, and proper amount of SAIB would significantly cut down the initial burst of PYM from the in situ gels; the increase of drug loaded would result in faster release, higher initial burst, shorter release period and higher accumulated release of PYM; trypsin would enhance drug release.
Small Angle X-ray Scattering (SAXS) was applied to study the three diamensions structure of zein in glycerol formal. Its Rg and Rc were 4.15±0.04 nm and 1.78±0.03 nm, respectively. It was ratiocinated that zein existed in glycerol formal as a pentamer with 3D of 13.0 nm×5.4 nm×3.0 nm. According to the result of light microscope, SEM and atomic force microscope (AFM), the mechanism of gel formation and drug release for PYM in situ gel was further discussed.
In vitro PYM plasma protein binding fractions in rabbit and canis familiaris blood were evaluated with microdialysis sampling technique. And the blood concentration of PYM in rabbits was studied with traditional blood sampling and microdialysis sampling simultaneously. The in vivo PYM plasma protein binding fraction in rabbits was 31.96＋7.51%, which was similar with the in vitro one. The drug release of PYM in situ gel in the animal model of venous malformation was investigated in conscious rabbits. Compared with the PYM solution, the in situ gel could sustain the release of PYM and prolong its local retention. In vivo releases of the in situ gels of PYM-Zein and PYM-Zein-SAIB were up to 3 days and 4days, respectively. SAIB could significantly cut down the initial burst of PYM and prolong drug release.
The result of inhibitory effect of PYM and PYM in stiu gel on ECV304 cell presented that the inhibitory effect had time and concentration dependent. IC_(50) for 24h, 48h and 72h were 16.05±1.21, 1.99±0.56 and 0.29±0.18μg·mL~(-1), respectively. PYM in situ gel could sustain the release of PYM. Molecular biological study found that inhibition of PYM on ECV304 cell was achieved by two ways, apoptosis and necrosis.
Pharmacodynamics of PYM in situ gel was studied with rabbit ear venous system. The results showed that PYM-Zcin-SAIB in situ gel could cmbolizc rabbit car venous and sclerize it. Its inflammatory reaction was slighter than PYM-Zcin in situ gel. Its therapeutic effect was better than PYM solution, blank in situ gel and PYM-Zein in situ gel. These results suggested considerable potential for use of PYG-loadcd injectable Zcin-SAIB-based in situ gels for sclcrotherapy of venous malformations.
经单因素考察和正交实验，确定了原位凝胶的主要基质——玉米醇溶蛋白(Zein)的精制工艺。十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)结果表明，精制所得的产品仅含有19 kDa和22 kDa两个分子量的条带。通过对有机溶剂、活性炭以及超临界萃取等脱色工艺的研究，确定了玉米醇溶蛋白的脱色工艺。
考察了该制剂体外栓塞效果的影响因素，将240.0 mg·mL~(-1)定为该制剂的玉米醇溶蛋白浓度；将拟栓塞血管瘤的最大引流血管口径定为2 mm；最为有效的栓塞部位是引流管口附近；适量的蔗糖醋酸异丁酯(sucrose acetate isobutyrate，SAIB)或PEG6000的加入对该制剂的栓塞效果无显著影响。
凝胶相转变过程的流变学研究表明，在与生理盐水接触之后的几十秒内，原位凝胶溶液的G′、G″、η急剧增加(约两个数量级)，而δ则急剧减小直至48-57°之间。说明在注入生理盐水之后，原位凝胶溶液与之接触的部分发生了从溶液向凝胶的相转变。SAIB的加入使平阳霉素原位凝胶的相角增大，从而调整其相转变行为，获得理想的栓塞和缓释效果。
体外释放的研究表明，释放面积、凝胶量、震荡速度、温度等因素的均会影响平阳霉素原位凝胶的释放行为。PEG6000的加入可使药物释放加快，适当量的SAIB的加入会减小药物的突释，延长药物释放的时间；载药量加大可使药物释放加快，突释加大，释放时间缩短，释放得更加完全；释放介质中加入胰蛋白酶，可使药物的释放加快。
应用小角X射线衍射(Small Angle X-ray Scattering，SAXS)技术对玉米醇溶蛋白在甲醛缩甘油中的三维结构进行了研究，测得其Rg和Rc分别为4.15±0.04 nm和1.78±0.03 nm，从而推断它在甲醛缩甘油中是以三维为13.0 nm×5.4 nm×3.0 nm的五聚体形式存在的。分别通过光学显微镜、扫描电镜和原子力显微镜(Atomic Force Microscope，AFM)对平阳霉素原位凝胶的结构进行观察，对平阳霉素原位凝胶形成及药物释放的机理进行了深入的探讨。
采用微渗析取样技术测定了平阳霉素在家兔和家犬体外的血浆蛋白结合率，并应用一般血样取样法和微渗析取样法同时监测了平阳霉素在家兔体内的经时过程，计算得到了平阳霉素在家兔体内的血浆蛋白结合率为31.96±7.51％，与体外测得结果无显著性差异(P＞0.05)。
平阳霉素原位凝胶在血管瘤模型中释放的研究表明，平阳霉素原位凝胶可明显的延长平阳霉素在局部的滞留时间，SAIB可以明显减少平阳霉素原位凝胶早期的突释，并使其后期的释放保持一定速度，使药物释放时间长达4天，局部药物浓度保持在10μg·mL~(-1)左右。
通过观察细胞形态学变化、绘制细胞生长曲线以及MTT法，研究了平阳霉素及其原位凝胶对人脐静脉内皮细胞ECV304的抑制作用，结果表明平阳霉素对ECV304细胞的抑制作用具有明显的时间和浓度依赖性，作用24、48、72h后的IC_(50)分别为16.05±1.21、1.99±0.56和0.29±0.18μg·mL~(-1)。应用分子生物学技术，研究了平阳霉素作用后的ECV304细胞DNA含量变化，对平阳霉素抑制ECV304细胞生长的机理进行初步探讨，发现此作用是通过诱导细胞凋亡和造成细胞坏死两条途径实现的。平阳霉素原位凝胶对ECV304细胞抑制作用的研究表明，该原位凝胶有明显的缓释作用。
以家兔耳缘静脉系统为血管畸形模型，研究了应用平阳霉素溶液、空白原位凝胶、PYM-Zein原位凝胶及PYM-Zein-SAIB原位凝胶后耳缘静脉的形态学及组织学的变化，结果表明，PYM-Zein-SAIB原位凝胶能有效地栓塞家兔的耳缘静脉并使之闭锁，且炎性反应较PYM-Zein原位凝胶小，疗效明显优于平阳霉素溶液、空白原位凝胶和PYM-Zein原位凝胶。PYM-Zein-SAIB原位凝胶是较为理想的治疗血管瘤的药物传递系统。
Sclerotherapy was frequently used for complicated haemangioma, and Pingyangmycin (PYM) was the most promising sclerosing agent. However, according to the reports, the cure rate of PYM to cavernous hemangioma, the most epidemic vascular malformation, was not satisfying. A new drug delivery system, Pingyangmycin in situ gel, was designed in this study to get better curative effect of haemangioma and vascular malformation.
The refining process of zein, the main matrix of Pingyangmycin in situ gel, was decided according to orthogonal experiment. The result of SDS-PAGE showed that the refined zein contained two compositions, and their molecular weight were 19 kDa and 22 kDa, respectively. The decolorized zein was produced with optimized decolorizing process.
Factors which could influence the in vitro embolizing effect of Pingyangmycin in situ gel were studied, and the proper concentration of zein was 240.0 mg·mL~(-1). The maximum caliber of the draining blood vessel for treated haemangioma and vascular malformation was 2 mm., and moreover the most effective embolizing site was around the orifice of the draining blood vessel. A certain amount of sucrose acetate isobutyrate or PEG 6000 would not influence obviously the embolizing effect.
Rheology study of in situ gel showed that G′, G″,ηincreased andδdecreased sharply when it contacted with normal sodium. These phenomena indicated that in situ gel solution contacting with NS changed into gel. SAIB could increaseδof PYM in situ gel, modulate its phase transition and improve the embolizing effect and delayed release.
In vitro release study revealed that release area, in situ get amount, shake rate and temperature would affect drug release; PEG 6000 would quicken drug release, and proper amount of SAIB would significantly cut down the initial burst of PYM from the in situ gels; the increase of drug loaded would result in faster release, higher initial burst, shorter release period and higher accumulated release of PYM; trypsin would enhance drug release.
Small Angle X-ray Scattering (SAXS) was applied to study the three diamensions structure of zein in glycerol formal. Its Rg and Rc were 4.15±0.04 nm and 1.78±0.03 nm, respectively. It was ratiocinated that zein existed in glycerol formal as a pentamer with 3D of 13.0 nm×5.4 nm×3.0 nm. According to the result of light microscope, SEM and atomic force microscope (AFM), the mechanism of gel formation and drug release for PYM in situ gel was further discussed.
In vitro PYM plasma protein binding fractions in rabbit and canis familiaris blood were evaluated with microdialysis sampling technique. And the blood concentration of PYM in rabbits was studied with traditional blood sampling and microdialysis sampling simultaneously. The in vivo PYM plasma protein binding fraction in rabbits was 31.96＋7.51%, which was similar with the in vitro one. The drug release of PYM in situ gel in the animal model of venous malformation was investigated in conscious rabbits. Compared with the PYM solution, the in situ gel could sustain the release of PYM and prolong its local retention. In vivo releases of the in situ gels of PYM-Zein and PYM-Zein-SAIB were up to 3 days and 4days, respectively. SAIB could significantly cut down the initial burst of PYM and prolong drug release.
The result of inhibitory effect of PYM and PYM in stiu gel on ECV304 cell presented that the inhibitory effect had time and concentration dependent. IC_(50) for 24h, 48h and 72h were 16.05±1.21, 1.99±0.56 and 0.29±0.18μg·mL~(-1), respectively. PYM in situ gel could sustain the release of PYM. Molecular biological study found that inhibition of PYM on ECV304 cell was achieved by two ways, apoptosis and necrosis.
Pharmacodynamics of PYM in situ gel was studied with rabbit ear venous system. The results showed that PYM-Zcin-SAIB in situ gel could cmbolizc rabbit car venous and sclerize it. Its inflammatory reaction was slighter than PYM-Zcin in situ gel. Its therapeutic effect was better than PYM solution, blank in situ gel and PYM-Zein in situ gel. These results suggested considerable potential for use of PYG-loadcd injectable Zcin-SAIB-based in situ gels for sclcrotherapy of venous malformations.
引文
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