纳米控释系统的制备及在血管再狭窄和肿瘤治疗中的应用
|
摘要
心血管疾病和肿瘤严重威胁着人类的健康,将纳米技术应用于这两类疾病的治疗具有积极的意义。
经皮冠状动脉腔内血管成形术(Percutaneous transluminal coronary angioplasty, PTCA)及支架置入术是当前治疗冠状动脉粥样硬化性心脏病最为有效的重要手段之一,但术后6个月内再狭窄的发生率高达30%-50%,是限制其远期临床疗效、增加医疗费用的主要原因。近年的研究表明血管内皮难愈合以及血管平滑肌细胞过度迁移、增殖所形成的新生内膜增殖性阻塞是再狭窄形成的两个主要成因。应用系统给药方法对再狭窄进行防治,常受限于超生理剂量所带来的全身毒副作用和血管内药物分布、代谢低效能等因素,难以在血管局部达到有效的作用浓度,药物在局部维持有效作用浓度的时间较短。局部给药能够将高浓度的治疗剂直接运送至血管病灶部位,既能提高给药效率,又能避免系统给药的上述弊端。现有的临床试验证实了局部给药具有良好的安全性和可行性,但临床疗效欠满意,考虑药物局部存留差是其主要原因。联合纳米技术在制剂学上的进展以改善药物在组织内渗透、再分布能力及药物滞留时间。
雷帕霉素(Rapamycin, RPM)是由链霉菌属丝状菌发酵产生的一种大环内酯类抗生素,能够抑制VSMC迁移和增殖作用,在动物实验和临床试验中能够减少损伤后内膜增殖、有效降低PTCA术后6个月至1年的再狭窄发生率,是当前防治再狭窄最有临床应用前景的药物之一。但是RPM也存在自身毒性作用大,吸收限制、亲水性差,对pH敏感和治疗指数偏低,生物应用受限于赋形剂、稳定性等药理学缺点。论文第二章研制了雷帕霉素(Rapamycin, RPM)纳米制剂做为抗增殖药物用于血管再狭窄,并在动物体内探索其用于再狭窄防治的效果。
内皮难愈合和平滑肌过度增殖是血管再狭窄发生的两个关键性的原因,本论文第三章针对这两个关键原因,即创造性的提出了双功能的构想,设计制备了可程序性释放的双功能纳米粒子,粒子可最初释放VEGF基因,后期缓慢释放紫杉醇。通过球囊灌注验证VEGF/紫杉醇双功能纳米粒子在兔球囊损伤模型上对血管再狭窄的治疗效果；进而结合超声喷涂技术制备纳米微孔双功能血管支架,最终在实验猪体内观察基因药物涂层支架植入体内后对血管再狭窄抑制效果。
抗增殖药物紫杉醇(paclitaxel, PTX)是现有已被广泛使用的抗增殖药,它是从红豆杉科红豆杉属植物中提取得到的二萜类化合物,脂溶性高,它能诱导和促进微管蛋白聚合,防止解聚,稳定微管,使细胞停留在G2/M期,从而导致细胞死亡.该药物被应用于肿瘤的临床治疗,但是其临床使用剂型易引起过敏反应,急待研制理想的新剂型.本论文第四章就此问题进行了探索,研制了紫杉醇PLGA纳米粒子,在小鼠乳腺癌模型上验证其肿瘤抑制效果。
本论文的具体研究结果总结如下：
1.通过超声乳化—溶剂挥发法成功制备了平均粒径为246.8nm的RPM—PLGA纳米粒子,平均载药量为19.42%；扫描电镜下观察为表面光滑的球体,体外释放近似于零级过程,至2周释放75%的药物。在灌注压力为1atm,灌注时间为10分钟条件下,经Di spatch导管球囊向新西兰兔腹主动脉腔内灌注5mg/ml RPM-PLGA纳米粒子,至给药后7天局部组织药物浓度仍可维持在22.45±2.64μg/10mg干重水平,给药后14天组织药物浓度为4.64±0.77μg/10mg干重,至给药后21天应用HPLC方法基本测不到药物；成功制备了中国实验用小型猪过大球囊损伤冠状动脉模型,术后30天冠状动脉造影显示：生理盐水灌注组、空白PLGA纳米粒子灌注组和RPM灌注组三组间血管形态学参数和冠状动脉造影显示狭窄程度无明显差异；RPM-PLGA纳米粒子组血管狭窄程度(23.4±5.35%)明显低于生理盐水和空白纳米粒子对照组(分别为46.07±18.33%和52.20±18.74%,P均<0.01)和RPM灌注组(39.32±9.91%,P<0.05)；冠状动脉损伤后30天新生内膜面积、增生指数和NEELA/EELA比值明显低于上述三组(P均<0.05)。免疫组织化学染提示RPM纳米粒子干预组增殖核抗原蛋白(PCNA)表达阳性细胞率及MMP-2和TIMP-2蛋白阳性表达量均低于生理盐水和空白纳米粒子对照组,而原位杂交p27mRNA水平明显高于上述三组。
2.成功制备了VEGF/紫杉醇双功能纳米粒子,平均粒径大小为78.82nm,Zeta电位测定平均值为-12.2。紫杉醇包封率为92%,载紫杉醇药量为28.58%,基因包封率为98%,载基因量为4.67%。在兔体内球囊灌注后,VEGF纳米粒子组与双功能纳米粒子组均有效的抑制了血管再狭窄,尤其是VEGF纳米粒子组显示了很好的愈后。免疫组织化学结果提示VEGF纳米粒子组和PTX/VEGF NPs纳米粒子组增殖核抗原蛋白(PCNA)表达阳性细胞率及MMP-2和TIMP-2蛋白阳性表达量均低于生理盐水和空白纳米粒子对照组。应用双功能纳米支架在实验猪体内有效地降低了管腔丢失率,双功能纳米粒子组管腔丢失率仅为23.2%,明显优于波士顿公司上市支架TAXUS(?)48％管腔丢失率。而VEGF纳米粒子组管腔丢失率也达到了25%。
3.制备了平均粒径为233.74nm的紫杉醇纳米粒子,载药量19.58%,包埋率为84.3%。对TA2系小鼠乳腺癌肺转移模型肿瘤生长抑制作用的观察,2周药物注射抑瘤率结果显示：紫杉醇纳米粒子中剂量组为70.21%、紫杉醇纳米粒子高剂量组为84.16%,紫素阳性对照组为48.96%,两者差异有显著性(P<0.001)。紫杉醇纳米粒子低剂量组为45.47%与紫素阳性对照组相比,两者亦有显著性差异(P<0.001)。
Cardiovascular diseases and cancer seriously threaten human health, and it is of positive significance to apply nanotechnology to treatment of these diseases.
At present, percutaneous transluminal coronary angioplasty (PTCA) and stent implantation is one of the most effective treatment means for coronary atherosclerotic heart disease. However, the incidence of restenosis within6months after the operation is as high as30%to50%, becoming a main cause for the restricted long-term clinical efficacy and the increased medical expenses. Recent studies show that the difficult healing of blood vessel endothelium and the neointimal proliferation emphraxis arising from excess migration and proliferation of vascular smooth muscle cell are two main causes for the formation of restenosis. Prevention and treatment of restenosis using systematic administration is often restricted by systematic toxic and side effect as a result of overdose and such factors as low efficiency of drug distribution and metabolizing in blood vessel, resulting in hardly effective local concentration of drug in blood vessel and short lasting of effective local concentration of drug. Local administration can directly deliver the high concentration therapeutic agent to the target tissue, improving the efficiency of administration and avoiding the above-mentioned defects of systematic administration. Existing clinical tests have confirmed the good safety and feasibility of local administration, but the clinical efficacy is unsatisfactory, which is mainly caused by poor local retention of drug. Nanotechnology can be used in manufacturing pharmacy to improve infiltration and redistribution of drug in tissues and increase local retention of drug.
Rapamycin (RPM) is a kind of macrolide antibiotic produced by means of fermentation of streptomyces hygro scopicus. In in-vitro experiments, this drug can inhibit VSMC migration and proliferation, in animal experiments and clinical tests it can reduce post-injury intimal proliferation and effectively lower the incidence of restenosis6months to1years after PTCA operation. It is one of the drugs with the greatest clinical application potential for prevention and treatment of restenosis at present. However, RPM also has such pharmacological defects as toxic effect, restricted absorption, poor hydrophilicity, restricted biological application by excipient and stability, sensitivity to pH and low treatment index. In Chapter Two of this paper, preparation of nanotechnology based RMP as anti-proliferation drug for vascular restenosis is explored.
In Chapter Three, an innovative double-function concept brought forward based on the two main causes for vascular restenosis, that is difficult healing of endothelium and excess proliferation of vascular smooth muscle cell; the treatment effect of VEGF/paclitaxel double-function nanoparticle for vascular restenosis on rabbit saccule injury model is verified by saccule perfusion; nanotechnology based micropore double-function intravascular stent is prepared using ultrasonic spraying process, and finally the effect of such stent to inhibit vascular restenosis in experimental pig body is observed.
Paclitaxel (PTX) is anti-proliferation drug with the widest application in clinic. It is diterpenes compound extracted from plants in Taxus Genus, Taxaceae Family. Being highly fat-soluble, it can induce and promote polymerization of tubulin, prevent depolymerization, stabilize tubulin, make cell rein in G2/M phase, and thus cause cell death. This drug is used for clinical treatment of cancer, but its formulation used clinically may easily cause anaphylactic reaction, so an ideal new drug form is in urgent need. In Chapter Four of this paper, such new drug form is explored, and its effect to inhibit breast cancer is verified on mouse mammary cancer model.
The detailed contents of this study are as follows:
1. RPM-PLGA NPs with a mean particle diameter of246.8nm and a mean drug load of19.42%were successfully prepared using ultrasonic emulsification&solvent volatilization method. Observed under scanning electron microscope, these NPs were spheres with smooth surface, and their in-vitro release was similar to a zero-order process, releasing75%drug by the end of Week2. Then,5mg/ml RPM-PLGA NPs were perfused into abdominal aorta cavity of New Zealand rabbit through dispatch perfusion balloon. After the administration7days, the drug concentration in local tissue was still as high as22.45±2.64μg/10mg dry weight, on the14th day after the administration the drug concentration in the tissue was4.64±0.77μg/10mg dry weight, and on the21st day after the administration no drug concentration was detected using HPLC method. A Chinese experimental minipig oversize saccule injury coronary artery model was successfully developed, and the coronary arteriongraphy on the30th day after the operation showed that:there was no significant difference among the control group perfused with physiological saline, the control group perfused with blank PLGA NPs and the group perfused with RPM, as indicated in vascular morphological indexes and coronary arteriongraphy; the degree of hemadostenosis in the group perfused with RMP-PLGA NPs (23.4±5.35%) was significantly lower than the physiological saline control group and the blank NPs control group (respectively46.07±18.33%and52.20±8.74%, P<0.01in both groups) and the group perfused with RMP (39.32±9.91%, P<0.05); the area of neointimal, the proliferation index and the NEELA/EELA ratio of the RMP-PLGA group on the30th day after coronary artery injury were significantly lower than the three control groups (P<0.05in all the three groups). Immunohistochemical staining results indicated that the RPM group had lower PCNA positive cell expression rate and MMP-2&TIMP-2protein positive expression volume than the physiological saline control group and the blank NPs control group, and the experimental group had significantly higher hybridization in situ p27mRNA level than the three control groups.
2. VEGF/PTX double-function nanoparticles (VEGF/PTX NPs) were successfully prepared, with a mean particle diameter of78.82nm and mean Zeta electric potential measurement of-12.2. The PTX entrapment rate was92%, the PTX load was28.58%, the gene entrapment rate was98%, and the gene load was4.67%. After in-vivo perfusion into saccule of rabbit, the vascular restenosis in both the VEGF NPs group and the VEGF/PTX NPs groups was inhibited. Particularly, good healing was observed in VEGF NPs group. Immunohistochemical results indicated that the VEGF NPs group and the VEGF/PTX NPs groups had lower PCNA positive cell expression rate and MMP-2&TIMP-2protein positive expression volume than the physiological saline control group and the blank NPs control group. The double-function nanotechnology micropore stent used in experimental pig body effectively inhibited vascular restenosis, and lumen loss in the VEGF/PTX NPs group was as low as22.3%±8%, significantly better than the48%provided by the TAXUS(?) stent sold by Boston Scientific Corporation. This study provides a new thought and approach for prevention and treatment of cardiovascular restenosis, and may probably provide a new kind of genetical stent for clinical treatment of vascular restenosis.
3. Paclitaxel nanoparticles (PTX NPs) with a mean particle diameter of233.74nm, entrapment efficiency is84.3%and PTX loading capacity is about19.58%, which means were successfully prepared, and was used to inhibit cancer growth in TA2mouse breast cancer pulmonary metastasis model. As shown in the two week injection observation, the cancer inhibition rate of the middle dose PTX NPs group was70.21%, that of the high dose PTX NPs group was84.16%, and that of the Taxol positive control group was48.96%, indicating a significant difference (P<0.001). Such rate of the low dose PTX NPs group was45.47%, which also had significant difference from the Taxol positive control group (P<0.001).
经皮冠状动脉腔内血管成形术(Percutaneous transluminal coronary angioplasty, PTCA)及支架置入术是当前治疗冠状动脉粥样硬化性心脏病最为有效的重要手段之一,但术后6个月内再狭窄的发生率高达30%-50%,是限制其远期临床疗效、增加医疗费用的主要原因。近年的研究表明血管内皮难愈合以及血管平滑肌细胞过度迁移、增殖所形成的新生内膜增殖性阻塞是再狭窄形成的两个主要成因。应用系统给药方法对再狭窄进行防治,常受限于超生理剂量所带来的全身毒副作用和血管内药物分布、代谢低效能等因素,难以在血管局部达到有效的作用浓度,药物在局部维持有效作用浓度的时间较短。局部给药能够将高浓度的治疗剂直接运送至血管病灶部位,既能提高给药效率,又能避免系统给药的上述弊端。现有的临床试验证实了局部给药具有良好的安全性和可行性,但临床疗效欠满意,考虑药物局部存留差是其主要原因。联合纳米技术在制剂学上的进展以改善药物在组织内渗透、再分布能力及药物滞留时间。
雷帕霉素(Rapamycin, RPM)是由链霉菌属丝状菌发酵产生的一种大环内酯类抗生素,能够抑制VSMC迁移和增殖作用,在动物实验和临床试验中能够减少损伤后内膜增殖、有效降低PTCA术后6个月至1年的再狭窄发生率,是当前防治再狭窄最有临床应用前景的药物之一。但是RPM也存在自身毒性作用大,吸收限制、亲水性差,对pH敏感和治疗指数偏低,生物应用受限于赋形剂、稳定性等药理学缺点。论文第二章研制了雷帕霉素(Rapamycin, RPM)纳米制剂做为抗增殖药物用于血管再狭窄,并在动物体内探索其用于再狭窄防治的效果。
内皮难愈合和平滑肌过度增殖是血管再狭窄发生的两个关键性的原因,本论文第三章针对这两个关键原因,即创造性的提出了双功能的构想,设计制备了可程序性释放的双功能纳米粒子,粒子可最初释放VEGF基因,后期缓慢释放紫杉醇。通过球囊灌注验证VEGF/紫杉醇双功能纳米粒子在兔球囊损伤模型上对血管再狭窄的治疗效果；进而结合超声喷涂技术制备纳米微孔双功能血管支架,最终在实验猪体内观察基因药物涂层支架植入体内后对血管再狭窄抑制效果。
抗增殖药物紫杉醇(paclitaxel, PTX)是现有已被广泛使用的抗增殖药,它是从红豆杉科红豆杉属植物中提取得到的二萜类化合物,脂溶性高,它能诱导和促进微管蛋白聚合,防止解聚,稳定微管,使细胞停留在G2/M期,从而导致细胞死亡.该药物被应用于肿瘤的临床治疗,但是其临床使用剂型易引起过敏反应,急待研制理想的新剂型.本论文第四章就此问题进行了探索,研制了紫杉醇PLGA纳米粒子,在小鼠乳腺癌模型上验证其肿瘤抑制效果。
本论文的具体研究结果总结如下：
1.通过超声乳化—溶剂挥发法成功制备了平均粒径为246.8nm的RPM—PLGA纳米粒子,平均载药量为19.42%；扫描电镜下观察为表面光滑的球体,体外释放近似于零级过程,至2周释放75%的药物。在灌注压力为1atm,灌注时间为10分钟条件下,经Di spatch导管球囊向新西兰兔腹主动脉腔内灌注5mg/ml RPM-PLGA纳米粒子,至给药后7天局部组织药物浓度仍可维持在22.45±2.64μg/10mg干重水平,给药后14天组织药物浓度为4.64±0.77μg/10mg干重,至给药后21天应用HPLC方法基本测不到药物；成功制备了中国实验用小型猪过大球囊损伤冠状动脉模型,术后30天冠状动脉造影显示：生理盐水灌注组、空白PLGA纳米粒子灌注组和RPM灌注组三组间血管形态学参数和冠状动脉造影显示狭窄程度无明显差异；RPM-PLGA纳米粒子组血管狭窄程度(23.4±5.35%)明显低于生理盐水和空白纳米粒子对照组(分别为46.07±18.33%和52.20±18.74%,P均<0.01)和RPM灌注组(39.32±9.91%,P<0.05)；冠状动脉损伤后30天新生内膜面积、增生指数和NEELA/EELA比值明显低于上述三组(P均<0.05)。免疫组织化学染提示RPM纳米粒子干预组增殖核抗原蛋白(PCNA)表达阳性细胞率及MMP-2和TIMP-2蛋白阳性表达量均低于生理盐水和空白纳米粒子对照组,而原位杂交p27mRNA水平明显高于上述三组。
2.成功制备了VEGF/紫杉醇双功能纳米粒子,平均粒径大小为78.82nm,Zeta电位测定平均值为-12.2。紫杉醇包封率为92%,载紫杉醇药量为28.58%,基因包封率为98%,载基因量为4.67%。在兔体内球囊灌注后,VEGF纳米粒子组与双功能纳米粒子组均有效的抑制了血管再狭窄,尤其是VEGF纳米粒子组显示了很好的愈后。免疫组织化学结果提示VEGF纳米粒子组和PTX/VEGF NPs纳米粒子组增殖核抗原蛋白(PCNA)表达阳性细胞率及MMP-2和TIMP-2蛋白阳性表达量均低于生理盐水和空白纳米粒子对照组。应用双功能纳米支架在实验猪体内有效地降低了管腔丢失率,双功能纳米粒子组管腔丢失率仅为23.2%,明显优于波士顿公司上市支架TAXUS(?)48％管腔丢失率。而VEGF纳米粒子组管腔丢失率也达到了25%。
3.制备了平均粒径为233.74nm的紫杉醇纳米粒子,载药量19.58%,包埋率为84.3%。对TA2系小鼠乳腺癌肺转移模型肿瘤生长抑制作用的观察,2周药物注射抑瘤率结果显示：紫杉醇纳米粒子中剂量组为70.21%、紫杉醇纳米粒子高剂量组为84.16%,紫素阳性对照组为48.96%,两者差异有显著性(P<0.001)。紫杉醇纳米粒子低剂量组为45.47%与紫素阳性对照组相比,两者亦有显著性差异(P<0.001)。
Cardiovascular diseases and cancer seriously threaten human health, and it is of positive significance to apply nanotechnology to treatment of these diseases.
At present, percutaneous transluminal coronary angioplasty (PTCA) and stent implantation is one of the most effective treatment means for coronary atherosclerotic heart disease. However, the incidence of restenosis within6months after the operation is as high as30%to50%, becoming a main cause for the restricted long-term clinical efficacy and the increased medical expenses. Recent studies show that the difficult healing of blood vessel endothelium and the neointimal proliferation emphraxis arising from excess migration and proliferation of vascular smooth muscle cell are two main causes for the formation of restenosis. Prevention and treatment of restenosis using systematic administration is often restricted by systematic toxic and side effect as a result of overdose and such factors as low efficiency of drug distribution and metabolizing in blood vessel, resulting in hardly effective local concentration of drug in blood vessel and short lasting of effective local concentration of drug. Local administration can directly deliver the high concentration therapeutic agent to the target tissue, improving the efficiency of administration and avoiding the above-mentioned defects of systematic administration. Existing clinical tests have confirmed the good safety and feasibility of local administration, but the clinical efficacy is unsatisfactory, which is mainly caused by poor local retention of drug. Nanotechnology can be used in manufacturing pharmacy to improve infiltration and redistribution of drug in tissues and increase local retention of drug.
Rapamycin (RPM) is a kind of macrolide antibiotic produced by means of fermentation of streptomyces hygro scopicus. In in-vitro experiments, this drug can inhibit VSMC migration and proliferation, in animal experiments and clinical tests it can reduce post-injury intimal proliferation and effectively lower the incidence of restenosis6months to1years after PTCA operation. It is one of the drugs with the greatest clinical application potential for prevention and treatment of restenosis at present. However, RPM also has such pharmacological defects as toxic effect, restricted absorption, poor hydrophilicity, restricted biological application by excipient and stability, sensitivity to pH and low treatment index. In Chapter Two of this paper, preparation of nanotechnology based RMP as anti-proliferation drug for vascular restenosis is explored.
In Chapter Three, an innovative double-function concept brought forward based on the two main causes for vascular restenosis, that is difficult healing of endothelium and excess proliferation of vascular smooth muscle cell; the treatment effect of VEGF/paclitaxel double-function nanoparticle for vascular restenosis on rabbit saccule injury model is verified by saccule perfusion; nanotechnology based micropore double-function intravascular stent is prepared using ultrasonic spraying process, and finally the effect of such stent to inhibit vascular restenosis in experimental pig body is observed.
Paclitaxel (PTX) is anti-proliferation drug with the widest application in clinic. It is diterpenes compound extracted from plants in Taxus Genus, Taxaceae Family. Being highly fat-soluble, it can induce and promote polymerization of tubulin, prevent depolymerization, stabilize tubulin, make cell rein in G2/M phase, and thus cause cell death. This drug is used for clinical treatment of cancer, but its formulation used clinically may easily cause anaphylactic reaction, so an ideal new drug form is in urgent need. In Chapter Four of this paper, such new drug form is explored, and its effect to inhibit breast cancer is verified on mouse mammary cancer model.
The detailed contents of this study are as follows:
1. RPM-PLGA NPs with a mean particle diameter of246.8nm and a mean drug load of19.42%were successfully prepared using ultrasonic emulsification&solvent volatilization method. Observed under scanning electron microscope, these NPs were spheres with smooth surface, and their in-vitro release was similar to a zero-order process, releasing75%drug by the end of Week2. Then,5mg/ml RPM-PLGA NPs were perfused into abdominal aorta cavity of New Zealand rabbit through dispatch perfusion balloon. After the administration7days, the drug concentration in local tissue was still as high as22.45±2.64μg/10mg dry weight, on the14th day after the administration the drug concentration in the tissue was4.64±0.77μg/10mg dry weight, and on the21st day after the administration no drug concentration was detected using HPLC method. A Chinese experimental minipig oversize saccule injury coronary artery model was successfully developed, and the coronary arteriongraphy on the30th day after the operation showed that:there was no significant difference among the control group perfused with physiological saline, the control group perfused with blank PLGA NPs and the group perfused with RPM, as indicated in vascular morphological indexes and coronary arteriongraphy; the degree of hemadostenosis in the group perfused with RMP-PLGA NPs (23.4±5.35%) was significantly lower than the physiological saline control group and the blank NPs control group (respectively46.07±18.33%and52.20±8.74%, P<0.01in both groups) and the group perfused with RMP (39.32±9.91%, P<0.05); the area of neointimal, the proliferation index and the NEELA/EELA ratio of the RMP-PLGA group on the30th day after coronary artery injury were significantly lower than the three control groups (P<0.05in all the three groups). Immunohistochemical staining results indicated that the RPM group had lower PCNA positive cell expression rate and MMP-2&TIMP-2protein positive expression volume than the physiological saline control group and the blank NPs control group, and the experimental group had significantly higher hybridization in situ p27mRNA level than the three control groups.
2. VEGF/PTX double-function nanoparticles (VEGF/PTX NPs) were successfully prepared, with a mean particle diameter of78.82nm and mean Zeta electric potential measurement of-12.2. The PTX entrapment rate was92%, the PTX load was28.58%, the gene entrapment rate was98%, and the gene load was4.67%. After in-vivo perfusion into saccule of rabbit, the vascular restenosis in both the VEGF NPs group and the VEGF/PTX NPs groups was inhibited. Particularly, good healing was observed in VEGF NPs group. Immunohistochemical results indicated that the VEGF NPs group and the VEGF/PTX NPs groups had lower PCNA positive cell expression rate and MMP-2&TIMP-2protein positive expression volume than the physiological saline control group and the blank NPs control group. The double-function nanotechnology micropore stent used in experimental pig body effectively inhibited vascular restenosis, and lumen loss in the VEGF/PTX NPs group was as low as22.3%±8%, significantly better than the48%provided by the TAXUS(?) stent sold by Boston Scientific Corporation. This study provides a new thought and approach for prevention and treatment of cardiovascular restenosis, and may probably provide a new kind of genetical stent for clinical treatment of vascular restenosis.
3. Paclitaxel nanoparticles (PTX NPs) with a mean particle diameter of233.74nm, entrapment efficiency is84.3%and PTX loading capacity is about19.58%, which means were successfully prepared, and was used to inhibit cancer growth in TA2mouse breast cancer pulmonary metastasis model. As shown in the two week injection observation, the cancer inhibition rate of the middle dose PTX NPs group was70.21%, that of the high dose PTX NPs group was84.16%, and that of the Taxol positive control group was48.96%, indicating a significant difference (P<0.001). Such rate of the low dose PTX NPs group was45.47%, which also had significant difference from the Taxol positive control group (P<0.001).
引文
[1]Schiller JS, Lucas JW, Ward BW, Peregoy JA. Summary health statistics for U.S. adult:National Health Interview Survery 2010 [J]. Vital Health Stat,2012,252:1-207.
[2]Kuntz, R. E. and D. S. Baim. Defining coronary restenosis. Newer clinical and angiographic paradigms [J]. Circulation,1993,88(3):1310-23.
[3]Farb, A., G. Sangiorgi, A. J. Carter, et al. Pathology of acute and chronic coronary stenting in humans [J]. Circulation,1999,99(1).44-52.
[4]PT Fattori, Piva T. Drug-eluting Stents in Vascular Intervention [J]. Lancet,2003,361 (9353):247-9.
[5]Tanabe K., P. W. Serruys, E. Grube, et al. TAXUS III Trial:in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation [J]. Circulation,2003,107(4):559-64.
[6]Grube E., S. Silber, K. E. Hauptmann, et al. TAXUS I:six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions [J]. Circulation, 2003,107(1):38-42.
[7]Roiron C, Sanchez P, Bouzamonda A, et al. Drug-eluting stents:an updated meta-analysis of randomized controlled trial [J]. Heart,2006,92:641-649.
[8]Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans:delayed healing and late thrombotic risk [J]. J Am Coll Cardial, 2006,48:193-202.
[9]Nebeker JR, Virmani R, Bennett CL, et al. Hypersensitivity cases associated with drug-eluting coronary stents:a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project [J]. J Am Coll Acrdiol,2006,47:175-181.
[10]Kastrati A, Mehilli J, Dirschinger J, et al. Restenosis after coronary placement of various stent types [J]. The American Journal of Cardiology, 2001,87(1):34-39.
[11]Serruys PW, Unger F, Sousa JE, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease [J]. N Engl J Med,2001,344(15):1117-1124.
[12]Violaris, A. G., R. Melkert, J. P. Herrman, et al. Role of angiographically identifiable thrombus on long-term luminal renarrowing after coronary angioplasty:a quantitative angiographic analysis [J]. Circulation,1996,93(5):889-97.
[13]Komatsu, R., M. Ueda, T. Naruko, et al. Neointimal tissue response at sites of coronary stenting in humans:macroscopic, histological, and immunohistochemical analyses [J]. Circulation,1998,98(3):224-33.
[14]Mickelson, J. K., N. M. Lakkis, G. Villarreal Levy, et al. Leukocyte activation with platelet adhesion after coronary angioplasty:a mechanism for recurrent disease [J].J Am Coll Cardiol,1996,28(2):345-53.
[15]Ciezki, J. P., U.0. Hafeli, P. Song, et al. Parenchymal cell proliferation in coronary arteries after percutaneous transluminal coronary angioplasty:a human tissue bank study [J]. Int J Radiat Oncol Biol Phys, 1999,45(4):963-8.
[16]Moreno, P. R., I. F. Palacios, M. N. Leon, et al. Histopathologic comparison of human coronary in-stent and post-balloon angioplasty restenotic tissue [J]. Am J Cardiol,1999,84(4):462-9.
[17]Arakawa, K., K. Isoda, Y. Sugiyabu, et al. Intimal proliferation after stenting reflected by increased stent-to-vessel cross-sectional area ratio: serial intravascular ultrasound study [J]. J Cardiol,1998,32(6):379-89.
[18]Lafont, A., E. Durand, J. L. Samuel, et al. Endothelial dysfunction and collagen accumulation:two independent factors for restenosis and constrictive remodeling after experimental angioplasty [J]. Circulation, 1999,100(10):1109-15.
[19]Waksman, R., J. C. Rodriguez, K. A. Robinson, et al. Effect of intravascular irradiation on cell proliferation, apoptosis, and vascular remodeling after balloon overstretch injury of porcine coronary arteries [J]. Circulation,1997,96(6):1944-52.
[20]Simsek C, Serruys PW. Developments in coronary artery stenting:primum non nocere [J]. Panminerva Med,2011,53(1):19-30.
[21]Takahashi, A., M. Palmer-Opolski, R.C. Smith, et al. Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent [J]. Gene Ther,2003,10(17):1471-8.
[22]Nakayama, Y., K. Ji-Youn, S. Nishi, et al. Development of high-performance stent:gelatinous photogel-coated stent that permits drug delivery and gene transfer [J]. J Biomed Mater Res,2001,57(4):559-66.
[23]Wilson, J. M., L. K. Birinyi, R. N. Salomon, et al. Implantation of vascular grafts lined with genetically modified endothelial cells [J]. Science,1989,244(4910):1344-6.
[24]Flugelman, M. Y., R. Virmani, M. B. Leon, et al. Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to flow in vitro [J]. Circ Res,1992,70(2):348-54.
[25]Panetta, C. J., K. Miyauchi, D. Berry, et al. A tissue-engineered stent for cell-based vascular gene transfer [J]. Hum Gene Ther,2002,13(3): 433-41.
[26]Solovey, A., Y. Lin, P. Browne, et al. Circulating activated endothelial cells in sickle cell anemia [J]. N Engl J Med,1997,337(22):1584-90.
[27]99. Lin, Y., D. J. Weisdorf, A. Solovey, et al. Origins of circulating endothelial cells and endothelial outgrowth from blood [J]. J Clin Invest, 2000,105(1):71-7.
[28]Bolz, A., M. Amon, C. Ozbek, et al. Coating of cardiovascular stents with a semiconductor to improve their hemocompatibility [J]. Tex Heart Inst J,1996,23(2):162-6.
[29]李可,卢才义.生物可降解血管内支架：希望和挑战[J]。国际心血管病杂志,2009,36(4)：193-195.
[30]Waksman R, Pakala R. Biodegradable and bioabsorbable stents [J]. Curr pharm Des,2010,16(36):4041-51.
[31]Tanabe, K., E. Regar, C. H. Lee, et al. Local drug delivery using coated stents:new developments and future perspectives [J]. Curr Pharm Des,2004, 10(4):357-67.
[32]钱杰,高润霖,史瑞文等.金属蛋白涂层支架用于小型猪冠状动脉质粒介导下转基因研究[J].中国循环杂志,1999,14(3)：152-154.
[33]袁晋青,高润霖,史瑞文等.在小型猪模型由蛋白涂层金属支架局部转染尿 激酶前体基因对冠状动脉再狭窄的影响[J].中华心血管病杂志,1999,27(5)：349-352.
[34]戴军,高润霖,汤健等,蛋白涂层支架携带一氧化氮合酶基因转染小型猪冠状动脉的可行性研究[J].中国循环杂志,2001,16(1)：61-63.
[35]钱杰,高润霖,汤健,等,质粒介导下转染血管内皮生长因子基因不能防治小型猪冠状动脉再狭窄[J].中国循环杂志,2002,17(5)：389-391.
[36]McKenna, C. J., A. R. Camrud, G. Sangiorgi, et al. Fibrin-film stenting in a porcine coronary injury model:efficacy and safety compared with uncoated stents [J]. J Am Coll Cardiol,1998,31(6):1434-8.
[37]Whelan, D. M., W. J. van der Giessen, S. C. Krabbendam, et al. Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries [J]. Heart,2000,83(3):338-45.
[38]吴隐雄,Johnson T, H. C., Baumbach A,等.包裹支架转移治疗基因到猪冠状动脉的实验研究[J].中山大学学报：医学科学版,2003,24(5)：471-474,478.
[39]van der Giessen, W. J., A. M. Lincoff, R. S. Schwartz, et al.,, Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries [J]. Circulation,1996,94(7):1690-7.
[40]De Scheerder, I. K., K. L. Wilczek, E. V. Verbeken, et al. Biocompatibility of polymer-coated oversized metallic stents implanted in normal porcine coronary arteries [J]. Atherosclerosis,1995,114(1):105-14.
[41]Hardhammar, P. A., H. M. van Beusekom, H. U. Emanuelsson, et al. Reduction in thrombotic events with heparin-coated Palmaz-Schatz stents in normal porcine coronary arteries [J]. Circulation,1996,93(3):423-30.
[42]Serruys, P. W., B. van Hout, H. Bonnier, et al. Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent Ⅱ) [J]. Lancet, 1998,352(9129):673-81.
[43]Christensen, K., R. Larsson, H. Emanuelsson, et al. Coagulation and complement activation [J]. Biomaterials,2001,22(4):349-55.
[44]Ahn, Y. K., M. H. Jeong, J. W. Kim, et al. Preventive effects of the heparin-coated stent on restenosis in the porcine model [J]. Catheter Cardiovasc Interv,1999,48(3):324-30.
[45]De Feyter, P. J. The quest for the ideal stent [J]. Eur Heart J,2001, 22(19):1766-8.
[46]Alt, E., I. Haehnel, C. Beilharz, et al. Inhibition of neointima formation after experimental coronary artery stenting:a new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost [J]. Circulation,2000,101(12):1453-8.
[47]De Scheerder, I., K. Wang, K. Wilczek, et al.,, Local methylprednisolone inhibition of foreign body response to coated intracoronary stents [J]. Coron Artery Dis,1996,7(2):161-6.
[48]Serruys, P. W., M. Degertekin, K. Tanabe, et al. Intravascular ultrasound findings in the multicenter, randomized, double-blind RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) trial [J]. Circulation,2002,106(7):798-803.
[49]Holmes, D. R., Jr., M. B. Leon, J. W. Moses, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial:a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis [J]. Circulation,2004,109(5):634-40.
[50]Virmani, R., F. Liistro, G. Stankovic, et al. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting polymer stent system in humans [J]. Circulation,2002,106(21):2649-51.
[51]Hong, M. K., G. S. Mintz, C. W. Lee, et al. Paclitaxel coating reduces in-stent intimal hyperplasia in human coronary arteries:a serial volumetric intravascular ultrasound analysis from the Asian Paclitaxel-Eluting Stent Clinical Trial (ASPECT) [J]. Circulatio,2003,107(4):517-20.
[52]Tanabe, K., P. W. Serruys, E. Grube, et al. TAXUS III Trial:in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation [J]. Circulation,2003,107(4):559-64.
[53]Grube, E., S. Silber, K. E. Hauptmann, et al. TAXUS I:six-and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions [J]. Circulation,2003, 107(1):38-42.
[54]Claessen BE, Henriques JP, Dangas GD. Clinical studies with Sirolimus, Zotarolimus, everolims and biolimus A9 drug-eluting stent systems [J]. Curr Pharm Des,2010,16(36):4012-24.
[55]Sharma S, Christopoulos C, Kukreja N, Gorog DA. Local drug delivery for percutaneous coronary intervention [J]. Pharmacol Ther,2011, 129(3):260-6.
[56]Liistro, F. and A. Colombo. Late acute thrombosis after paclitaxel eluting stent implantation [J]. Heart,2001,86(3):262-4.
[57]Klugherz, B. D., C. Song, S. DeFelice, et al. Gene delivery to pig coronary arteries from stents carrying antibody-tethered adenovirus [J]. Hum Gene Ther,2002,13(3):443-54.
[58]Ye, Y. W., C. Landau, R. S. Meidell, et al. Improved bioresorbable microporous intravascular stents for gene therapy [J]. Asaio J,1996,42(5): M823-7.
[59]Klugherz, B. D., P. L. Jones, X. Cui, et al. Gene delivery from a DNA controlled-release stent in porcine coronary arteries [J]. Nat Biotechnol, 2000,18(11):1181-4.
[60]Perlstein, I., J.M. Connolly, X. Cui, et al. DNA delivery from an intravascular stent with a denatured collagen-polylactic-polyglycolic acid-controlled release coating:mechanisms of enhanced transfection [J]. Gene Ther,2003,10(17):1420-8.
[61]Takahashi, A., M. Palmer-Opolski, R. C. Smith, et al. Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent [J]. Gene Ther,2003,10(17):1471-8.
[62]Nakayama, Y., K. Ji-Youn, S. Nishi, et al. Development of high-performance stent:gelatinous photogel-coated stent that permits drug delivery and gene transfer [J]. J Biomed Mater Res,2001,57(4):559-66.
[63]Wilson, J. M., L. K. Birinyi, R. N. Salomon, et al. Implantation of vascular grafts lined with genetically modified endothelial cells [J]. Science,1989,244(4910):1344-6.
[64]Flugelman, M. Y., R. Virmani, M. B. Leon, et al. Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to flow in vitro [J]. Circ Res,1992,70(2):348-54.
[65]Panetta, C. J., K. Miyauchi, D. Berry, et al. A tissue-engineered stent for cell-based vascular gene transfer [J]. Hum Gene Ther,2002,13(3): 433-41.
[66]罗全勇.放射性支架预防血管再狭窄的研究现状[J].同位素,2005,15(1)：32-37.
[67]Solovey, A., Y. Lin, P. Browne, et al. Circulating activated endothelial cells in sickle cell anemia [J]. N Engl J Med,1997,337(22):1584-90.
[68]Lin, Y., D. J. Weisdorf, A. Solovey, et al. Origins of circulating endothelial cells and endothelial outgrowth from blood [J]. J Clin Invest, 2000,105(1):71-7.
[69]Bolz, A., M. Amon, C. Ozbek, et al. Coating of cardiovascular stents with a semiconductor to improve their hemocompatibility [J]. Tex Heart Inst J,1996,23(2):162-6.
[70]Farokhzad OC, Langer R. Nanomedicine:developing smarter therapeutic and diagnostic modalities [J]. Adv Drug Deliv Rev,2006,58:1456-1459.
[71]Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids [J]. J Mol Bioll,1965,13:238-252.
[72]Haley B, Frenkel E. Nanoparticles for drug delivery in cancer treatment [J]. Urol Oncol,2008,26:57-64.
[73]Harries M, Ellis P, Harper P. Nanoparticle albumin-bound paclitaxel for metastatic breast cancer [J]. J Clin Oncol,2005,23:7768-7777.
[74]Damascelli B, Patelli G, Ticha V et al. Feasibility and effcacy of percutaneous transcatheter intrarterial chemotherapy with paclitaxel in albumin nanoparticles for advancedsqua mous-cell carcinoma of the oral cavity, oropharynx, and hypo pharynx [J]. J Vasc Interv Radio,2007, 118:1395-1403.
[75]Reddy G R, Bhojani M S, McConville P et al. Vascular targeted nanoparticles for imagingand treatment of brain tumours [J]. Clin Cancer Res, 2006,12:6677-6686.
[76]Soma CE, Dubernet C, Bentolila D et al. Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkycyanoacrylate nanoparticles [J]. Biomaterials,2000,21:1-7.
[77]Westedt U, Barbu-Tudoran L, Schaper AK, et al.2002. Deposition of nanoparticles in the arterial vessel by porous balloon catheters: Localization by confocal laser scanning microscopy and transmission electron microscopy [J]. AAPS PharmSci,2002,4(4):1-6.
[77]Gradus-Pizlo I, Wilensky RL, March KL, et al. Local delivery ofbiodegradable manalogue:Effects on restenosis and implications for catheter-based drug delivery [J]. Journal of the American College of Cardiology,1995,26(6):1549-1557.
[78]Dev V, Eigler N, Fishbein MC, et al. Sustained local drug delivery to the arterial wall via biodegradable microspheres [J]. Catheterization and Cardiovascular Diagnosis,1997,41(3):324-332.
[79]Mousavi SA, Malerod L, Berg T, et al. Clathrin-dependent endocytosis [J]. J Biochem,2004,377(1):1-16.
[80]Sieczkarski SB, Whittaker GR. Dissecting virus entry via endocytosis [J]. The Journal Of General Virology,2002,83(7):1535-1545.
[81]Tahlil O, Brami M, Feldman LJ, et al. The dispatchTM catheter as a delivery tool for arterial gene transfer [J]. Cardiovascular Research,1997, 33(1):181-187.
[82]Fishbein I, Chorny M, Rabinovich L, et al. Nanoparticulate delivery system of a tyrphostin for the treatment of restenosis [J]. Journal of Controlled Release,2000,65(1-2):221-9.
[83]Danenberg HD, Fishbein I, Epstein H, et al. Systemic depletion of macrophages by liposomal bisphosphonates reduces neointimal formation following balloon-injury in the rat carotid artery [J]. Journal of Cardiovascular Pharmacology,2003,42(5):671-679.
[84]Danenberg HD, Fishbein I, Gao J, et al. Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits [J]. Circulation,2002,106(5):599-605.
[85]Magaraggia M, Visona A, Furlan A, et al. Inactivation of vascular smooth muscle cells photosensitised by liposome-delivered Zn(II)-phthalocyanine [J]. Journal of Photochemistry and Photobiology B:Biology,2006, 82(1):53-58.
[86]Chnari E, Nikitczuk JS, Wang J, et al. Engineered polymeric nanoparticles for receptor-targeted blockage of oxidized low density lipoprotein uptake and atherogenesis in macrophages [J]. Biomacromol ecules, 2006,7 (6):1796-1805.
[87]Cohen-Sacks H, Najajreh Y, Tchaikovski V, et al. Novel PDGFbetaR antisense encapsulated in polymeric nanospheres for the treatment of restenosis [J]. Gene Therapy,2002,9(23):1607-16.
[88]Banai S, Chorny M, Gertz SD, et al. Locally delivered nanoencapsu lated tyrphostin (AGL-2043) reduces neointima formation in balloon injured rat carotid and stented porcine coronary arteries [J]. Biomaterials,2005, 26(4):451-46.
[89]Pan S, Wang C, Zeng X, et al. Short muti- armed polylysine- graft-polylysine copolymer as effectient gene vectors [J]. Int J Pharm,2011, 420(2):206-15.
[90]Sollott SJ, Cheng L, Pauly RR, et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat [J]. J Clin Invest, 1995,95(4):1869-1876.
[91]Axel DI, Kunert W, Goggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery [J]. Circulation,1997,96(2):636-645.
[92]Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter [J]. N Engl J Med, 2006,355(20):2113-2124.
[93]Kittleson MM, Needham DM, Kim SJ, et al. The efficacy of sirolimus-and paclitaxel-eluting stents:a meta-analysis of randomized controlled trials [J]. Can J Cardiol,2005,21(7):581-7.
[94]Perin EC. Choosing a drug-eluting stent:a comparison between CYPHER and TAXUS [J]. Rev Cardiovasc Med,2005,6(Suppl 1):S13-2.
[95]Tung R, Kaul S, Diamond GA, et al. Narrative review:drug-eluting stents for the management of restenosis:A Critical appraisal of the evidence [J]. Ann Intern Med,2006,144(12):913-919.
[96]Bhargava B, Reddy NK, Karthikeyan G, et al. A novel paclitaxel eluting porous carbon-carbon nanoparticle coated, nonpolymeric cobalt-chromium stent:Evaluation in a porcine model [J]. Catheterization and Cardiovascular Interventions,2006,67 (5):698-702.
[97]Kolodgie FD, John M, Khurana C, et al. Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel [J]. Circulation,2002,106(10):1195-1198.
[98]Lanza GM, Yu X, Winter PM, et al. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent:Implications for rational therapy of restenosis [J]. Circulation,2002,106(22):2842-2847.
[99]Qiao T, Liu CJ, Ran F, et al. Experimental study of recombinant eukaryotic expression vector of human eNOS in ECV304 [J]. Swiss Med Wkly, 2006,136(1-2):19-25.
[100]Stephan DJ, Yang ZY, San H, et al. A new cationic liposome DNA complex enhances the ef ciency of arterial gene transfer in vivo [J]. Hum Gene Ther, 1996,7(15):1803-12.
[101]Pelisek J, Fuchs AT, Kuehnl A, et al. C-type natriuretic peptide for reduction of restenosis:gene transfer is superior over single peptide administration [J]. The Journal of Gene Medicine,2006,8(7):835-844.
[102]Meng QH, Jamal W, Hart SL, et al. Application to vascular adven titia of a nonviral vector for TIMP-1 gene therapy to prevent intimal hyperplasia [J]. Human Gene Therapy,2006,17:1-11.
[103]Yin X, Yutani C, Ikeda Y, et al. Tissue factor pathway inhibitor gene delivery using HVJ-AVE liposomes markedly reduces restenosis in atherosclerotic arteries [J]. Cardiovascular Research,2002,56 (3):454 463.
[104]Numaguchi Y, Okumura K, Harada M, et al. Catheter-based pros tacyclin synthase gene transfer prevents in-stent restenosis in rabbit atheromatous arteries [J]. Cardiovascular Research,2004,61(1):177-185.
[105]Cohen-Sacks H, Najajreh Y, Tchaikovski V, et al. Novel PDGFbetaR antisense encapsulated in polymeric nanospheres for the treatment of restenosis [J]. Gene Therapy,2002,9(23):1607-16.
[106]Lenter M, Garidel P, Pelisek J, et al. Stabilized nonviral formulations for the delivery of MCP-1 gene into cells of the vasculoendothelial system [J]. Pharmaceutical Research,2004,21(4):683-691.
[107]J Yang, Y Zeng, YJ Li, et al. Intravascular site-specific delivery of a therapeutic antisense for the inhibition of restenosis [J]. Eue J Pharmaceu Sci,2008,35:427-434
[108]Dijkgraaf I, Kruijtzer JA, Liu S, et al. Improved targeting of the v 3 integrin by multimerisation of RGD peptides [J]. Eur J Nucl Med Mol Imaging,2007,34(2):267-273.
[109]Mardilovich A, Craig JA, McCammon MQ, et al. Design of a novel bronectin-mimetic peptide-amphiphile for functionalized biomaterials [J]. Langmuir,2006,22(7):3259-3264.
[110]Kelly K, Nahrendorf M, Yu A, et al. In vivo phage display selection yields atherosclerotic plaque targeted peptides for imaging [J]. Mol Imaging Biol,2006,8(4):201-207.
[111]Muro S, Dziubla T, Qiu W, et al. Endothelial targeting of high-afnity multivalent polymer nanocarriers directed to intercellular adhesion molecule 1 [J]. J Pharmacol Exp Ther,2006,317(3):1161-9.
1. Gregory C, Huie P, Billingham M, et al. Rapamycin inbibits arterial inimal thickening caused by both alloimmune and mechanical injury [J].Transplantation,1993,55:1409-1418.
2. Meiser B,Billingham M, Morris R. Effects of cyclosporin, FK506, and rapamycin of graft-vessel disease [J]. Lancet,1991,338:1297-1298.
3. Almond PS, Moss A, Nalhleh RE, et al. Rapamycin:immunosuppression, hyporesponsiveness, and side effects in a porcine renal allograft model [J]. Transplantation,1993,56:275-281.
4. Hashemolhosseini S, Nagamine Y, Morley S, et al. Rapamycin inhibition of the G1 to S transition is mediated by effets on CyclinDl mRNA and proterin stability [J]. J Biol Chem,1998,273(23):14424-14429.
5. Marx SO, Jayaraman T, Go L0, et al. Rapamycn-FKBP inhibits cell cycle regulators of proliferation in VSMC [J]. Circ Res,1995,76:412-417.
6. Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulatous of the cell cycle [J]. Circulation,1999,99:2164-2170.
7. Roque M, Cordon-Cardo C, Fuster V, Reis ED, Drobnjak M, Badimon JJ. Modulation of apoptosis, proliferation, and p27 expression in a porcine coronary angioplasty model [J]. Atherosclerosis,2000,153(2):315-322.
8. Carter AJ, Bailey LR, Llanos G, et al. Stent-based sirolimus delivery reduces neointimal prolifration in a porcine coronary model of restenosis [J].J Am Coll Cardiol,2000,35:13.
9. Morice CM, Serruys PW, Sousa JE, et al. for the RAVEL Study Group. A Randomized Comparison of a Sirolimus-Eluting Stent with a Standard Stent for Coronary Revascularization [J]. N Engl J Med,2002,346:1773-80.
10. Morice MC, Serruys PW, Sousa JE. The RAVEL study:a randomized study with the sirolimus coated Bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions [J]. Eur Heart J,2001,22:484.
11. Regar E, Serruys PW, Bode C, et al. Angiographic Findings of the Multicenter Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL):Sirolimus-Eluting Stents Inhibit Restenosis Irrespective of the Vessel Size [J]. Circulation,2002,106: 1949-1956.
12. Sgueglia GA, Burzotta F, Trani C, et al. Comparative assessment of mammalian target of rapamycin inhibitor-eluting stents in the treatment of coronary artery bifurcation lesions:the Castor-bifurcation registry [J]. Catheter Cardiovasc Interv.2011,77(4):503-9.
13. Alexandre C, Zago, Jose C. Raudales, Guiherme Attizzani, et al. Local delivery of sirolimus nanoparticles for the treatment of in-stent restenosis [J]. Catheterization and Cardiovascular Interventions,2013, 81:E124-E129.
14.Poston RS, Billingham M, Hoyt G, et al. Rapamycin reverses chronicgraft vascular disease in a novel cardiac allograft model [J]. Circulation,1999, 100:67-74.
1. Li D, Zhang C, Song F, et al. VEGF regulates FGF-2 and TGF-betal expression in injury endothelial cells and mediates smooth muscle cells proliferation and migration [J]. Microvasc Res,2009,77(2):134-42.
2. Carmeliet P, Moons L, Dewerchin M, et al. Insights in vessel development and vascular discoders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system [J]. Ann N Y Acad Sci,1997,15(811):191-206.
3. Jing Yang, Cunxian Song, Hongfan Sun, Li Wu, Lina Tang, Yong Zeng, Wenling Zhu. A New Type Gene Delivery System-Gene nanoparticles [J]. Key Engineering Materials,2005,288-289:143-146.
4. Schiff P B. HorwitZ SB. Taxol stabilizes micmtubul in mouse fibroblast ceHs [J]. Proceeding of tIle national academy of sciences of the United States of America,1980,77(3):1561—1565.
5. J Yang, Y Zeng, YJ Li, CX Song, WL Zhu. Intravascular site-specific delivery of a therapeutic antisense for the inhibition of restenosis [J]. Eue J Pharmaceu Sci,2008,35:427-434
6. Chan JM, Rhee JW, Drum CL, et al. In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles [J]. Proc Natl Acad Sci U S A,2011,108(48):19347-52.
1. Schiff P B, Fant J, Horwitz S B. Promotion ofmicrotubule as—embly in vitro by taxol [J]. Nature,1979,277(5698):665—667
2. Schiff P B,Horwitz. Taxol stabilizes micmtubul in mouse fibroblast ceHs [J]. Proceeding of tile national academy of sciences of the Unitcd States of America,1980,77(3):1561—1565.
3.郭仁宏,王金万.紫杉醇脂质体的研究进展[J].中国肿瘤,2008,17(8)：698 -703.
4.邓联东,孙多先,董岸杰.紫杉醇注射剂的研究[J].药学进展,2002,26(3)：152—155.
5. Huang Y, Chen X M, Zhao B X, et al. Antiangiogenie active of sterically stabilized liposomes containing paclitaxel(SSLPTX):in vitro and in vivo [J]. AAPs Pharm Sci Tech,2010, (2):752—759.
6. Yang T, Choi M K, Cui F D, et al. Anfitumor effect of paclitax—oated PEGylated immunolipesomes against human breast canc cells[J]. Pharmaceutical Research,2007,24(12):2402—2411.
7. Zhang J Q, Hang J Q, Zhang Z R, et al. Lyophilized paclitaxel magnetoliposomes as potential drug delivery system for breast carcinoma v/a parenteral administration:In vitro and in vivo studies [J]. Pharmaceutical Research,2005,22(4):573—582.
8.温志强,桂双英,王均,等.脂质体作为抗癌药载体的应用进展[J].中国新药杂志,2009,18(9)：788—792.
[2]Kuntz, R. E. and D. S. Baim. Defining coronary restenosis. Newer clinical and angiographic paradigms [J]. Circulation,1993,88(3):1310-23.
[3]Farb, A., G. Sangiorgi, A. J. Carter, et al. Pathology of acute and chronic coronary stenting in humans [J]. Circulation,1999,99(1).44-52.
[4]PT Fattori, Piva T. Drug-eluting Stents in Vascular Intervention [J]. Lancet,2003,361 (9353):247-9.
[5]Tanabe K., P. W. Serruys, E. Grube, et al. TAXUS III Trial:in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation [J]. Circulation,2003,107(4):559-64.
[6]Grube E., S. Silber, K. E. Hauptmann, et al. TAXUS I:six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions [J]. Circulation, 2003,107(1):38-42.
[7]Roiron C, Sanchez P, Bouzamonda A, et al. Drug-eluting stents:an updated meta-analysis of randomized controlled trial [J]. Heart,2006,92:641-649.
[8]Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans:delayed healing and late thrombotic risk [J]. J Am Coll Cardial, 2006,48:193-202.
[9]Nebeker JR, Virmani R, Bennett CL, et al. Hypersensitivity cases associated with drug-eluting coronary stents:a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project [J]. J Am Coll Acrdiol,2006,47:175-181.
[10]Kastrati A, Mehilli J, Dirschinger J, et al. Restenosis after coronary placement of various stent types [J]. The American Journal of Cardiology, 2001,87(1):34-39.
[11]Serruys PW, Unger F, Sousa JE, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease [J]. N Engl J Med,2001,344(15):1117-1124.
[12]Violaris, A. G., R. Melkert, J. P. Herrman, et al. Role of angiographically identifiable thrombus on long-term luminal renarrowing after coronary angioplasty:a quantitative angiographic analysis [J]. Circulation,1996,93(5):889-97.
[13]Komatsu, R., M. Ueda, T. Naruko, et al. Neointimal tissue response at sites of coronary stenting in humans:macroscopic, histological, and immunohistochemical analyses [J]. Circulation,1998,98(3):224-33.
[14]Mickelson, J. K., N. M. Lakkis, G. Villarreal Levy, et al. Leukocyte activation with platelet adhesion after coronary angioplasty:a mechanism for recurrent disease [J].J Am Coll Cardiol,1996,28(2):345-53.
[15]Ciezki, J. P., U.0. Hafeli, P. Song, et al. Parenchymal cell proliferation in coronary arteries after percutaneous transluminal coronary angioplasty:a human tissue bank study [J]. Int J Radiat Oncol Biol Phys, 1999,45(4):963-8.
[16]Moreno, P. R., I. F. Palacios, M. N. Leon, et al. Histopathologic comparison of human coronary in-stent and post-balloon angioplasty restenotic tissue [J]. Am J Cardiol,1999,84(4):462-9.
[17]Arakawa, K., K. Isoda, Y. Sugiyabu, et al. Intimal proliferation after stenting reflected by increased stent-to-vessel cross-sectional area ratio: serial intravascular ultrasound study [J]. J Cardiol,1998,32(6):379-89.
[18]Lafont, A., E. Durand, J. L. Samuel, et al. Endothelial dysfunction and collagen accumulation:two independent factors for restenosis and constrictive remodeling after experimental angioplasty [J]. Circulation, 1999,100(10):1109-15.
[19]Waksman, R., J. C. Rodriguez, K. A. Robinson, et al. Effect of intravascular irradiation on cell proliferation, apoptosis, and vascular remodeling after balloon overstretch injury of porcine coronary arteries [J]. Circulation,1997,96(6):1944-52.
[20]Simsek C, Serruys PW. Developments in coronary artery stenting:primum non nocere [J]. Panminerva Med,2011,53(1):19-30.
[21]Takahashi, A., M. Palmer-Opolski, R.C. Smith, et al. Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent [J]. Gene Ther,2003,10(17):1471-8.
[22]Nakayama, Y., K. Ji-Youn, S. Nishi, et al. Development of high-performance stent:gelatinous photogel-coated stent that permits drug delivery and gene transfer [J]. J Biomed Mater Res,2001,57(4):559-66.
[23]Wilson, J. M., L. K. Birinyi, R. N. Salomon, et al. Implantation of vascular grafts lined with genetically modified endothelial cells [J]. Science,1989,244(4910):1344-6.
[24]Flugelman, M. Y., R. Virmani, M. B. Leon, et al. Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to flow in vitro [J]. Circ Res,1992,70(2):348-54.
[25]Panetta, C. J., K. Miyauchi, D. Berry, et al. A tissue-engineered stent for cell-based vascular gene transfer [J]. Hum Gene Ther,2002,13(3): 433-41.
[26]Solovey, A., Y. Lin, P. Browne, et al. Circulating activated endothelial cells in sickle cell anemia [J]. N Engl J Med,1997,337(22):1584-90.
[27]99. Lin, Y., D. J. Weisdorf, A. Solovey, et al. Origins of circulating endothelial cells and endothelial outgrowth from blood [J]. J Clin Invest, 2000,105(1):71-7.
[28]Bolz, A., M. Amon, C. Ozbek, et al. Coating of cardiovascular stents with a semiconductor to improve their hemocompatibility [J]. Tex Heart Inst J,1996,23(2):162-6.
[29]李可,卢才义.生物可降解血管内支架：希望和挑战[J]。国际心血管病杂志,2009,36(4)：193-195.
[30]Waksman R, Pakala R. Biodegradable and bioabsorbable stents [J]. Curr pharm Des,2010,16(36):4041-51.
[31]Tanabe, K., E. Regar, C. H. Lee, et al. Local drug delivery using coated stents:new developments and future perspectives [J]. Curr Pharm Des,2004, 10(4):357-67.
[32]钱杰,高润霖,史瑞文等.金属蛋白涂层支架用于小型猪冠状动脉质粒介导下转基因研究[J].中国循环杂志,1999,14(3)：152-154.
[33]袁晋青,高润霖,史瑞文等.在小型猪模型由蛋白涂层金属支架局部转染尿 激酶前体基因对冠状动脉再狭窄的影响[J].中华心血管病杂志,1999,27(5)：349-352.
[34]戴军,高润霖,汤健等,蛋白涂层支架携带一氧化氮合酶基因转染小型猪冠状动脉的可行性研究[J].中国循环杂志,2001,16(1)：61-63.
[35]钱杰,高润霖,汤健,等,质粒介导下转染血管内皮生长因子基因不能防治小型猪冠状动脉再狭窄[J].中国循环杂志,2002,17(5)：389-391.
[36]McKenna, C. J., A. R. Camrud, G. Sangiorgi, et al. Fibrin-film stenting in a porcine coronary injury model:efficacy and safety compared with uncoated stents [J]. J Am Coll Cardiol,1998,31(6):1434-8.
[37]Whelan, D. M., W. J. van der Giessen, S. C. Krabbendam, et al. Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries [J]. Heart,2000,83(3):338-45.
[38]吴隐雄,Johnson T, H. C., Baumbach A,等.包裹支架转移治疗基因到猪冠状动脉的实验研究[J].中山大学学报：医学科学版,2003,24(5)：471-474,478.
[39]van der Giessen, W. J., A. M. Lincoff, R. S. Schwartz, et al.,, Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries [J]. Circulation,1996,94(7):1690-7.
[40]De Scheerder, I. K., K. L. Wilczek, E. V. Verbeken, et al. Biocompatibility of polymer-coated oversized metallic stents implanted in normal porcine coronary arteries [J]. Atherosclerosis,1995,114(1):105-14.
[41]Hardhammar, P. A., H. M. van Beusekom, H. U. Emanuelsson, et al. Reduction in thrombotic events with heparin-coated Palmaz-Schatz stents in normal porcine coronary arteries [J]. Circulation,1996,93(3):423-30.
[42]Serruys, P. W., B. van Hout, H. Bonnier, et al. Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent Ⅱ) [J]. Lancet, 1998,352(9129):673-81.
[43]Christensen, K., R. Larsson, H. Emanuelsson, et al. Coagulation and complement activation [J]. Biomaterials,2001,22(4):349-55.
[44]Ahn, Y. K., M. H. Jeong, J. W. Kim, et al. Preventive effects of the heparin-coated stent on restenosis in the porcine model [J]. Catheter Cardiovasc Interv,1999,48(3):324-30.
[45]De Feyter, P. J. The quest for the ideal stent [J]. Eur Heart J,2001, 22(19):1766-8.
[46]Alt, E., I. Haehnel, C. Beilharz, et al. Inhibition of neointima formation after experimental coronary artery stenting:a new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost [J]. Circulation,2000,101(12):1453-8.
[47]De Scheerder, I., K. Wang, K. Wilczek, et al.,, Local methylprednisolone inhibition of foreign body response to coated intracoronary stents [J]. Coron Artery Dis,1996,7(2):161-6.
[48]Serruys, P. W., M. Degertekin, K. Tanabe, et al. Intravascular ultrasound findings in the multicenter, randomized, double-blind RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) trial [J]. Circulation,2002,106(7):798-803.
[49]Holmes, D. R., Jr., M. B. Leon, J. W. Moses, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial:a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis [J]. Circulation,2004,109(5):634-40.
[50]Virmani, R., F. Liistro, G. Stankovic, et al. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting polymer stent system in humans [J]. Circulation,2002,106(21):2649-51.
[51]Hong, M. K., G. S. Mintz, C. W. Lee, et al. Paclitaxel coating reduces in-stent intimal hyperplasia in human coronary arteries:a serial volumetric intravascular ultrasound analysis from the Asian Paclitaxel-Eluting Stent Clinical Trial (ASPECT) [J]. Circulatio,2003,107(4):517-20.
[52]Tanabe, K., P. W. Serruys, E. Grube, et al. TAXUS III Trial:in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation [J]. Circulation,2003,107(4):559-64.
[53]Grube, E., S. Silber, K. E. Hauptmann, et al. TAXUS I:six-and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions [J]. Circulation,2003, 107(1):38-42.
[54]Claessen BE, Henriques JP, Dangas GD. Clinical studies with Sirolimus, Zotarolimus, everolims and biolimus A9 drug-eluting stent systems [J]. Curr Pharm Des,2010,16(36):4012-24.
[55]Sharma S, Christopoulos C, Kukreja N, Gorog DA. Local drug delivery for percutaneous coronary intervention [J]. Pharmacol Ther,2011, 129(3):260-6.
[56]Liistro, F. and A. Colombo. Late acute thrombosis after paclitaxel eluting stent implantation [J]. Heart,2001,86(3):262-4.
[57]Klugherz, B. D., C. Song, S. DeFelice, et al. Gene delivery to pig coronary arteries from stents carrying antibody-tethered adenovirus [J]. Hum Gene Ther,2002,13(3):443-54.
[58]Ye, Y. W., C. Landau, R. S. Meidell, et al. Improved bioresorbable microporous intravascular stents for gene therapy [J]. Asaio J,1996,42(5): M823-7.
[59]Klugherz, B. D., P. L. Jones, X. Cui, et al. Gene delivery from a DNA controlled-release stent in porcine coronary arteries [J]. Nat Biotechnol, 2000,18(11):1181-4.
[60]Perlstein, I., J.M. Connolly, X. Cui, et al. DNA delivery from an intravascular stent with a denatured collagen-polylactic-polyglycolic acid-controlled release coating:mechanisms of enhanced transfection [J]. Gene Ther,2003,10(17):1420-8.
[61]Takahashi, A., M. Palmer-Opolski, R. C. Smith, et al. Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent [J]. Gene Ther,2003,10(17):1471-8.
[62]Nakayama, Y., K. Ji-Youn, S. Nishi, et al. Development of high-performance stent:gelatinous photogel-coated stent that permits drug delivery and gene transfer [J]. J Biomed Mater Res,2001,57(4):559-66.
[63]Wilson, J. M., L. K. Birinyi, R. N. Salomon, et al. Implantation of vascular grafts lined with genetically modified endothelial cells [J]. Science,1989,244(4910):1344-6.
[64]Flugelman, M. Y., R. Virmani, M. B. Leon, et al. Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to flow in vitro [J]. Circ Res,1992,70(2):348-54.
[65]Panetta, C. J., K. Miyauchi, D. Berry, et al. A tissue-engineered stent for cell-based vascular gene transfer [J]. Hum Gene Ther,2002,13(3): 433-41.
[66]罗全勇.放射性支架预防血管再狭窄的研究现状[J].同位素,2005,15(1)：32-37.
[67]Solovey, A., Y. Lin, P. Browne, et al. Circulating activated endothelial cells in sickle cell anemia [J]. N Engl J Med,1997,337(22):1584-90.
[68]Lin, Y., D. J. Weisdorf, A. Solovey, et al. Origins of circulating endothelial cells and endothelial outgrowth from blood [J]. J Clin Invest, 2000,105(1):71-7.
[69]Bolz, A., M. Amon, C. Ozbek, et al. Coating of cardiovascular stents with a semiconductor to improve their hemocompatibility [J]. Tex Heart Inst J,1996,23(2):162-6.
[70]Farokhzad OC, Langer R. Nanomedicine:developing smarter therapeutic and diagnostic modalities [J]. Adv Drug Deliv Rev,2006,58:1456-1459.
[71]Bangham AD, Standish MM, Watkins JC. Diffusion of univalent ions across the lamellae of swollen phospholipids [J]. J Mol Bioll,1965,13:238-252.
[72]Haley B, Frenkel E. Nanoparticles for drug delivery in cancer treatment [J]. Urol Oncol,2008,26:57-64.
[73]Harries M, Ellis P, Harper P. Nanoparticle albumin-bound paclitaxel for metastatic breast cancer [J]. J Clin Oncol,2005,23:7768-7777.
[74]Damascelli B, Patelli G, Ticha V et al. Feasibility and effcacy of percutaneous transcatheter intrarterial chemotherapy with paclitaxel in albumin nanoparticles for advancedsqua mous-cell carcinoma of the oral cavity, oropharynx, and hypo pharynx [J]. J Vasc Interv Radio,2007, 118:1395-1403.
[75]Reddy G R, Bhojani M S, McConville P et al. Vascular targeted nanoparticles for imagingand treatment of brain tumours [J]. Clin Cancer Res, 2006,12:6677-6686.
[76]Soma CE, Dubernet C, Bentolila D et al. Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkycyanoacrylate nanoparticles [J]. Biomaterials,2000,21:1-7.
[77]Westedt U, Barbu-Tudoran L, Schaper AK, et al.2002. Deposition of nanoparticles in the arterial vessel by porous balloon catheters: Localization by confocal laser scanning microscopy and transmission electron microscopy [J]. AAPS PharmSci,2002,4(4):1-6.
[77]Gradus-Pizlo I, Wilensky RL, March KL, et al. Local delivery ofbiodegradable manalogue:Effects on restenosis and implications for catheter-based drug delivery [J]. Journal of the American College of Cardiology,1995,26(6):1549-1557.
[78]Dev V, Eigler N, Fishbein MC, et al. Sustained local drug delivery to the arterial wall via biodegradable microspheres [J]. Catheterization and Cardiovascular Diagnosis,1997,41(3):324-332.
[79]Mousavi SA, Malerod L, Berg T, et al. Clathrin-dependent endocytosis [J]. J Biochem,2004,377(1):1-16.
[80]Sieczkarski SB, Whittaker GR. Dissecting virus entry via endocytosis [J]. The Journal Of General Virology,2002,83(7):1535-1545.
[81]Tahlil O, Brami M, Feldman LJ, et al. The dispatchTM catheter as a delivery tool for arterial gene transfer [J]. Cardiovascular Research,1997, 33(1):181-187.
[82]Fishbein I, Chorny M, Rabinovich L, et al. Nanoparticulate delivery system of a tyrphostin for the treatment of restenosis [J]. Journal of Controlled Release,2000,65(1-2):221-9.
[83]Danenberg HD, Fishbein I, Epstein H, et al. Systemic depletion of macrophages by liposomal bisphosphonates reduces neointimal formation following balloon-injury in the rat carotid artery [J]. Journal of Cardiovascular Pharmacology,2003,42(5):671-679.
[84]Danenberg HD, Fishbein I, Gao J, et al. Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits [J]. Circulation,2002,106(5):599-605.
[85]Magaraggia M, Visona A, Furlan A, et al. Inactivation of vascular smooth muscle cells photosensitised by liposome-delivered Zn(II)-phthalocyanine [J]. Journal of Photochemistry and Photobiology B:Biology,2006, 82(1):53-58.
[86]Chnari E, Nikitczuk JS, Wang J, et al. Engineered polymeric nanoparticles for receptor-targeted blockage of oxidized low density lipoprotein uptake and atherogenesis in macrophages [J]. Biomacromol ecules, 2006,7 (6):1796-1805.
[87]Cohen-Sacks H, Najajreh Y, Tchaikovski V, et al. Novel PDGFbetaR antisense encapsulated in polymeric nanospheres for the treatment of restenosis [J]. Gene Therapy,2002,9(23):1607-16.
[88]Banai S, Chorny M, Gertz SD, et al. Locally delivered nanoencapsu lated tyrphostin (AGL-2043) reduces neointima formation in balloon injured rat carotid and stented porcine coronary arteries [J]. Biomaterials,2005, 26(4):451-46.
[89]Pan S, Wang C, Zeng X, et al. Short muti- armed polylysine- graft-polylysine copolymer as effectient gene vectors [J]. Int J Pharm,2011, 420(2):206-15.
[90]Sollott SJ, Cheng L, Pauly RR, et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat [J]. J Clin Invest, 1995,95(4):1869-1876.
[91]Axel DI, Kunert W, Goggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery [J]. Circulation,1997,96(2):636-645.
[92]Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter [J]. N Engl J Med, 2006,355(20):2113-2124.
[93]Kittleson MM, Needham DM, Kim SJ, et al. The efficacy of sirolimus-and paclitaxel-eluting stents:a meta-analysis of randomized controlled trials [J]. Can J Cardiol,2005,21(7):581-7.
[94]Perin EC. Choosing a drug-eluting stent:a comparison between CYPHER and TAXUS [J]. Rev Cardiovasc Med,2005,6(Suppl 1):S13-2.
[95]Tung R, Kaul S, Diamond GA, et al. Narrative review:drug-eluting stents for the management of restenosis:A Critical appraisal of the evidence [J]. Ann Intern Med,2006,144(12):913-919.
[96]Bhargava B, Reddy NK, Karthikeyan G, et al. A novel paclitaxel eluting porous carbon-carbon nanoparticle coated, nonpolymeric cobalt-chromium stent:Evaluation in a porcine model [J]. Catheterization and Cardiovascular Interventions,2006,67 (5):698-702.
[97]Kolodgie FD, John M, Khurana C, et al. Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel [J]. Circulation,2002,106(10):1195-1198.
[98]Lanza GM, Yu X, Winter PM, et al. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent:Implications for rational therapy of restenosis [J]. Circulation,2002,106(22):2842-2847.
[99]Qiao T, Liu CJ, Ran F, et al. Experimental study of recombinant eukaryotic expression vector of human eNOS in ECV304 [J]. Swiss Med Wkly, 2006,136(1-2):19-25.
[100]Stephan DJ, Yang ZY, San H, et al. A new cationic liposome DNA complex enhances the ef ciency of arterial gene transfer in vivo [J]. Hum Gene Ther, 1996,7(15):1803-12.
[101]Pelisek J, Fuchs AT, Kuehnl A, et al. C-type natriuretic peptide for reduction of restenosis:gene transfer is superior over single peptide administration [J]. The Journal of Gene Medicine,2006,8(7):835-844.
[102]Meng QH, Jamal W, Hart SL, et al. Application to vascular adven titia of a nonviral vector for TIMP-1 gene therapy to prevent intimal hyperplasia [J]. Human Gene Therapy,2006,17:1-11.
[103]Yin X, Yutani C, Ikeda Y, et al. Tissue factor pathway inhibitor gene delivery using HVJ-AVE liposomes markedly reduces restenosis in atherosclerotic arteries [J]. Cardiovascular Research,2002,56 (3):454 463.
[104]Numaguchi Y, Okumura K, Harada M, et al. Catheter-based pros tacyclin synthase gene transfer prevents in-stent restenosis in rabbit atheromatous arteries [J]. Cardiovascular Research,2004,61(1):177-185.
[105]Cohen-Sacks H, Najajreh Y, Tchaikovski V, et al. Novel PDGFbetaR antisense encapsulated in polymeric nanospheres for the treatment of restenosis [J]. Gene Therapy,2002,9(23):1607-16.
[106]Lenter M, Garidel P, Pelisek J, et al. Stabilized nonviral formulations for the delivery of MCP-1 gene into cells of the vasculoendothelial system [J]. Pharmaceutical Research,2004,21(4):683-691.
[107]J Yang, Y Zeng, YJ Li, et al. Intravascular site-specific delivery of a therapeutic antisense for the inhibition of restenosis [J]. Eue J Pharmaceu Sci,2008,35:427-434
[108]Dijkgraaf I, Kruijtzer JA, Liu S, et al. Improved targeting of the v 3 integrin by multimerisation of RGD peptides [J]. Eur J Nucl Med Mol Imaging,2007,34(2):267-273.
[109]Mardilovich A, Craig JA, McCammon MQ, et al. Design of a novel bronectin-mimetic peptide-amphiphile for functionalized biomaterials [J]. Langmuir,2006,22(7):3259-3264.
[110]Kelly K, Nahrendorf M, Yu A, et al. In vivo phage display selection yields atherosclerotic plaque targeted peptides for imaging [J]. Mol Imaging Biol,2006,8(4):201-207.
[111]Muro S, Dziubla T, Qiu W, et al. Endothelial targeting of high-afnity multivalent polymer nanocarriers directed to intercellular adhesion molecule 1 [J]. J Pharmacol Exp Ther,2006,317(3):1161-9.
1. Gregory C, Huie P, Billingham M, et al. Rapamycin inbibits arterial inimal thickening caused by both alloimmune and mechanical injury [J].Transplantation,1993,55:1409-1418.
2. Meiser B,Billingham M, Morris R. Effects of cyclosporin, FK506, and rapamycin of graft-vessel disease [J]. Lancet,1991,338:1297-1298.
3. Almond PS, Moss A, Nalhleh RE, et al. Rapamycin:immunosuppression, hyporesponsiveness, and side effects in a porcine renal allograft model [J]. Transplantation,1993,56:275-281.
4. Hashemolhosseini S, Nagamine Y, Morley S, et al. Rapamycin inhibition of the G1 to S transition is mediated by effets on CyclinDl mRNA and proterin stability [J]. J Biol Chem,1998,273(23):14424-14429.
5. Marx SO, Jayaraman T, Go L0, et al. Rapamycn-FKBP inhibits cell cycle regulators of proliferation in VSMC [J]. Circ Res,1995,76:412-417.
6. Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulatous of the cell cycle [J]. Circulation,1999,99:2164-2170.
7. Roque M, Cordon-Cardo C, Fuster V, Reis ED, Drobnjak M, Badimon JJ. Modulation of apoptosis, proliferation, and p27 expression in a porcine coronary angioplasty model [J]. Atherosclerosis,2000,153(2):315-322.
8. Carter AJ, Bailey LR, Llanos G, et al. Stent-based sirolimus delivery reduces neointimal prolifration in a porcine coronary model of restenosis [J].J Am Coll Cardiol,2000,35:13.
9. Morice CM, Serruys PW, Sousa JE, et al. for the RAVEL Study Group. A Randomized Comparison of a Sirolimus-Eluting Stent with a Standard Stent for Coronary Revascularization [J]. N Engl J Med,2002,346:1773-80.
10. Morice MC, Serruys PW, Sousa JE. The RAVEL study:a randomized study with the sirolimus coated Bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions [J]. Eur Heart J,2001,22:484.
11. Regar E, Serruys PW, Bode C, et al. Angiographic Findings of the Multicenter Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL):Sirolimus-Eluting Stents Inhibit Restenosis Irrespective of the Vessel Size [J]. Circulation,2002,106: 1949-1956.
12. Sgueglia GA, Burzotta F, Trani C, et al. Comparative assessment of mammalian target of rapamycin inhibitor-eluting stents in the treatment of coronary artery bifurcation lesions:the Castor-bifurcation registry [J]. Catheter Cardiovasc Interv.2011,77(4):503-9.
13. Alexandre C, Zago, Jose C. Raudales, Guiherme Attizzani, et al. Local delivery of sirolimus nanoparticles for the treatment of in-stent restenosis [J]. Catheterization and Cardiovascular Interventions,2013, 81:E124-E129.
14.Poston RS, Billingham M, Hoyt G, et al. Rapamycin reverses chronicgraft vascular disease in a novel cardiac allograft model [J]. Circulation,1999, 100:67-74.
1. Li D, Zhang C, Song F, et al. VEGF regulates FGF-2 and TGF-betal expression in injury endothelial cells and mediates smooth muscle cells proliferation and migration [J]. Microvasc Res,2009,77(2):134-42.
2. Carmeliet P, Moons L, Dewerchin M, et al. Insights in vessel development and vascular discoders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system [J]. Ann N Y Acad Sci,1997,15(811):191-206.
3. Jing Yang, Cunxian Song, Hongfan Sun, Li Wu, Lina Tang, Yong Zeng, Wenling Zhu. A New Type Gene Delivery System-Gene nanoparticles [J]. Key Engineering Materials,2005,288-289:143-146.
4. Schiff P B. HorwitZ SB. Taxol stabilizes micmtubul in mouse fibroblast ceHs [J]. Proceeding of tIle national academy of sciences of the United States of America,1980,77(3):1561—1565.
5. J Yang, Y Zeng, YJ Li, CX Song, WL Zhu. Intravascular site-specific delivery of a therapeutic antisense for the inhibition of restenosis [J]. Eue J Pharmaceu Sci,2008,35:427-434
6. Chan JM, Rhee JW, Drum CL, et al. In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles [J]. Proc Natl Acad Sci U S A,2011,108(48):19347-52.
1. Schiff P B, Fant J, Horwitz S B. Promotion ofmicrotubule as—embly in vitro by taxol [J]. Nature,1979,277(5698):665—667
2. Schiff P B,Horwitz. Taxol stabilizes micmtubul in mouse fibroblast ceHs [J]. Proceeding of tile national academy of sciences of the Unitcd States of America,1980,77(3):1561—1565.
3.郭仁宏,王金万.紫杉醇脂质体的研究进展[J].中国肿瘤,2008,17(8)：698 -703.
4.邓联东,孙多先,董岸杰.紫杉醇注射剂的研究[J].药学进展,2002,26(3)：152—155.
5. Huang Y, Chen X M, Zhao B X, et al. Antiangiogenie active of sterically stabilized liposomes containing paclitaxel(SSLPTX):in vitro and in vivo [J]. AAPs Pharm Sci Tech,2010, (2):752—759.
6. Yang T, Choi M K, Cui F D, et al. Anfitumor effect of paclitax—oated PEGylated immunolipesomes against human breast canc cells[J]. Pharmaceutical Research,2007,24(12):2402—2411.
7. Zhang J Q, Hang J Q, Zhang Z R, et al. Lyophilized paclitaxel magnetoliposomes as potential drug delivery system for breast carcinoma v/a parenteral administration:In vitro and in vivo studies [J]. Pharmaceutical Research,2005,22(4):573—582.
8.温志强,桂双英,王均,等.脂质体作为抗癌药载体的应用进展[J].中国新药杂志,2009,18(9)：788—792.