眼眶腺样囊性癌临床治疗与局部化疗的实验研究
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摘要
目的
总结分析目前眼眶泪腺腺样囊性癌的临床治疗方法和预后,评估可能影响预后的因素。利用纳米技术及局部化疗减少全身化疗缺乏选择性、副作用大的问题。制备连接有叶酸(folic acid,FA)的长春新碱(vinscristine, VCR)靶向缓释纳米微球(nanopaticles, NPs),简称为FA-PLGA(VCR)-NPs,观察其理化特征；评估该药物对腺样囊性癌细胞株(ACC-2)及裸鼠眼眶移植瘤的抑制作用。进一步寻找眼眶腺样囊性癌治疗的新靶标,即肿瘤干细胞。观察肿瘤干细胞相关标志蛋白CD44、CD133和ABCG2在泪腺腺样囊性癌中的表达,研究它们与病理分型、预后的关系,为进一步开展针对肿瘤干细胞的靶向治疗奠定基础。
方法
1.采用回顾性系列病例研究,分析75例眼眶腺样囊性癌患者相关临床资料,包括患者的手术记录、病理分型及随访记录。
2.采用改良的复乳法制备FA-PLGA(VCR)-NPs;MTT比色法观察空白微球PLGA-NPs的毒性,比较VCR原药、载药微球PLGA(VCR)-NP和FA-PLGA (VCR)-NPs在不同时间和不同浓度条件下对ACC-2细胞的影响；FITC标记微球,荧光显微镜观察PLGA-NPs与FA-PLGA-NPs对肿瘤细胞的作用；瘤细胞悬液接种法建立裸鼠眼眶腺样囊性癌移植瘤,分别予以瘤内注射生理盐水、VCR、PLGA-NPs、PLGA(VCR)-NPs和FA-PLGA(VCR)-NPs,局部给药一次,隔天测量肿瘤体积变化,计算体积抑制率,高效液相色谱法测定给药后不同时间肿瘤组织内残余VCR浓度,透射电镜及HE染色观察肿瘤组织标本。
3.采用二步法免疫组织化学检测人眼眶腺样囊性癌肿瘤组织标本33例,复发切除标本5例及6例荷瘤裸鼠移植瘤标本的CD44、CD133和ABCG2的表达情况,分析其与病理分型及预后的关系。
结果
1.眼眶实体型腺样囊性癌2年复发率为85%(17／20)、5年复发率为100%(19／19),而腺样-管状型分别为23.53%(8／34)和64.52%(20／31),差异有统计学意义(2年,p=0.000；5年,p=0.003)。前者发生局部蔓延和远处转移例数亦多于后者。肿瘤切除术后联合放射治疗的5年复发率为70%(14／20),低于单纯手术切除的复发率92.86%(13／14)(p=0.198)。首次手术行眶内容物剜除术的5年复发率为25%(1／4),低于复发后再行眶内容物剜除术的病例的75%(6／8)(p=0.222),γ刀、粒子刀、化疗及生物治疗的效果不能确定。局部蔓延主要是至颅内、副鼻窦和颞窝,远处转移可到达肺、骨、肝、耳前淋巴结。5年远处转移率为25.71%(9／35),肺转移和骨转移各占33.33%(3／9)。5年生存率74.29%(26／35),死亡率25.71%(9／35),无瘤生存率37.14%(13／35),10年无瘤生存率17.14%(6／35)。最常见的死亡原因是颅内蔓延。肿瘤切除联合放射治疗可以使5年生存率提高到80%(16／20)。
2.FA-PLGA(VCR)-NPs呈规则球形,平均粒径249.2nm,载药率4.53%,体外释放时间达14天；PLGA-NPs与ACC-2细胞共培养5天,细胞存活率达80%以上；给药后第4、5天FA-PLGA(VCR)-NPs对ACC-2细胞的抑制率显著高于VCR,呈时间和浓度依赖性；微球附着于肿瘤细胞表面,这种识别可以被FA竞争性抑制；FA-PLGA(VCR)-NPs组及PLGA(VCR)-NPs组对裸鼠肿瘤的体积抑制率显著高于VCR组(前者p=0.016,后者p=0.029),FA-PLGA(VCR)-NPs组高于PLGA(VCR)-NPs组,但无统计学差异(p=0.376)；给药后第1、7、14天肿瘤组织中残留药物浓度存在差异(p=0.000)；透射电镜观察14天肿瘤细胞内仍有高电子密度的纳米颗粒聚集,肿瘤细胞坏死明显,注射周围组织结构形态正常。
3.CD44阳性表达率为54.5%(18／33)。实体型阳性率76.9%(10／13),多呈片状散在分布于肿瘤边缘浸润灶,而在肿瘤细胞密集处常常没有着染；筛网型阳性率为40%(8／20),大多分布在腺管样结构的外层细胞,即肌上皮细胞,二者差异不具有统计学意义(p=0.072)；在非炎症及恶性肿瘤性疾病切除的正常泪腺组织中CD44亦有阳性表达。CD133阳性表达率为57.6%(19／33),在实体型和筛网型中分别为76.92%(10／13)、45%(9／20),差异不具有统计学意义(p=0.087)；表达产物定位于细胞膜和细胞浆,呈淡黄色至棕褐色,部分病例同时表达于胞浆和胞核,其中实体型标本有46.15%(6／13),均属于发生转移或死亡的病例,筛网型有40%(8／20),其中4例发生复发或转移,4例四年内无复发；在非恶性肿瘤性疾病切除的正常泪腺组织中均无表达。ABCG2阳性表达率为21.2%(7／33),在实体型和筛网型中分别为30.77%(4／13)、15%(3／20),差异不具有统计学意义(p=0.393)；ABCG2阳性表达细胞具有沿血管分布的倾向。CD44、CD133及ABCG2在预后较好组(4年无复发)的阳性表达率均低于预后差组,无复发组低于发生转移或死亡组,但差异均不具有统计学意义(p<0.05)。Spearman相关分析提示CD44阳性表达和CD133的阳性表达之间存在正相关关系,(rs=0.416,p=0.016)。在6例荷瘤裸鼠肿瘤组织标本中,CD44阳性1例,CD133表达阳性1例,ABCG2表达阳性4例。
结论
1.腺样囊性癌是高度恶性的眼眶肿瘤,复发率和死亡率均较高,病理分型、治疗方法均影响预后。采取综合治疗方法,可以减少复发,提高生存率。
2.叶酸靶向长春新碱纳米缓释微球具有稳定的载药率和体外释放行为,具有良好的靶向识别力,体外细胞学实验及荷瘤裸鼠体内实验均证实具有优于原药的抗肿瘤能力。
3.在眼眶腺样囊性癌肿瘤组织中存在CD44、CD133及ABCG2阳性细胞,分别表达于腺样囊性癌肿瘤组织的不同部位,其表达随着病程进展而变化,可能会影响预后,但并不能作为评估预后的因素。
Objective
1.To summarize the treatment outcomes of orbital adenoid cystic carcinoma and to evaluate prognostic factors.
2.To prepare and observe the character of Folate Receptor-mediated VCR-loaded Nanoparticles, which is abbreviated to FA-PLGA (VCR)-NPs. Study the inhibitive effect on ACC-2 cells in vitro and the xenograft tumor in BALB/c-nu mice.
3.To observe the expression and distribution of CD44, CD133,and ABCG2 in orbital ACC and investigate their correlations with pathological type and prognosis.
Method
1.A retrospective case series study was performed on 75 patients with orbital adenoid cystic carcinoma.
2.The modified W/O/W extraction-evaporation technique was chosen to prepare FA-PLGA (VCR)-NPs. These particles were characterized for size, modality, encapsulation efficiency, and release in vitro.The cytotoxicity of high concentration blank particles PLGA-NPs towards tumor cells was evaluated by MTT colorimetry. The tumor cells were divided into three groups:VCR、PLGA(VCR)-NPs and FA-PLGA(VCR)-NPs.Seven doses of VCR were tested: 0.05μg/ml,0.25μg/ml,0.5μg/ml,1μg/ml,5μg/ml, 10μg/ml,30μg/ml.After 1day, 2day,3day,4day,5day, the cells growth inhibition ratio were evaluated also by MTT colorimetry. PLGA-NPs and FA-PLGA-NPs were labeled by FITC. Conditions of those particles uptaked by ACC-2 cells with or without free FA were observed with fluorescence microscope. ACC xenograft tumor of nude mice orbit was built by injecting ACC cell suspension and divided into four groups: VCR, PLGA(VCR)-NPs, FA-PLGA(VCR)-NPs, and control group.The inhibition ratio of gross tumor volume was observed every two days. Residual concentrations of VCR in tumors were evaluated by HPLC.The feature of histopathology was observed by electron microscope and HE stain.
3.Two stages method of immunohistochemical staining was employed in 33 cases paraffin embedded surgical specimens of human orbital ACC,5 cases recurrence samples,3 cases excisional lachrymal gland caused by neither inflammation nor tumor diseases, and 6 cases xenografts tumor in nude mice.
Results
1.The 2- and 5- year local recurrence rate of solid type orbital adenoid cystic carcinoma was significantly higher than that of the adeno-tubiform type. [2-year, 85%(17/20) vs 23.53%(8/34),χ2=19.14, p=0.000; 5-year,100%(19/19) vs 64.52% (20/31),Fisher's exact test, p=0.003] The regional extension and distant metastasis of solid type were more than those of adeno-tubiform type. The 5-year local recurrence rate treated by postoperative radiation was lower than that treated only by surgical excision [70%(14/20) vs 92.86%(13/14);Fisher's exact test, p=0.198].The 5-year local recurrence rate in patients initially treated by orbital evisceration during the first time was lower than that of cases which evisceration procedure was used after the recurrence. [25% (1/4)) vs 75% (6/8), Fisher's exact test, p=0.222].Tumors always extend into intracalvarium, nasal cavity and temporal fossa. They may spread to the lung, bone, liver and lymph node. The 5-year metastasis rate was 25.71% (9/35).Both of the lung and bone metastasis rates were 33.33% (3/9).The overall 5-year accumulative survival was 74.29% (26/35), mortality was 25.71% (9/35), and rate of survival without tumor recurrence was 37.14%(13/35).The 10-year disease free survival rate was 17.14% (6/35).Patients were most likely to die with intracranial extension. Surgical excision with postoperative radiation improved the 5-year survival rate to 80%(16/20).
2.FA-PLGA (VCR)-NPs were smooth and spherical with a mean particle size 249.2nm. The drug loading rate was 4.53%.The release of VCR from PLGA nanoparticles persists for 14d. After blank particles PLGA-NPs and ACC-2 cells co-cultured for 5 days, cell viability had remained at more than 80 percent. The inhibitive effect of FA-PLGA (VCR)-NPs was more effective than VCR at 4th and 5th day. They were both in dose-dependent and time-dependent manner. Targeting particles could attach to tumor surface, via folate receptor. FA was competitive inhibitor of this recognization. The volume inhibition ratios of FA-PLGA(VCR)-NPs and PLGA(VCR)-NPs were significant higher than VCR. (p=0.016,p=0.029) The inhibition ratio of FA-PLGA(VCR)-NPs was higher than PLGA(VCR)-NPs. (p=0.376) There was signigicant different between residual concentrations of VCR at the 1st day,7th day and 14th day. (p=0.000) TEM pictures showed lots of electron-dense microspheres in tumor cells at the 14th day. Tumor necrosis was obviously, while surrounding tissues were normal.
3.The positive rate of CD44 was 54.5% (18/33),with 76.9%(10/13)in solid type and 40% (8/20) in adeno-tubiform type. There wasn't statistically different between them (p=0.072).In solid type the positive expression part often located at the marginal part of the cancer nest. While in the adeno-tubiform type positive cells often located at the outer layer of the tubiform structure, which were the myoepithelial cells. It was also expressed in some normal tissues.The positive rate of CD133 was 57.6%(19/33),with 76.9%(10/13)in solid type and 45% (9/20) in adeno-tubiform type. There wasn't statistically different between them (p=0.087).Parts of the expression of CD133 antigen were both on the cytoplasm and the nucleus. The positive rate of ABCG2 was 21.2%(7/33),with 30.77% (4/13) in solid type and 15%(3/20) in adeno-tubiform type. There wasn't statistically different between them (p=0.393). Lots of positive cells surrounded vessels in tumor tissues.There were no significant difference between different prognosis groups of there surface phenotypes. The correlative analysis results of three surface phenotypes showed that CD44+ cells have positive correlation with CD133+ cells (Spearman, r,=0.416,p=0.016). Besides 1 case CD44+,1 case CD133+ and 4 cases ABCG2+ were detected in transplanted tumor of nude mice.
Conclusions
1.Orbital adenoid cystic carcinoma is one of the most malignant tumors in the orbit. They have a high local recurrence rate and low survival rate. Tumor histological types and treatment procedure can influence the prognosis. Combined therapy may decrease the recurrence and increase the survival rate.
2.FA-PLGA(VCR)-NPs are stable and have high drug entrapment efficiency and high effect of growth inhibition in vitro and vivo.It is targeted and can be proposed as a potential controlled and targeted delivery system for the treatment of ACC.
3.The expression of CD44, CD133 and ABCG2 in ACC should have some clinical significance in the progress of ACC.But it couldn't be regarded as one of the factors to evaluate the prognosis.
总结分析目前眼眶泪腺腺样囊性癌的临床治疗方法和预后,评估可能影响预后的因素。利用纳米技术及局部化疗减少全身化疗缺乏选择性、副作用大的问题。制备连接有叶酸(folic acid,FA)的长春新碱(vinscristine, VCR)靶向缓释纳米微球(nanopaticles, NPs),简称为FA-PLGA(VCR)-NPs,观察其理化特征；评估该药物对腺样囊性癌细胞株(ACC-2)及裸鼠眼眶移植瘤的抑制作用。进一步寻找眼眶腺样囊性癌治疗的新靶标,即肿瘤干细胞。观察肿瘤干细胞相关标志蛋白CD44、CD133和ABCG2在泪腺腺样囊性癌中的表达,研究它们与病理分型、预后的关系,为进一步开展针对肿瘤干细胞的靶向治疗奠定基础。
方法
1.采用回顾性系列病例研究,分析75例眼眶腺样囊性癌患者相关临床资料,包括患者的手术记录、病理分型及随访记录。
2.采用改良的复乳法制备FA-PLGA(VCR)-NPs;MTT比色法观察空白微球PLGA-NPs的毒性,比较VCR原药、载药微球PLGA(VCR)-NP和FA-PLGA (VCR)-NPs在不同时间和不同浓度条件下对ACC-2细胞的影响；FITC标记微球,荧光显微镜观察PLGA-NPs与FA-PLGA-NPs对肿瘤细胞的作用；瘤细胞悬液接种法建立裸鼠眼眶腺样囊性癌移植瘤,分别予以瘤内注射生理盐水、VCR、PLGA-NPs、PLGA(VCR)-NPs和FA-PLGA(VCR)-NPs,局部给药一次,隔天测量肿瘤体积变化,计算体积抑制率,高效液相色谱法测定给药后不同时间肿瘤组织内残余VCR浓度,透射电镜及HE染色观察肿瘤组织标本。
3.采用二步法免疫组织化学检测人眼眶腺样囊性癌肿瘤组织标本33例,复发切除标本5例及6例荷瘤裸鼠移植瘤标本的CD44、CD133和ABCG2的表达情况,分析其与病理分型及预后的关系。
结果
1.眼眶实体型腺样囊性癌2年复发率为85%(17／20)、5年复发率为100%(19／19),而腺样-管状型分别为23.53%(8／34)和64.52%(20／31),差异有统计学意义(2年,p=0.000；5年,p=0.003)。前者发生局部蔓延和远处转移例数亦多于后者。肿瘤切除术后联合放射治疗的5年复发率为70%(14／20),低于单纯手术切除的复发率92.86%(13／14)(p=0.198)。首次手术行眶内容物剜除术的5年复发率为25%(1／4),低于复发后再行眶内容物剜除术的病例的75%(6／8)(p=0.222),γ刀、粒子刀、化疗及生物治疗的效果不能确定。局部蔓延主要是至颅内、副鼻窦和颞窝,远处转移可到达肺、骨、肝、耳前淋巴结。5年远处转移率为25.71%(9／35),肺转移和骨转移各占33.33%(3／9)。5年生存率74.29%(26／35),死亡率25.71%(9／35),无瘤生存率37.14%(13／35),10年无瘤生存率17.14%(6／35)。最常见的死亡原因是颅内蔓延。肿瘤切除联合放射治疗可以使5年生存率提高到80%(16／20)。
2.FA-PLGA(VCR)-NPs呈规则球形,平均粒径249.2nm,载药率4.53%,体外释放时间达14天；PLGA-NPs与ACC-2细胞共培养5天,细胞存活率达80%以上；给药后第4、5天FA-PLGA(VCR)-NPs对ACC-2细胞的抑制率显著高于VCR,呈时间和浓度依赖性；微球附着于肿瘤细胞表面,这种识别可以被FA竞争性抑制；FA-PLGA(VCR)-NPs组及PLGA(VCR)-NPs组对裸鼠肿瘤的体积抑制率显著高于VCR组(前者p=0.016,后者p=0.029),FA-PLGA(VCR)-NPs组高于PLGA(VCR)-NPs组,但无统计学差异(p=0.376)；给药后第1、7、14天肿瘤组织中残留药物浓度存在差异(p=0.000)；透射电镜观察14天肿瘤细胞内仍有高电子密度的纳米颗粒聚集,肿瘤细胞坏死明显,注射周围组织结构形态正常。
3.CD44阳性表达率为54.5%(18／33)。实体型阳性率76.9%(10／13),多呈片状散在分布于肿瘤边缘浸润灶,而在肿瘤细胞密集处常常没有着染；筛网型阳性率为40%(8／20),大多分布在腺管样结构的外层细胞,即肌上皮细胞,二者差异不具有统计学意义(p=0.072)；在非炎症及恶性肿瘤性疾病切除的正常泪腺组织中CD44亦有阳性表达。CD133阳性表达率为57.6%(19／33),在实体型和筛网型中分别为76.92%(10／13)、45%(9／20),差异不具有统计学意义(p=0.087)；表达产物定位于细胞膜和细胞浆,呈淡黄色至棕褐色,部分病例同时表达于胞浆和胞核,其中实体型标本有46.15%(6／13),均属于发生转移或死亡的病例,筛网型有40%(8／20),其中4例发生复发或转移,4例四年内无复发；在非恶性肿瘤性疾病切除的正常泪腺组织中均无表达。ABCG2阳性表达率为21.2%(7／33),在实体型和筛网型中分别为30.77%(4／13)、15%(3／20),差异不具有统计学意义(p=0.393)；ABCG2阳性表达细胞具有沿血管分布的倾向。CD44、CD133及ABCG2在预后较好组(4年无复发)的阳性表达率均低于预后差组,无复发组低于发生转移或死亡组,但差异均不具有统计学意义(p<0.05)。Spearman相关分析提示CD44阳性表达和CD133的阳性表达之间存在正相关关系,(rs=0.416,p=0.016)。在6例荷瘤裸鼠肿瘤组织标本中,CD44阳性1例,CD133表达阳性1例,ABCG2表达阳性4例。
结论
1.腺样囊性癌是高度恶性的眼眶肿瘤,复发率和死亡率均较高,病理分型、治疗方法均影响预后。采取综合治疗方法,可以减少复发,提高生存率。
2.叶酸靶向长春新碱纳米缓释微球具有稳定的载药率和体外释放行为,具有良好的靶向识别力,体外细胞学实验及荷瘤裸鼠体内实验均证实具有优于原药的抗肿瘤能力。
3.在眼眶腺样囊性癌肿瘤组织中存在CD44、CD133及ABCG2阳性细胞,分别表达于腺样囊性癌肿瘤组织的不同部位,其表达随着病程进展而变化,可能会影响预后,但并不能作为评估预后的因素。
Objective
1.To summarize the treatment outcomes of orbital adenoid cystic carcinoma and to evaluate prognostic factors.
2.To prepare and observe the character of Folate Receptor-mediated VCR-loaded Nanoparticles, which is abbreviated to FA-PLGA (VCR)-NPs. Study the inhibitive effect on ACC-2 cells in vitro and the xenograft tumor in BALB/c-nu mice.
3.To observe the expression and distribution of CD44, CD133,and ABCG2 in orbital ACC and investigate their correlations with pathological type and prognosis.
Method
1.A retrospective case series study was performed on 75 patients with orbital adenoid cystic carcinoma.
2.The modified W/O/W extraction-evaporation technique was chosen to prepare FA-PLGA (VCR)-NPs. These particles were characterized for size, modality, encapsulation efficiency, and release in vitro.The cytotoxicity of high concentration blank particles PLGA-NPs towards tumor cells was evaluated by MTT colorimetry. The tumor cells were divided into three groups:VCR、PLGA(VCR)-NPs and FA-PLGA(VCR)-NPs.Seven doses of VCR were tested: 0.05μg/ml,0.25μg/ml,0.5μg/ml,1μg/ml,5μg/ml, 10μg/ml,30μg/ml.After 1day, 2day,3day,4day,5day, the cells growth inhibition ratio were evaluated also by MTT colorimetry. PLGA-NPs and FA-PLGA-NPs were labeled by FITC. Conditions of those particles uptaked by ACC-2 cells with or without free FA were observed with fluorescence microscope. ACC xenograft tumor of nude mice orbit was built by injecting ACC cell suspension and divided into four groups: VCR, PLGA(VCR)-NPs, FA-PLGA(VCR)-NPs, and control group.The inhibition ratio of gross tumor volume was observed every two days. Residual concentrations of VCR in tumors were evaluated by HPLC.The feature of histopathology was observed by electron microscope and HE stain.
3.Two stages method of immunohistochemical staining was employed in 33 cases paraffin embedded surgical specimens of human orbital ACC,5 cases recurrence samples,3 cases excisional lachrymal gland caused by neither inflammation nor tumor diseases, and 6 cases xenografts tumor in nude mice.
Results
1.The 2- and 5- year local recurrence rate of solid type orbital adenoid cystic carcinoma was significantly higher than that of the adeno-tubiform type. [2-year, 85%(17/20) vs 23.53%(8/34),χ2=19.14, p=0.000; 5-year,100%(19/19) vs 64.52% (20/31),Fisher's exact test, p=0.003] The regional extension and distant metastasis of solid type were more than those of adeno-tubiform type. The 5-year local recurrence rate treated by postoperative radiation was lower than that treated only by surgical excision [70%(14/20) vs 92.86%(13/14);Fisher's exact test, p=0.198].The 5-year local recurrence rate in patients initially treated by orbital evisceration during the first time was lower than that of cases which evisceration procedure was used after the recurrence. [25% (1/4)) vs 75% (6/8), Fisher's exact test, p=0.222].Tumors always extend into intracalvarium, nasal cavity and temporal fossa. They may spread to the lung, bone, liver and lymph node. The 5-year metastasis rate was 25.71% (9/35).Both of the lung and bone metastasis rates were 33.33% (3/9).The overall 5-year accumulative survival was 74.29% (26/35), mortality was 25.71% (9/35), and rate of survival without tumor recurrence was 37.14%(13/35).The 10-year disease free survival rate was 17.14% (6/35).Patients were most likely to die with intracranial extension. Surgical excision with postoperative radiation improved the 5-year survival rate to 80%(16/20).
2.FA-PLGA (VCR)-NPs were smooth and spherical with a mean particle size 249.2nm. The drug loading rate was 4.53%.The release of VCR from PLGA nanoparticles persists for 14d. After blank particles PLGA-NPs and ACC-2 cells co-cultured for 5 days, cell viability had remained at more than 80 percent. The inhibitive effect of FA-PLGA (VCR)-NPs was more effective than VCR at 4th and 5th day. They were both in dose-dependent and time-dependent manner. Targeting particles could attach to tumor surface, via folate receptor. FA was competitive inhibitor of this recognization. The volume inhibition ratios of FA-PLGA(VCR)-NPs and PLGA(VCR)-NPs were significant higher than VCR. (p=0.016,p=0.029) The inhibition ratio of FA-PLGA(VCR)-NPs was higher than PLGA(VCR)-NPs. (p=0.376) There was signigicant different between residual concentrations of VCR at the 1st day,7th day and 14th day. (p=0.000) TEM pictures showed lots of electron-dense microspheres in tumor cells at the 14th day. Tumor necrosis was obviously, while surrounding tissues were normal.
3.The positive rate of CD44 was 54.5% (18/33),with 76.9%(10/13)in solid type and 40% (8/20) in adeno-tubiform type. There wasn't statistically different between them (p=0.072).In solid type the positive expression part often located at the marginal part of the cancer nest. While in the adeno-tubiform type positive cells often located at the outer layer of the tubiform structure, which were the myoepithelial cells. It was also expressed in some normal tissues.The positive rate of CD133 was 57.6%(19/33),with 76.9%(10/13)in solid type and 45% (9/20) in adeno-tubiform type. There wasn't statistically different between them (p=0.087).Parts of the expression of CD133 antigen were both on the cytoplasm and the nucleus. The positive rate of ABCG2 was 21.2%(7/33),with 30.77% (4/13) in solid type and 15%(3/20) in adeno-tubiform type. There wasn't statistically different between them (p=0.393). Lots of positive cells surrounded vessels in tumor tissues.There were no significant difference between different prognosis groups of there surface phenotypes. The correlative analysis results of three surface phenotypes showed that CD44+ cells have positive correlation with CD133+ cells (Spearman, r,=0.416,p=0.016). Besides 1 case CD44+,1 case CD133+ and 4 cases ABCG2+ were detected in transplanted tumor of nude mice.
Conclusions
1.Orbital adenoid cystic carcinoma is one of the most malignant tumors in the orbit. They have a high local recurrence rate and low survival rate. Tumor histological types and treatment procedure can influence the prognosis. Combined therapy may decrease the recurrence and increase the survival rate.
2.FA-PLGA(VCR)-NPs are stable and have high drug entrapment efficiency and high effect of growth inhibition in vitro and vivo.It is targeted and can be proposed as a potential controlled and targeted delivery system for the treatment of ACC.
3.The expression of CD44, CD133 and ABCG2 in ACC should have some clinical significance in the progress of ACC.But it couldn't be regarded as one of the factors to evaluate the prognosis.
引文
[1]唐东润,宋国祥,孙丰源,等.眼眶泪腺腺样囊性癌手术联合放疗的疗效观察[J].眼科研究,2002,20：69-71.
[2]林婷婷,何彦滓,张虹,等.眼眶腺样囊性癌的治疗与预后分析[J].中华眼科杂志,2009,45(4)：309-313.
[3]Brem H, Gabikian P. Biodegradable polymer implants to treat brain tumors[J].J Controlled Release,2001,74:63-67.
[4]Engelhard HH.The role of interstitial BCNU chemotherapy in the treatment of malignant glioma[J].Surg Neurol,2000,53:458-64.
[5]Harper E, Dang W,Lapidus RG, et al.Enhanced efficacy of a novel controlled release paclitaxel formulation (PACLIMER delivery system) for local-regional therapy of lung cancer tumor nodules in mice[J].Clin Cancer Res,1999,5:4242-4248.
[6]Low PS,Antony AC.Folate receptor-targeted drugs for cancer and in flammatory diseases[J].Adv Drug Deliv Rev,2004,56:1055-1058.
[7]Leamon CP, Reddy JA. Folate-targeted chemotherapy[J].Adv Drug Deliv Rev, 2004,56:1127-1141.
[8]Wang S,Lee RJ, Cauchon G, et al.Delivery of antisense oligodeoxyribo-nucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol[J].Proc Natl Acad Sci USA,1995,92:3312-3318.
[9]Yoo HS,Park TG. Folate receptor targeted biodegradable polymeric doxorubicin micelles[J].Controlled Release,2004,96(2):273-283.
[10]Ni S,Stephenson SM, Lee RJ.Folate receptor targeted delivery of liposomal daunorubicin into tumor cells[J].Anticancer Res,2002,22:2131-2135.
[11]Park EK, Lee SB,Lee YM.Preparation and characterization of methoxy poly (ethylene glycol)/poly(s-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folat-mediated targeting of anticancer drugs[J].Biomaterials, 2005,26(9):1053-1061.
[12]张良珂,侯世祥,毛声俊,等,受体介导米托蒽醌白蛋白纳米粒肿瘤细胞靶向性研究[J].四川大学学报(医学版),2006,37(1)：77-79.
[13]Seigel GM, Campbell LM, Narayan M, et al. Evidence for cancer stem cells in retinoblastoma[J].Mol Vis,2005,11:729-732.
[14]刘斌,李永平,彭展.人眼脉络膜黑色素瘤OCM-1细胞中肿瘤干细胞的分离纯化[J].中华眼底病杂志,2007,23：87-90.
[15]Guo W, Lasky JL, Wu H.Cancer Stem Cells [J].Pediatr Res,2006,59:59-64.
[16]Galmozzi E, Facchetti F, La Porta C A. Cancer stem cells and therapeutic perspectives[J].Curr Med Chem,2006,13(6):603-607.
[17]温玉明,刘坤,华成舸,等.腺样囊性癌细胞系中肿瘤干细胞的生物学特性初探[J].中国口腔颌面外科杂志,2006,4：289-294.
[18]Liu K, Hua CG, Wen YM, et al.Cancer stem cells:its existence, proliferation and differentiation in an adenoid cystic carcinoma cell line[J].Zhonghua Kou Qiang Yi Xue Za Zhi,2007,42:284-287.
[19]关晓峰,杨捷琳,朱乃硕,等,腺样囊性癌高、低转移细胞株基因表达谱差异性及转移相关基因研究[J].中华口腔医学杂志,2004,39：118-121.
[20]韩媛媛.局部应用化疗药物治疗眼眶腺样囊性癌的实验研究[D].天津：天津医科大学,2006.
[21]Fordice J, Kershaw C, El-Naggar A, et al.Adenoid cystic carcinoma of the head and neck; predictors of morbidity and mortality[J].Arch Otolaryngol Head Neck Surg, 1999,125:149-152.
[22]郑刚,郭传瑸,俞光岩,等.腺样囊性癌患者生存预测模型的建立[J].中华口腔医学杂志,2006,41：350-353.
[23]Ben Simon GJ, Schwarcz RM, Douglas R, et al.Orbital exenteration:one size does not fit all[J].Am J Ophthalmol,2005,139:11-17.
[24]Gurney TA, Eisele DW, Weinberg V, et al.Adenoid cystic carcinoma of the major salivary glands treated with surgery and radiation[J].Laryngoscope,2005, 115:1278-1282.
[25]Khafif A, Anavi Y, Haviv J, et al. Adenoid cystic carcinoma of the salivary glands:a 20-year review with long-term follow-up[J].Ear Nose Throat J,2005, 84:662,664-667.
[26]Kawaguchi O, Kunieda E, Fujii H, et al.Adenoid cystic carcinoma with hyperostosis after stereotactic radiosurgery[J].Radiat Med,2004,22:198-200.
[27]徐德生,贾强,郑立高,等.眶内及眶颅沟通性肿瘤的伽玛刀放射治疗[J].立体定向和功能性神经外科杂志,2005,18：43-45.
[28]彭诚,邓嘉胤,王东,等.放射性核素1251粒子植入治疗晚期腺样囊性癌[J]. 中华口腔医学研究杂志(电子版),2008,2：270-276.
[29]Meldrum ML, Tse DT, Benedetto P. Neoadjuvant intracarotid chemotherapy for treatment of advanced adenocystic carcinoma of the lacrimal gland[J].Arch Ophthalmol,1998,116:315-321.
[30]Sun CX, He RG, Cheung LK. The biological behaviour of human adenoid cystic carcinoma cells transduced with interleukin-2-gene[J].Int J Oral Maxillofac Surg, 2002,31:650-656.
[31]Guan X, Qiu w, He R, et al.Selection of adenoid cystic carcinoma cell clone highly metastatic to the lung:an experimental study[J].Inter J Oral Maxi Surg,1997, 26:116-119.
[32]杨捷琳,朱乃硕,王颖,等.涎腺腺样囊性癌高低转移细胞系mRNA及蛋白质表达谱差异研究[J].生物化学与生物物理进展,2004,31：313-321.
[33]臧光祥,孙宏晨,穆亚冰,等.腺病毒介导的TRAIL基因诱导腺样囊性癌细胞凋亡研究[J].实用口腔医学杂志,2008,24：37-40.
[34]李亚娟,周洪澜,葛岩,等.槲寄生碱对腺样囊性癌细胞的抑制作用[J].吉林大学学报(医学版),2008,34：601-604,729-730.
[35]董青,杨湲波,王琳,等.紫杉醇联合肿瘤坏死因子α对腺样囊性癌细胞的抑制作用[J].军医进修学院学报,2008,29：265-267.
[36]Maclaughlin FC, Mumper RJ, Wanf J, et al.Chitosan and depolymerized chiton as condensing carriers for in vivo plasmid delivery[J].J Control Rel,1998,56: 259-272.
[37]Hermanson GT. Bioconjugate techniques[J].New York:Academic Press,1996, 56-60.
[38]赵硕,常津,卢剑.载药纳米微粒制备技术[J].化学通报,2002,65(93)：3-5.
[39]胡云霞,原续波,张晓金,等.聚乳酸载药纳米微粒的表面修饰及体外评价[J].中国生物医学工程学报,2004,23(1)：30-36.
[40]Kumar M. Nano and microparticles as controlled drug delivery devices[J].J Pharm Sci,2000,3:234-258.
[41]Berkland C, Kipper M. J, Narasimhan B, Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres[J].Journal of Controlled Release,2004,94(1):129-141.
[42]Liu J, Meisner D, Wu XY, et al.A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA-paclitaxel microspheres[J]. Biomaterials,2007,28(21):3236-3244.
[43]Lambert G, Fattal E.Nanoparticulate system for the delivery of antisense oligonucleotides[J].Advanced Drug Delivery Reiew,2001,47(1):99-112.
[44]Fonseca C, Simoes S,Gaspar R. Paclitaxel-loaded PLGA nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity[J]. Journal of Controlled Release,2002,83(2):273-286.
[45]Mu L, Fellg SS.A novel controlled release formulation for the anticancer drug paclitaxel(Taxol):PLGA nanopartlcles containing vitamin ETPGS[J].Control Release,2003,86:33-48.
[46]欧敬民,张一楚.叶酸与肿瘤发生[J].国外医学外科学分册,2002,29(2)：57-60.
[47]Ratnam M, Hao H, Zheng X, et al.Receptor induction and targeted drug delivery:a new antileukaemia strategy[J].Expert Biol Ther,2003,3:563-574.
[48]崔正刚,殷福珊.微乳化技术及应用[M].北京：中国轻工业出版社,2001：8-9.
[49]Gelse K, Aigner T. Development and characterization of PLGA nanospheres and nanocapsules[J].Advanced Drug Delivery Reviews,2003,55(10):1531-1546.
[50]Wang HT, Schmitt E, Flanagan FR, et al.Influence of formulation methods on the in vitro controlled release of protein from Poly(ester)microspheres[J].J Control Release,1991,17(1):23-32.
[51]宋国祥,吴中耀.眼眶病学[M].北京：人民卫生出版社,1999：235-239.
[52]Linda M. Pilarski,Michael D.Mehta,Timothy Caulfield.Microsystems and Nanoscience for Biomedic al plications:A View to the Future[J].Bulletin of Science, Technology & Society,2004,24(1):40-45.
[53]秦建民,张阳德.纳米药物在疾病治疗中的应用及其进展[J].中国现代医学杂志,2003,13(11)：19-53.
[54]Low PS, Antony AC.Folate receptor-targeted drugs for cancer and inflammatory diseases[J].Adv Drug Deliv Rev,2004,56 (8):1055-1058.
[55]Lu Y, Low PS.Folate-mediated delivery of macromolecular anticancer therapeutic agents[J].Adv Drug Deliv Rev,2002,54 (5):675-693.
[56]Leamon CP,Reddy JA.Folate-targeted chemotherapy[J].Adv Drug Deliv Rev, 2004,56:1127-1141.
[57]Wang S,Lee RJ, Cauchon G, et al.Delivery of antisense oligodeoxyribo-nucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol[J].Proc Natl Acad Sci USA,1995,92:3312-3318.
[58]Yoo HS,Park TG.Folate receptor targeted biodegradable polymeric doxorubicin micelles[J].Controlled Release,2004,96:273-283.
[59]Ni S,Stephenson SM, Lee RJ.Folate receptor targeted delivery of liposomal daunorubicin into tumor cells[J].Anticancer Res,2002,22:2131-2135.
[60]王元天,孙颖浩,邱镇.人类前列腺癌裸鼠原位移植模型的建立[J].中华泌尿外科杂志,2005,26(3)：208-209.
[61]Zimmer A, Kreuter J.Microspheres and nanoparticles used in ocular delivery systems[J].Adv Drug Deliv Rev,1995,16:61-73.
[62]Park EK, Lee SB,Lee YM. Preparation and characterization of methoxy poly(ethylene glycol)/poly(s-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folat-mediated targeting of anticancer drugs[J]. Biomaterials,2005,26:1053-1061.
[63]Kaul G, Amiji M. Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles:in vitro and in vivo studies[J].Pharm Res, 2005,22:951-961.
[64]李筱荣,刘新玲,常津,等.靶向5-氟尿嘧啶纳米微球对体外培养的人晶状体上皮细胞作用的研究[J].中华眼科杂志,2006,42：526-530.
[65]Pignatello R, Bucolo C, Spedalieri G,et al.Flurbipro-fen-loaded aerylate polymer nanosuspensions for ophthalmic application[J].Biomaterials,2002,23: 3247-3255.
[66]Calvo P, Vila-Jato JL, Alonso MJ. Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers[J].Int J Pharm,1997,153:41-50.
[67]Chouinard, M.L, Martin, et al.Pharmacokinetics and biochemical efficacy of pirmagrel, a thromboxane synthase inhibitor, in renal allograft recipients[J].Clinical Pharmacology and Therapeutics,1991,52:597-604.
[68]Saito N, MurakamiT N, Takahashi J, et al.Synthetic biodegradable polymers as drug delivery systems for bone morphogenetic proteins[J].Adv. Drug Deliv. Rev., 2005,57:1037-1048.
[69]Chu TC, He Q, David E.P. Biodegradable calcium phosphate nanoparticles as a new vehicle for delivery of a potential ocular hypotensive agent[J].J Ocul Pharmacol Ther,2002,18:507-514.
[70]Kompella UB, Bandi N, Ayalasomayajula SP. Subconjunctival nano-and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression[J].Invest Ophthalmol Vis Sci,2003,44:1192-1201.
[71]Lallemand F, Felt-baeyens O, Besseghir K, et al. Cyclosporine a delivery to the eye:a pharmaceutical challenge[J].Eur J Pharm Bio,2003,56:307-318.
[72]费文雷,陈家祺,庞志清,等.FK506纳米粒对大鼠角膜移植排斥反应的影响[J].眼科研究,2006,24：156-159.
[73]Cavalli R, Gasco MR, Chetoni P, et al.Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin[J].Int J Pharm,2002,238:241-245.
[74]Fresta M, Fontana G, Bucolo C, et al.Ocular tolerability and in vivo bioavailability of poly-(ethylene glycol)(PEG)-coated polyethyl-2-cyanoacrylate nanosphere-encapsulated acyclovir[J].J Pharm Sci,2001,90:288.
[75]Sharma D, Chelvi TP, Kaur J, et al.Novel Taxol formulation:polyvinyl plyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy[J]. Oncol Res,1996,8:282-286.
[76]Chiannilkulchai N, Driouich Z, Benoit JP,et al.Doxorubicin-loaded nanoparticles:increased efficiency in murine hepatic metastases[J].Sel Cancer Ther, 1989,5:1-11.
[77]Llobet MI, Egea MA, Valero J, et al.Methotrexate-loaded nanoparticles:analysis of drug content and study of the matrix structure[J].Drug development and industrial pharmacy,1995,21:1761-1771.
[78]Maincent P, Le Verge R, Couvreur P, et al.Disposition kinetics and oral bioavailability of vincamine-loaded polyalkylcyanoacrylate nanoparticles[J].J Pharm Sci,1986,75:955-958.
[79]Silverman D A, Carlson T P, Khuntia D, et al. Role for postoperative radiation therapy in adenoid cystic carcinoma of the head and neek[J].Laryngoseope,2004, 114:1194-1199.
[80]吴细丕,钱林法.实验动物与肿瘤研究[M].北京：中国医药科技大学出版社,2000：398.
[81]Shimizu M,Saitoh Y, Itoh H.Immunohistochemical staining of Ha-ras oncogene product in normal,benin,and malinant human pancrestic tissue [J].Hum Pat hol,1990,21(9):607-612.
[82]Guo W, Lasky JL, Wu H.Cancer Stem Cells[J].Pediatr Res,2006,59:59-64.
[83]Al-Hajj M, Wicha MS,Benito HA, Morrison SJ, Clarke MF.Prospective identification of tumorigenic breast cancer cells[J].Proc Natl Acad Sci USA,2003, 100:3983-3988.
[84]Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. Identification of a cancer stem cell in human brain tumors[J].Cancer Res,2003, 63:5821-5828.
[85]董强刚,姚明,耿沁,周瑾,闫明霞.人肺腺癌干细胞的分离及鉴定[J].肿瘤,2008,28：1-7.
[86]Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ.Prospective identification of tumorigenic prostate cancer stem cells[J].Cancer Res,2005, 65:10946-10951.
[87]Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V,Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells[J].J Surg Res,2006, 130:194-195.
[88]Yang YM, Chang JW. Bladder cancer initiating cells (BCICs) are among EMA-CD44v6+ subset:novel methods for isolating undetermined cancer stem (initiating) cells[J].Cancer Invest,2008,26(7):725-733.
[89]Seigel GM, Hackam AS,Ganguly A, Mandell LM, Gonzalez-Fernandez F. Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis,2007, 13:823-832.
[90]刘斌,李永平,彭展.人眼脉络膜黑色素瘤OCM-1细胞中肿瘤干细胞的分离纯化[J].中华眼底病杂志,2007,23：87-90.
[91]Lizuka N, Miyamoto K, Tangoku A, Hayashi H, Hazama S, Yoshino S, Yoshimura K, Hirose K, Yoshida H, Oka M.Downregulation of intracellular nm23-Hl prevents cisplatin-induced DNA damage in oesophageal cancer cells:possible association withNa(+),K(+)-ATPase[J].Br J Cancer.2000,83:1209-1215.
[92]Pries R, Witrkopf N, Trenkle T, Nitsch SM, Wollenberg B.Potential stem cell marker CD44 is constitutively expressed in permanent cell lines of head and neck cancer[J].In Vivo.2008,22:89-92.
[93]Roye GD, Myers RB, Brown D, et al. CD44v6 expression in dysplastic epithelium and squamous cell carcinoma of the esophagus[J].Int J Cancer,1996, 69:254-261.
[94]Pals ST, Horst E. Expression of lymphocyte homing receptor(CD44) as a mechanism of dissemination in non-Hodgkins lymphoma[J].Blood,1989,73(6): 885-893.
[95]Gotley DC, Fawcett J, Walsh MD, et al.Alternatively spliced variants of the cell adhesion molecule CD44 and tumor progression in Colorectal cancer[J].Br J Cancer, 1996,74(3):342-351.
[96]Herokd-Mende C, Seiter S,Born A I, et al.Expression of CD44 splice variants in squamous epithelia and squamous cell carcinoma of the head and neck[J].J Patho 1, 1996,179(1):66.
[97]Kunishi M, Kayada Y Down-regulated poor survival in squamous cell carcinoma of tongue[J].Oral Oncol,2000,36(6):545.
[98]Kanke M, Fujii M, Kameyama K, et al.Role of CD44 varriant exon 6 in invasion of head and neck squamons cell carcinoma[J].Arch Otolaryngol Head Neck Surg,2000,126(10):1217.
[99]Xing RD,Regezi J, Stern M, et al.Hyaluronan and CD44 expression in minor salivary gland tumors[J].Oral Dis,1998,4(4):241.
[100]李文,王昌美,温玉明,等.CD44v6在腺样囊性癌中的表达及临床意义[J].临床口腔医学杂志,2003,19(7)：407-408.
[101]陈伟军,王成,曾亮.COX-2、CD44在腺样囊性癌中的表达及意义[J].中国现代医生,2009,47(16)：36-37.
[102]吴轶群,王英,张伟国,等.CD44s和CD44v6在涎腺腺样囊性癌中的表达[J].上海口腔医学,1999,8(3)：159-162.
[103]宋琦,陈芳,李萍,等.CD44、CD24、MMP9在涎腺腺样囊性癌的表达及意义[J].贵州医药,2009,33(9)：782-783.
[104]Gunthert U.CD44 in malignant disorders [J].Curr Top Microbio Immunol, 1996,213:271.
[105]温玉明,刘坤,华成舸,等.腺样囊性癌细胞系中肿瘤干细胞的生物学特性初探[J].中国口腔颌面外科杂志,2006,4：289-294.
[106]Liu K, Hua CG, Wen YM, Pan J, Chen SW, Gao QH.Cancer stem cells:its existence, proliferation and differentiation in an adenoid cystic carcinoma cell line[J]. Zhonghua Kou Qiang Yi Xue Za Zhi.2007,42:284-287.
[107]Ricci-Vitiani L, Lombardi DG,Pilozzi E,et al.Identification and expansion of human colon-cancer-initiating cells[J].Nature,2007,445(2007):111-115.
[108]O'Brien CA, Pollett A, Gallinger S,et al.A human colon cancer cell capable of initiating tumor growth in immunodeficient mice[J].Nature.2007,445(7123): 106-110.
[109]Zhou L, Wei X, Cheng L, et al.CD133,one of the markers of cancer stem cells inHep-2 cell line[J].Laryngoscope,2007,117(3):455-460.
[110]Ma S,Chan KW, Hu L, et al.Identification and characterization of tumorigenic liver cancer stem/progenitor cells[J].Gastroenterology,2007,132(7):2542-255.
[111]Griguer CE, Oliva CR, Gobin E, et al.CD133 is a marker of bioenergetic stress in human glioma[J].PloS ONE,2008,3(11):e3655.
[112]黄华兵.CD133在前列腺、前列腺增生及前列腺癌中的表达[D].江西：南昌大学,2007.
[113]Doyle L A, Yang W, Abruzzo L V, et al.A multidrug resistance transporter from human MCF-7 breast cancer cells[J].Proc Natl Acad Sci USA.1998,22;95(26): 15665-15670.
[114]Zhou S,Schuetz JD, Bunting KD,et al.The ABC transporter Bcrpl/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype[J].Nat Med,2001,7(9):1028-1034.
[115]Maliepaard M, Scheffer G L, Faneyte I F, et al.Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues[J].Cancer Res,2001,61(8):3458-3464.
[116]Diestra JE, Scheffer GL, Catala I, et al. Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material[J].J Pathol.2002, 198(2):213-9.
[117]储亮,黄强,翟德忠,等.ABCG2在胶质瘤组织中的表达及意义[J].癌症,2007,26(10)：1090-1094.
[118]陈芳,宋琦,李萍,等.ABCG2在腺样囊性癌的表达及意义[J].贵州医药,2008,32(6)：501-502.
[119]胡振宇.ABCG2、MCM2在涎腺发育及肿瘤发生干细胞表达中的关系[D].浙江：浙江大学,2007.
[120]Naylor CS,Jwaorska E, Branson K, et al.Side population/ABCG2-positive cells represent a heterogeneous group of haemopoietic cells:implications for the use of adult stem cells in transplantation and plastieity protocols[J].Bone Marrow Transplant,2005,35(4):353-60.
[121]刘继东.ABCG2、CD133在人脑胶质瘤中的表达及意义[D].云南：昆明医学院,2006.
[122]Monzania E, Facchett F, Galmozzi E. Melanoma contains CD133 and ABCG2 positive cells with enhanced tumorrigenic potential[J].Eur J Cancer,2007,43(5): 935-946.
[123]Dalerba P, Dylla SJ, Park IK, et al.Phenotypic characterization of human colorectal cancer stem cells[J].Proc Natl Acad Sci U S A,2007,104:10158-10163.
[124]Collins AT, Berry PA, Hyde C, et al.Prospective identification of tumorigenic prostate cancer stem cells[J].Cancer Res,2005,65(23):10946-10951.
[1]Siegel RW. Creating nanophase materials.Scj Am.1996,275:42-47.
[2]Kumar M. Nano and microparticles as controlled drug delivery devices. J Pharm Sci.2000,3:234-258.
[3]Pignatello R, Bucolo C, Puglisi G. Ocular tolerability of Eudragit RS100 and RL100 nanosuspensions as carriers for ophthalmic controlled drug delivery [J].J Pharm Sci.2002,91:2636-2641.
[4]黄潇,魏锐利.纳米技术在眼科基础研究中的应用.眼科新进展.2006,26：794-795.
[5]Lydataki S,Lesniewska E, Tsilimbaris MK, et al.Observation of the posterior endothelial surface of the rabbit cornea using atomic force microscopy. Cornea.2003, 22:651-664.
[6]姜涛,王德文,高亚兵,等.电磁脉冲对离体角膜上皮细胞损伤的实验研究.军事医学科学院院刊.2004,28：358-360.
[7]Goto E. Quantification of tear interference image:tear fluid surface nanotechnology. Cornea.2004,23:S20-S24.
[8]Sjostrand FS.Kuffler's inhibitory surround, the function of the inner plexiform layer and an information processing unit in the retina. Neural interaction at the nanometer level.J Submicrosc Cytol Pathol.2003,35:359-371.
[9]Teixeira AI, Abrams GA, Bertics PJ,et al.Epithelial contact guidance on well-defined micro and nanostructured substrates.J Cell Sci.2003,116:1881-1892.
[10]Karuri NW, Liliensiek S,Teixeira AI, et al.Biological length scale topography enhances cell-sustratum adhesion of human corneal epithelial cells. J Cell Sci.2004, 117:3153-3164.
[11]Karuri N, Nealey PF, Campbell S, et al.Fluid shear induced detachment of SV-40 corneal epithelial cells from planar and nano-structured substrates. Invest Ophthalmol Vis Sci.2002,43:1690.
[12]Anthony B, William R. Evolving and experimental technologies in medical imaging. Radiology.2006,238:16-39.
[13]Kokate A, Li X, Jasti BR, et al.Physiological and biochemical barriers to drug delivery. In Design of Controlled Release Drug Delivery Systems.2006,12:41-73.
[14]Ravivarapu H, Li X, Jasti BR, et al.Biodegradable polymeric delivery systems. In Design of Controlled Release Drug Delivery Systems.2006,12:271-303.
[15]Yasukawa T. Drug delivery systems for vitreoretinal diseases. Prog Retin Eye Res.2004,23:253-281.
[16]Wong CG. et al. Intravitreal VEGF and bFGF produce florid retinal neovascularization and hemorrhage in the rabbit. Curr Eye Res.2001,22:140-147.
[17]Zimmer A, Kreuter J. Microspheres and nanoparticles used in ocular delivery systems. Adv Drug Deliv Rev.1995,16:61-73.
[18]Bourges JL, Gautier SE, Delie F, et al.Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Ophthalmol Vis Sci.2003,44:3562-3569.
[19]Park EK, Lee SB,Lee YM.Preparation and characterization of methoxy poly(ethylene glycol)/poly(ε-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folat-mediated targeting of anticancer drugs. Biomaterials.2005,26:1053-1061.
[20]张良珂,侯世祥,毛声俊,等.受体介导米托葸醌白蛋白纳米粒肿瘤细胞靶向性研究.四川大学学报(医学版).2006,37：77-79.
[21]Kaul G, Amiji M.Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles:in vitro and in vivo studies.Pharm Res.2005, 22:951-961.
[22]李筱荣,刘新玲，常津,等.靶向5-氟尿嘧啶纳米微球对体外培养的人晶状体上皮细胞作用的研究.中华眼科杂志.2006,42：526-530.
[23]Zimmer A, Kreuter J, Robinson JR. Studies on the transport pathway of PBCA nanoparticles in ocular tissues.J Microencapsul.1991,8:497-504.
[24]Pilar C, Charles T, Maria J, et al.Study of the mechanism of interaction of poly (-caprolactone) nanocapsules with the cornea by confocal laser scanning microscopy. Int J Pharma.1994,103:283-291.
[25]Calvo P, Thomas C, Alonso MJ, et al.Study of the mechanism of interaction of poly(epsilon-caprolactone) nanocapsules with the cornea by confocal laser scanning microscopy. Int J Pharm.1994,103:283-291.
[26]De Campos AM, Sanchez A, Gref R, et al.The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa. Eur J Pharm Sci.2003,20:73.
[27]Le Bourlais CA, Chevanne F, Turlin B,et al.Effect of cyclosporine A formulations on bovine corneal absorption:ex-vivo study. J Microencapsul.1997,14: 457-467.
[28]Qaddoumi MG, Gukasyan HJ, Davda J, et al.Clathrin and caveolin-1 expression in primary pigmented rabbit conjunctival epithelia cells:role in PLGA nanoparticle endocytosis.Mol Vis.2003,15:559-568.
[29]Wood RW, Li VHK, Kreuter J, et al.Ocular disposition of polyhexyl-2-cyano [3-14C] acrylate nanoparticles in the albino rabbit. Int J Pharm.1985,23:175-183.
[30]Calvo P, Vila-Jato JL, Alonso MJ.Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers.Int J Pharm.1997,153:41-50.
[31]Giannavola C, Bucolo C, Paolino D, et al.Influence of preparation conditions on acyclovir-loaded poly-d,1-lactic acid nanospheres and effect of PEG coating on drug bioavailability. Pharm Res.2003,20:584-590.
[32]Aukunuru JV, Kompella UB, Delivery of nano-and micro-particles to human rentinal pigment epithelial(ARPE-19)cells.Drug Del Tech.2002,2:50.
[33]Bejjani RA, BenEzra D, Bourges JL. Phagocytosis of polylactides (PLA) nanoparticles by bovine and human RPE cells in vitro. Invest Ophthalmol Vis Sci. 2002,43:2295.
[34]李越,王雨生,宋存先,等.地塞米松-PLGA纳米粒兔眼玻璃体内注射的药 物代谢动力学.眼科新进展.2005,25：229-231.
[35]李筱荣,刘新玲,常津,等.靶向5-氟尿嘧啶纳米微球对体外培养的人晶状体上皮细胞作用的研究.中华眼科杂志.2006,42：526-530.
[36]Pignatello R, Bucolo C, Spedalieri G, et al.Flurbipro-fen-loaded aerylate polymer nanosuspensions for ophthalmic application. Biomaterials.2002,23:3247-3255.
[37]Gupta AK, Madan S,Majumdar DK, et al.Ketorolac entrapped in polymeric micelles:preparation, characterisation and ocular anti-inflammatory studies.Int J Pharm.2000,209:1-14.
[38]Marchal-Heussler L, Maincent P, Hoffman M, et al.Antiglaucomatous activity of hetaxolol chlorhydrate sorbed onto different isobutylcyanoacrylate nanoparticle preparations.Int J Pharm.1990,58:115-122.
[39]Hsiue GH, Hsu SH, Yang ChC, et al.Preparation of controlled release ophthalmic drops, for glaucoma therapy using thermosensitive poly-N-isoptopylaerylamide. Biomaterials.2002,23:457-462.
[40]Chu TC, He Q, David EP. Biodegradable calcium phosphate nanoparticles as a new vehicle for delivery of a potential ocular hypotensive agent. J Ocul Pharmacol Ther.2002,18:507-514.
[41]Chiang CH, Tung SM, Lu DW, et al.In vitro and vivo evaluation of an ocular delivery system of 5-fluorouracil microspheres[J].J Ocul Phama col Ther.2001.17(6): 545.
[42]Herrero-Vanrell R, Alvarez-Santiago C, Barcia E.Biodegradable microspheres loaded with dexamethasone for intravitreal administration.Invest Ophthalmol Vis Sci. 1999,40:84.
[43]Kompella UB,Bandi N, Ayalasomayajula SP. Subconjunctival nano-and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci.2003,44:1192-1201.
[44]Giannavola C, Bucolo C, Paolino D, et al.Influence of preparation conditions on acyclovir-loaded poly-d,1-lactic acid nanospheres and effect of PEG coating on drug bioavailability. Pharm Res.2003,20:584-590.
[45]Pignatello R, Bucolo C, Spedalieri G, et al.Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials.2002,23:3247-3255.
[46]Vega E, Gamisans F, Garcia ML, et al. PLGA nanospheres for the ocular delivery of flurbiprofen:drug release and ineractions. Journal of Pharmaceutical Sciences. 2008,97:5306-5317.
[47]De Campos AM, Sanchez A, Alonso MJ.Chitosan nanoparticles:a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporine A. Int J Pharm.2001,224:159.
[48]Lallemand F, Felt-baeyens O, Besseghir K, et al.Cyclosporine a delivery to the eye:a pharmaceutical challenge.Eur J Pharm Bio.2003,56:307-318.
[49]费文雷,陈家祺,庞志清,等.FK506纳米粒对大鼠角膜移植排斥反应的影响.眼科研究.2006,24：156-159.
[50]费文雷,陈家祺,钟诗龙,等.FK506及其纳米粒的房水药代动力学的实验研究.中华眼科杂志.2006,42：305-308.
[51]平其能.纳米药物和纳米载体系统.中国新药杂志.2002,11(1)：42-46.
[52]张晓佳,梁慷,卞春及,等.维甲酸纳米粒混悬剂预防实验性增生性玻璃体视网膜病变.眼科研究.2005,23：34-36.
[53]栾洁,张瑞,夏强,等.维甲酸纳米粒的视网膜毒性实验研究.眼科新进展.2003,23(5)：314-315.
[54]王梓,栾洁,李长生,等.维甲酸纳米粒滴眼液抑制后发性白内障的实验研究.东南大学学报(医学版).2005,24：147-150.
[55]Cavalli R, Gasco MR, Chetoni P, et al.Solid lipid nanoparticles (SLN)as ocular delivery system for tobramycin. Int J Pharm.2002,238:241-245.
[56]李剑波,魏锐利.加替沙星-羧甲基壳聚糖纳米粒的制备及其兔眼局部应用研究.第二军医大学.2007年硕士学位论文.
[57]Fresta M, Fontana G, Bucolo C, et al.Ocular tolerability and in vivo bio-availability of poly-(ethylene glycol)(PEG)-coated polyethyl-2-cyanoacrylate nanosphere-encapsulated acyclovir. J Pharm Sci.2001,90:288.
[58]Veloso AAS,Zhu Q, Herrero-Vanrell R, et al.Ganciclovir-loaded polymer microspheres in rabbit eyes inoculated with human cytomegalovirus. Invest Ophthal Vis Sci.1999,38:665.
[59]Merodio M, Irachea JM, Valamaneshb F, et al.Ocular disposition and tolerance of ganciclovir-loaded alhumin nanoparticles after intravitreal injection in rats. Biomaterials.2002,23;1587-1594.
[60]Sharma D, Chelvi TP, Kaur J, et al.Novel Taxol formulation:polyvinyl plyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy. Oncol Res.1996,8:282-286.
[61]杨凯,温玉明,李龙江,等.颈淋巴结靶向葫芦素BE聚乳酸纳米微粒冻干针 剂的研制.华西口腔医学杂志.2001,19：347-350.
[62]杨凯,温玉明,李龙江,等.颈淋巴结靶向葫芦素BE聚乳酸纳米微粒的急性毒性和局部刺激实验研究.华西口腔医学杂志.2001,19：380-382.
[63]常津.阿霉素免疫磁性毫微粒的体内磁靶向定位研究[J].中国生物医学工程学报.1996,15：216-221.
[64]Chiannilkulchai N,Driouich Z, Benoit JP,et al.Doxorubicin-loaded nanoparticles:increased efficiency in murine hepatic metastases.Sel Cancer Ther. 1989,5:1-11.
[65]Llobet MI, Egea MA, Valero J, et al. Methotrexate-loaded nanoparticles:analysis of drug content and study of the matrix structure. Drug development and industrial pharmacy.1995,21:1761-1771.
[66]Maincent P, Le Verge R, Couvreur P, et al.Disposition kinetics and oral bioavailability of vincamine-loaded polyalkylcyanoacrylate nanoparticles.J Pharm Sci.1986,75:955-958.
[67]Freitas RA.Exploratory design in medical nanotechnology:a mechanical artificial red cell.Artif Cell Blood Substit Immobil Biotechnol,1998,26:411-430.
[68]Ellis-Behnke RG, Liang YX, You SW, et al.Nano neuro knitting:Peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision. Proc Natl Acad Sci USA.2006,103:5054-5059.
[69]Seisuke K. Application of hydroxyapatite-solas drug carrier. Bio Med Mater and Eng.1994,4:283-290.
[70]姚晓明,邓宏伟,李玉宝,等.多孔纳米羟基磷灰石-聚乙烯醇水凝胶人工角膜的实验研究.中国实用眼科杂志.2004,22：667-669.
[71]许凤兰,李玉宝,姚晓明,等.纳米羟基磷灰石／聚乙烯醇复合人工角膜材料.复合材料学报.2005,22：27-31.
[72]Bourlais CL. Ophthalmic drug delivery systems-recent advances. Prog Retin Eye Res.1998,17:33-58.
[73]McNamara NA. Tear mixing under a soft contact lens:effects of lens diameter. Am J Ophthalmol.1999,127:659-665.
[74]Anderson SA, Rader RK, Westlin WF, et al.Magnetic resonance contrast enhancement of neovasculature with alpha(v)beta(3)-targeted nanoparticles.Magn Reson Med.2000,44:433-439.
[75]Krause M, Kwong KK, Xion J, et al.MRI of blood volume and cellular up take of super paramagnetic iron in animal model of choroidal melanoma. Ophthalmic Res. 2002,34:241-250.
[76]Davis PB,Cooper MJ.Vectors for airway gene delivery. The AAPS Journal. 2007,9:11-17.
[77]Jackson DA, Juranek S,Lipps HJ.Designing nonviral vectors for efficient gene transfer and long-term gene expression. Molecular Therapy.2006,14:613-626.
[78]Thomas CE, Ehrhardt A, Kay MA.Progress and problems with the use of viral vectors for gene therapy. Nature Reviews Genetics.2003,4:346-358.。
[79]Andrieu-Soler C, Bejjani RA,de Bizemont T, et al.Ocular gene therapy:A review of nonviral strategies. Molecular Vision.2006,12:1334-1347.
[80]Hayes ME, Drummond DC, Kirpotin DB, et al.Genospheres:Self-assembling nucleic acid-lipid nanoparticles suitable for targeted gene delivery. Gene Therapy. 2006,13:646-651.
[81]Cai X, Conley S,Naash M. Nanoparticle applications in ocular gene therapy. Vision Research.2008,48:319-324.
[82]Lee D, Zhang W,Shirley SA, et al.Thiolated chitosan/DNA nanocomplexes exhibit enhanced and sustained gene delivery. Pharmaceutical Research.2007,24: 157-167.
[83]Zhang Y, Zhang Y, Chen J, et al.Polybutylcyanoacrylate nanoparticles as novel vectors in cancer gene therapy. Nanomedicine.2007,3:144-153.
[84]Ziady AG, Gedeon CR, Miller T, et al.Transfection of airway epithelium by stable PEGylated poly-L-lysineDNAnanoparticles invivo.Molecular Therapy.2003,8: 936-947.
[85]Bondi ML, Azzolina A, Craparo EF, et al.Novel cationic solid-lipid nanoparticles as non-viral vectors for gene delivery. Journal of Drug Targeting.2007, 15:295-301.
[86]Walsh M, Tangney M, O'Neill MJ, et al.Evaluation of cellular uptake and gene transfer efficiency of pegylated poly-L-lysine compacted DNA:Implications for cancer gene therapy. Molecular Pharmacology.2006,3:644-653.
[87]Harush-Frenkel O, Debotton N, Benita S,et al.Targeting of nanoparticles to the clathrin-mediated endocytic pathway. Biochemical and Biophysical Research Communications.2007,353:26-32.
[88]Liu G,Li D, Pasumarthy MK, et al.Nanoparticles of compacted DNA transfect postmitotic cells. The Journal of Biological Chemistry.2003,278;32578-32586.
[89]Yurek DM, Fletcher-Turner A, Cooper MJ.Comepacted DNA nanoparticles effectively transfect brain cells in vitro and in vivio.Molecular Therapy.2005,11:253.
[90]Guo P. RNA nanotechnology:Engineering, assembly and applications in detection, gene delivery and therapy. Journal of Nanoscience and Nanotechnology. 2005,5:1964-1982.
[91]Sesenoglu-Laird O, Svenson AG, Tyr O, et al.Nuclease stability of siRNA and DNA condensed with PEGylated polylysine. Molecular Therapy.2007,15:S200.
[92]Chavany C, Le Doan T, Convreur P, et al.Plyalkylcyanoacrylate nanoparticles as polymeric carriers for antisense oligonucleotides [J].Pharm Res.1992,9:441-449.
[93]Chavany C, Saison BT, Le DT, et al.Absorption of oligonucleotides onto polyisohexylcyanoacrylate nanoparticles protects them against nucleases and increases their cellular uptake [J].Pharm Res.1996,11:1370-1378.
[94]Fink TL, Klepcyk PJ, Oette SM, et al.Plasmid size up to 20 kbp does not limit effective in vivo lung gene transfer using compacted DNA nanoparticles.Gene Therapy.2006,13:1048-1051.
[95]Farjo R, Skaggs J, Quiambao AB,et al.Efficient non-viral ocular gene transfer with compacted DNA nanoparticles.PLoS ONE.2006,1:e38.
[96]Konstan MW, Davis PB, Wagener JS,et al.Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Human Gene Therapy.2004,15:1255-1269.
[97]Li SD, Huang L. Surface-modified LPD nanoparticles for tumor targeting. Annals of the New York Academy of Sciences.2006,1082:1-8.
[98]Peeters L, Sanders N, Braeckmans K, et al.Vitreous:A barrier to nonviral ocular gene therapy. Invest Ophthalmol Vis Sci.2005,46:3553-3561.
[99]Bejjani RA, BenEzra D, Cohen H, et al.Targeted non-viral gene transfer into RPE cells.Invest Ophthalmol Vis Sci.2003,44:2333.
[100]Hood JD, Bedna, Frausto R, el al.Tumor regression by targeted gene delivery to the neovasculature[J].Science.2002,296(5577):2404-2407.
[101]Reynolds AR, Moein MS, Hodivala DK. Nanoparticle-mediated gene delivery to tumor neovasculature. Trends Mol Med.2003,9:2-4.
[102]Ito A,Shinkai M,Honda H, et al.Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy[J].Cancer Gene Ther.2001,8(9):649-654.
[103]Costas M, Edwin K, Wei XB, et al.Selective cell targeting with light-absorbing microparticles and nanoparticles.Biophy J.2003,84:4023-4032.
[104]Yesin KB,Karl Vollmers, Bradley J, et al.Modeling and control of untethered biomicrorobots in a fluidic environment using electromagnetic fields.Inter J Robot Res.2006,25:527-536.
[105]Gourley PL. Brief overview of bio micro nanotechnologies.Biotechnol Prog. 2005,21:2-10.
[106]Orosz KE, Gupta S,Hassink M, et al.Delivery of antiangiogenic and antioxidant drugs of ophthalmic interest through a nanoporous inorganic filter. Mol Vis.2004,10:555-565.
[107]Nanotechnology in ocular drug delivery. Drug discovery today.2008,13:144-151.
[2]林婷婷,何彦滓,张虹,等.眼眶腺样囊性癌的治疗与预后分析[J].中华眼科杂志,2009,45(4)：309-313.
[3]Brem H, Gabikian P. Biodegradable polymer implants to treat brain tumors[J].J Controlled Release,2001,74:63-67.
[4]Engelhard HH.The role of interstitial BCNU chemotherapy in the treatment of malignant glioma[J].Surg Neurol,2000,53:458-64.
[5]Harper E, Dang W,Lapidus RG, et al.Enhanced efficacy of a novel controlled release paclitaxel formulation (PACLIMER delivery system) for local-regional therapy of lung cancer tumor nodules in mice[J].Clin Cancer Res,1999,5:4242-4248.
[6]Low PS,Antony AC.Folate receptor-targeted drugs for cancer and in flammatory diseases[J].Adv Drug Deliv Rev,2004,56:1055-1058.
[7]Leamon CP, Reddy JA. Folate-targeted chemotherapy[J].Adv Drug Deliv Rev, 2004,56:1127-1141.
[8]Wang S,Lee RJ, Cauchon G, et al.Delivery of antisense oligodeoxyribo-nucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol[J].Proc Natl Acad Sci USA,1995,92:3312-3318.
[9]Yoo HS,Park TG. Folate receptor targeted biodegradable polymeric doxorubicin micelles[J].Controlled Release,2004,96(2):273-283.
[10]Ni S,Stephenson SM, Lee RJ.Folate receptor targeted delivery of liposomal daunorubicin into tumor cells[J].Anticancer Res,2002,22:2131-2135.
[11]Park EK, Lee SB,Lee YM.Preparation and characterization of methoxy poly (ethylene glycol)/poly(s-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folat-mediated targeting of anticancer drugs[J].Biomaterials, 2005,26(9):1053-1061.
[12]张良珂,侯世祥,毛声俊,等,受体介导米托蒽醌白蛋白纳米粒肿瘤细胞靶向性研究[J].四川大学学报(医学版),2006,37(1)：77-79.
[13]Seigel GM, Campbell LM, Narayan M, et al. Evidence for cancer stem cells in retinoblastoma[J].Mol Vis,2005,11:729-732.
[14]刘斌,李永平,彭展.人眼脉络膜黑色素瘤OCM-1细胞中肿瘤干细胞的分离纯化[J].中华眼底病杂志,2007,23：87-90.
[15]Guo W, Lasky JL, Wu H.Cancer Stem Cells [J].Pediatr Res,2006,59:59-64.
[16]Galmozzi E, Facchetti F, La Porta C A. Cancer stem cells and therapeutic perspectives[J].Curr Med Chem,2006,13(6):603-607.
[17]温玉明,刘坤,华成舸,等.腺样囊性癌细胞系中肿瘤干细胞的生物学特性初探[J].中国口腔颌面外科杂志,2006,4：289-294.
[18]Liu K, Hua CG, Wen YM, et al.Cancer stem cells:its existence, proliferation and differentiation in an adenoid cystic carcinoma cell line[J].Zhonghua Kou Qiang Yi Xue Za Zhi,2007,42:284-287.
[19]关晓峰,杨捷琳,朱乃硕,等,腺样囊性癌高、低转移细胞株基因表达谱差异性及转移相关基因研究[J].中华口腔医学杂志,2004,39：118-121.
[20]韩媛媛.局部应用化疗药物治疗眼眶腺样囊性癌的实验研究[D].天津：天津医科大学,2006.
[21]Fordice J, Kershaw C, El-Naggar A, et al.Adenoid cystic carcinoma of the head and neck; predictors of morbidity and mortality[J].Arch Otolaryngol Head Neck Surg, 1999,125:149-152.
[22]郑刚,郭传瑸,俞光岩,等.腺样囊性癌患者生存预测模型的建立[J].中华口腔医学杂志,2006,41：350-353.
[23]Ben Simon GJ, Schwarcz RM, Douglas R, et al.Orbital exenteration:one size does not fit all[J].Am J Ophthalmol,2005,139:11-17.
[24]Gurney TA, Eisele DW, Weinberg V, et al.Adenoid cystic carcinoma of the major salivary glands treated with surgery and radiation[J].Laryngoscope,2005, 115:1278-1282.
[25]Khafif A, Anavi Y, Haviv J, et al. Adenoid cystic carcinoma of the salivary glands:a 20-year review with long-term follow-up[J].Ear Nose Throat J,2005, 84:662,664-667.
[26]Kawaguchi O, Kunieda E, Fujii H, et al.Adenoid cystic carcinoma with hyperostosis after stereotactic radiosurgery[J].Radiat Med,2004,22:198-200.
[27]徐德生,贾强,郑立高,等.眶内及眶颅沟通性肿瘤的伽玛刀放射治疗[J].立体定向和功能性神经外科杂志,2005,18：43-45.
[28]彭诚,邓嘉胤,王东,等.放射性核素1251粒子植入治疗晚期腺样囊性癌[J]. 中华口腔医学研究杂志(电子版),2008,2：270-276.
[29]Meldrum ML, Tse DT, Benedetto P. Neoadjuvant intracarotid chemotherapy for treatment of advanced adenocystic carcinoma of the lacrimal gland[J].Arch Ophthalmol,1998,116:315-321.
[30]Sun CX, He RG, Cheung LK. The biological behaviour of human adenoid cystic carcinoma cells transduced with interleukin-2-gene[J].Int J Oral Maxillofac Surg, 2002,31:650-656.
[31]Guan X, Qiu w, He R, et al.Selection of adenoid cystic carcinoma cell clone highly metastatic to the lung:an experimental study[J].Inter J Oral Maxi Surg,1997, 26:116-119.
[32]杨捷琳,朱乃硕,王颖,等.涎腺腺样囊性癌高低转移细胞系mRNA及蛋白质表达谱差异研究[J].生物化学与生物物理进展,2004,31：313-321.
[33]臧光祥,孙宏晨,穆亚冰,等.腺病毒介导的TRAIL基因诱导腺样囊性癌细胞凋亡研究[J].实用口腔医学杂志,2008,24：37-40.
[34]李亚娟,周洪澜,葛岩,等.槲寄生碱对腺样囊性癌细胞的抑制作用[J].吉林大学学报(医学版),2008,34：601-604,729-730.
[35]董青,杨湲波,王琳,等.紫杉醇联合肿瘤坏死因子α对腺样囊性癌细胞的抑制作用[J].军医进修学院学报,2008,29：265-267.
[36]Maclaughlin FC, Mumper RJ, Wanf J, et al.Chitosan and depolymerized chiton as condensing carriers for in vivo plasmid delivery[J].J Control Rel,1998,56: 259-272.
[37]Hermanson GT. Bioconjugate techniques[J].New York:Academic Press,1996, 56-60.
[38]赵硕,常津,卢剑.载药纳米微粒制备技术[J].化学通报,2002,65(93)：3-5.
[39]胡云霞,原续波,张晓金,等.聚乳酸载药纳米微粒的表面修饰及体外评价[J].中国生物医学工程学报,2004,23(1)：30-36.
[40]Kumar M. Nano and microparticles as controlled drug delivery devices[J].J Pharm Sci,2000,3:234-258.
[41]Berkland C, Kipper M. J, Narasimhan B, Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres[J].Journal of Controlled Release,2004,94(1):129-141.
[42]Liu J, Meisner D, Wu XY, et al.A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA-paclitaxel microspheres[J]. Biomaterials,2007,28(21):3236-3244.
[43]Lambert G, Fattal E.Nanoparticulate system for the delivery of antisense oligonucleotides[J].Advanced Drug Delivery Reiew,2001,47(1):99-112.
[44]Fonseca C, Simoes S,Gaspar R. Paclitaxel-loaded PLGA nanoparticles: preparation, physicochemical characterization and in vitro anti-tumoral activity[J]. Journal of Controlled Release,2002,83(2):273-286.
[45]Mu L, Fellg SS.A novel controlled release formulation for the anticancer drug paclitaxel(Taxol):PLGA nanopartlcles containing vitamin ETPGS[J].Control Release,2003,86:33-48.
[46]欧敬民,张一楚.叶酸与肿瘤发生[J].国外医学外科学分册,2002,29(2)：57-60.
[47]Ratnam M, Hao H, Zheng X, et al.Receptor induction and targeted drug delivery:a new antileukaemia strategy[J].Expert Biol Ther,2003,3:563-574.
[48]崔正刚,殷福珊.微乳化技术及应用[M].北京：中国轻工业出版社,2001：8-9.
[49]Gelse K, Aigner T. Development and characterization of PLGA nanospheres and nanocapsules[J].Advanced Drug Delivery Reviews,2003,55(10):1531-1546.
[50]Wang HT, Schmitt E, Flanagan FR, et al.Influence of formulation methods on the in vitro controlled release of protein from Poly(ester)microspheres[J].J Control Release,1991,17(1):23-32.
[51]宋国祥,吴中耀.眼眶病学[M].北京：人民卫生出版社,1999：235-239.
[52]Linda M. Pilarski,Michael D.Mehta,Timothy Caulfield.Microsystems and Nanoscience for Biomedic al plications:A View to the Future[J].Bulletin of Science, Technology & Society,2004,24(1):40-45.
[53]秦建民,张阳德.纳米药物在疾病治疗中的应用及其进展[J].中国现代医学杂志,2003,13(11)：19-53.
[54]Low PS, Antony AC.Folate receptor-targeted drugs for cancer and inflammatory diseases[J].Adv Drug Deliv Rev,2004,56 (8):1055-1058.
[55]Lu Y, Low PS.Folate-mediated delivery of macromolecular anticancer therapeutic agents[J].Adv Drug Deliv Rev,2002,54 (5):675-693.
[56]Leamon CP,Reddy JA.Folate-targeted chemotherapy[J].Adv Drug Deliv Rev, 2004,56:1127-1141.
[57]Wang S,Lee RJ, Cauchon G, et al.Delivery of antisense oligodeoxyribo-nucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol[J].Proc Natl Acad Sci USA,1995,92:3312-3318.
[58]Yoo HS,Park TG.Folate receptor targeted biodegradable polymeric doxorubicin micelles[J].Controlled Release,2004,96:273-283.
[59]Ni S,Stephenson SM, Lee RJ.Folate receptor targeted delivery of liposomal daunorubicin into tumor cells[J].Anticancer Res,2002,22:2131-2135.
[60]王元天,孙颖浩,邱镇.人类前列腺癌裸鼠原位移植模型的建立[J].中华泌尿外科杂志,2005,26(3)：208-209.
[61]Zimmer A, Kreuter J.Microspheres and nanoparticles used in ocular delivery systems[J].Adv Drug Deliv Rev,1995,16:61-73.
[62]Park EK, Lee SB,Lee YM. Preparation and characterization of methoxy poly(ethylene glycol)/poly(s-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folat-mediated targeting of anticancer drugs[J]. Biomaterials,2005,26:1053-1061.
[63]Kaul G, Amiji M. Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles:in vitro and in vivo studies[J].Pharm Res, 2005,22:951-961.
[64]李筱荣,刘新玲,常津,等.靶向5-氟尿嘧啶纳米微球对体外培养的人晶状体上皮细胞作用的研究[J].中华眼科杂志,2006,42：526-530.
[65]Pignatello R, Bucolo C, Spedalieri G,et al.Flurbipro-fen-loaded aerylate polymer nanosuspensions for ophthalmic application[J].Biomaterials,2002,23: 3247-3255.
[66]Calvo P, Vila-Jato JL, Alonso MJ. Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers[J].Int J Pharm,1997,153:41-50.
[67]Chouinard, M.L, Martin, et al.Pharmacokinetics and biochemical efficacy of pirmagrel, a thromboxane synthase inhibitor, in renal allograft recipients[J].Clinical Pharmacology and Therapeutics,1991,52:597-604.
[68]Saito N, MurakamiT N, Takahashi J, et al.Synthetic biodegradable polymers as drug delivery systems for bone morphogenetic proteins[J].Adv. Drug Deliv. Rev., 2005,57:1037-1048.
[69]Chu TC, He Q, David E.P. Biodegradable calcium phosphate nanoparticles as a new vehicle for delivery of a potential ocular hypotensive agent[J].J Ocul Pharmacol Ther,2002,18:507-514.
[70]Kompella UB, Bandi N, Ayalasomayajula SP. Subconjunctival nano-and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression[J].Invest Ophthalmol Vis Sci,2003,44:1192-1201.
[71]Lallemand F, Felt-baeyens O, Besseghir K, et al. Cyclosporine a delivery to the eye:a pharmaceutical challenge[J].Eur J Pharm Bio,2003,56:307-318.
[72]费文雷,陈家祺,庞志清,等.FK506纳米粒对大鼠角膜移植排斥反应的影响[J].眼科研究,2006,24：156-159.
[73]Cavalli R, Gasco MR, Chetoni P, et al.Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin[J].Int J Pharm,2002,238:241-245.
[74]Fresta M, Fontana G, Bucolo C, et al.Ocular tolerability and in vivo bioavailability of poly-(ethylene glycol)(PEG)-coated polyethyl-2-cyanoacrylate nanosphere-encapsulated acyclovir[J].J Pharm Sci,2001,90:288.
[75]Sharma D, Chelvi TP, Kaur J, et al.Novel Taxol formulation:polyvinyl plyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy[J]. Oncol Res,1996,8:282-286.
[76]Chiannilkulchai N, Driouich Z, Benoit JP,et al.Doxorubicin-loaded nanoparticles:increased efficiency in murine hepatic metastases[J].Sel Cancer Ther, 1989,5:1-11.
[77]Llobet MI, Egea MA, Valero J, et al.Methotrexate-loaded nanoparticles:analysis of drug content and study of the matrix structure[J].Drug development and industrial pharmacy,1995,21:1761-1771.
[78]Maincent P, Le Verge R, Couvreur P, et al.Disposition kinetics and oral bioavailability of vincamine-loaded polyalkylcyanoacrylate nanoparticles[J].J Pharm Sci,1986,75:955-958.
[79]Silverman D A, Carlson T P, Khuntia D, et al. Role for postoperative radiation therapy in adenoid cystic carcinoma of the head and neek[J].Laryngoseope,2004, 114:1194-1199.
[80]吴细丕,钱林法.实验动物与肿瘤研究[M].北京：中国医药科技大学出版社,2000：398.
[81]Shimizu M,Saitoh Y, Itoh H.Immunohistochemical staining of Ha-ras oncogene product in normal,benin,and malinant human pancrestic tissue [J].Hum Pat hol,1990,21(9):607-612.
[82]Guo W, Lasky JL, Wu H.Cancer Stem Cells[J].Pediatr Res,2006,59:59-64.
[83]Al-Hajj M, Wicha MS,Benito HA, Morrison SJ, Clarke MF.Prospective identification of tumorigenic breast cancer cells[J].Proc Natl Acad Sci USA,2003, 100:3983-3988.
[84]Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. Identification of a cancer stem cell in human brain tumors[J].Cancer Res,2003, 63:5821-5828.
[85]董强刚,姚明,耿沁,周瑾,闫明霞.人肺腺癌干细胞的分离及鉴定[J].肿瘤,2008,28：1-7.
[86]Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ.Prospective identification of tumorigenic prostate cancer stem cells[J].Cancer Res,2005, 65:10946-10951.
[87]Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V,Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells[J].J Surg Res,2006, 130:194-195.
[88]Yang YM, Chang JW. Bladder cancer initiating cells (BCICs) are among EMA-CD44v6+ subset:novel methods for isolating undetermined cancer stem (initiating) cells[J].Cancer Invest,2008,26(7):725-733.
[89]Seigel GM, Hackam AS,Ganguly A, Mandell LM, Gonzalez-Fernandez F. Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis,2007, 13:823-832.
[90]刘斌,李永平,彭展.人眼脉络膜黑色素瘤OCM-1细胞中肿瘤干细胞的分离纯化[J].中华眼底病杂志,2007,23：87-90.
[91]Lizuka N, Miyamoto K, Tangoku A, Hayashi H, Hazama S, Yoshino S, Yoshimura K, Hirose K, Yoshida H, Oka M.Downregulation of intracellular nm23-Hl prevents cisplatin-induced DNA damage in oesophageal cancer cells:possible association withNa(+),K(+)-ATPase[J].Br J Cancer.2000,83:1209-1215.
[92]Pries R, Witrkopf N, Trenkle T, Nitsch SM, Wollenberg B.Potential stem cell marker CD44 is constitutively expressed in permanent cell lines of head and neck cancer[J].In Vivo.2008,22:89-92.
[93]Roye GD, Myers RB, Brown D, et al. CD44v6 expression in dysplastic epithelium and squamous cell carcinoma of the esophagus[J].Int J Cancer,1996, 69:254-261.
[94]Pals ST, Horst E. Expression of lymphocyte homing receptor(CD44) as a mechanism of dissemination in non-Hodgkins lymphoma[J].Blood,1989,73(6): 885-893.
[95]Gotley DC, Fawcett J, Walsh MD, et al.Alternatively spliced variants of the cell adhesion molecule CD44 and tumor progression in Colorectal cancer[J].Br J Cancer, 1996,74(3):342-351.
[96]Herokd-Mende C, Seiter S,Born A I, et al.Expression of CD44 splice variants in squamous epithelia and squamous cell carcinoma of the head and neck[J].J Patho 1, 1996,179(1):66.
[97]Kunishi M, Kayada Y Down-regulated poor survival in squamous cell carcinoma of tongue[J].Oral Oncol,2000,36(6):545.
[98]Kanke M, Fujii M, Kameyama K, et al.Role of CD44 varriant exon 6 in invasion of head and neck squamons cell carcinoma[J].Arch Otolaryngol Head Neck Surg,2000,126(10):1217.
[99]Xing RD,Regezi J, Stern M, et al.Hyaluronan and CD44 expression in minor salivary gland tumors[J].Oral Dis,1998,4(4):241.
[100]李文,王昌美,温玉明,等.CD44v6在腺样囊性癌中的表达及临床意义[J].临床口腔医学杂志,2003,19(7)：407-408.
[101]陈伟军,王成,曾亮.COX-2、CD44在腺样囊性癌中的表达及意义[J].中国现代医生,2009,47(16)：36-37.
[102]吴轶群,王英,张伟国,等.CD44s和CD44v6在涎腺腺样囊性癌中的表达[J].上海口腔医学,1999,8(3)：159-162.
[103]宋琦,陈芳,李萍,等.CD44、CD24、MMP9在涎腺腺样囊性癌的表达及意义[J].贵州医药,2009,33(9)：782-783.
[104]Gunthert U.CD44 in malignant disorders [J].Curr Top Microbio Immunol, 1996,213:271.
[105]温玉明,刘坤,华成舸,等.腺样囊性癌细胞系中肿瘤干细胞的生物学特性初探[J].中国口腔颌面外科杂志,2006,4：289-294.
[106]Liu K, Hua CG, Wen YM, Pan J, Chen SW, Gao QH.Cancer stem cells:its existence, proliferation and differentiation in an adenoid cystic carcinoma cell line[J]. Zhonghua Kou Qiang Yi Xue Za Zhi.2007,42:284-287.
[107]Ricci-Vitiani L, Lombardi DG,Pilozzi E,et al.Identification and expansion of human colon-cancer-initiating cells[J].Nature,2007,445(2007):111-115.
[108]O'Brien CA, Pollett A, Gallinger S,et al.A human colon cancer cell capable of initiating tumor growth in immunodeficient mice[J].Nature.2007,445(7123): 106-110.
[109]Zhou L, Wei X, Cheng L, et al.CD133,one of the markers of cancer stem cells inHep-2 cell line[J].Laryngoscope,2007,117(3):455-460.
[110]Ma S,Chan KW, Hu L, et al.Identification and characterization of tumorigenic liver cancer stem/progenitor cells[J].Gastroenterology,2007,132(7):2542-255.
[111]Griguer CE, Oliva CR, Gobin E, et al.CD133 is a marker of bioenergetic stress in human glioma[J].PloS ONE,2008,3(11):e3655.
[112]黄华兵.CD133在前列腺、前列腺增生及前列腺癌中的表达[D].江西：南昌大学,2007.
[113]Doyle L A, Yang W, Abruzzo L V, et al.A multidrug resistance transporter from human MCF-7 breast cancer cells[J].Proc Natl Acad Sci USA.1998,22;95(26): 15665-15670.
[114]Zhou S,Schuetz JD, Bunting KD,et al.The ABC transporter Bcrpl/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype[J].Nat Med,2001,7(9):1028-1034.
[115]Maliepaard M, Scheffer G L, Faneyte I F, et al.Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues[J].Cancer Res,2001,61(8):3458-3464.
[116]Diestra JE, Scheffer GL, Catala I, et al. Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material[J].J Pathol.2002, 198(2):213-9.
[117]储亮,黄强,翟德忠,等.ABCG2在胶质瘤组织中的表达及意义[J].癌症,2007,26(10)：1090-1094.
[118]陈芳,宋琦,李萍,等.ABCG2在腺样囊性癌的表达及意义[J].贵州医药,2008,32(6)：501-502.
[119]胡振宇.ABCG2、MCM2在涎腺发育及肿瘤发生干细胞表达中的关系[D].浙江：浙江大学,2007.
[120]Naylor CS,Jwaorska E, Branson K, et al.Side population/ABCG2-positive cells represent a heterogeneous group of haemopoietic cells:implications for the use of adult stem cells in transplantation and plastieity protocols[J].Bone Marrow Transplant,2005,35(4):353-60.
[121]刘继东.ABCG2、CD133在人脑胶质瘤中的表达及意义[D].云南：昆明医学院,2006.
[122]Monzania E, Facchett F, Galmozzi E. Melanoma contains CD133 and ABCG2 positive cells with enhanced tumorrigenic potential[J].Eur J Cancer,2007,43(5): 935-946.
[123]Dalerba P, Dylla SJ, Park IK, et al.Phenotypic characterization of human colorectal cancer stem cells[J].Proc Natl Acad Sci U S A,2007,104:10158-10163.
[124]Collins AT, Berry PA, Hyde C, et al.Prospective identification of tumorigenic prostate cancer stem cells[J].Cancer Res,2005,65(23):10946-10951.
[1]Siegel RW. Creating nanophase materials.Scj Am.1996,275:42-47.
[2]Kumar M. Nano and microparticles as controlled drug delivery devices. J Pharm Sci.2000,3:234-258.
[3]Pignatello R, Bucolo C, Puglisi G. Ocular tolerability of Eudragit RS100 and RL100 nanosuspensions as carriers for ophthalmic controlled drug delivery [J].J Pharm Sci.2002,91:2636-2641.
[4]黄潇,魏锐利.纳米技术在眼科基础研究中的应用.眼科新进展.2006,26：794-795.
[5]Lydataki S,Lesniewska E, Tsilimbaris MK, et al.Observation of the posterior endothelial surface of the rabbit cornea using atomic force microscopy. Cornea.2003, 22:651-664.
[6]姜涛,王德文,高亚兵,等.电磁脉冲对离体角膜上皮细胞损伤的实验研究.军事医学科学院院刊.2004,28：358-360.
[7]Goto E. Quantification of tear interference image:tear fluid surface nanotechnology. Cornea.2004,23:S20-S24.
[8]Sjostrand FS.Kuffler's inhibitory surround, the function of the inner plexiform layer and an information processing unit in the retina. Neural interaction at the nanometer level.J Submicrosc Cytol Pathol.2003,35:359-371.
[9]Teixeira AI, Abrams GA, Bertics PJ,et al.Epithelial contact guidance on well-defined micro and nanostructured substrates.J Cell Sci.2003,116:1881-1892.
[10]Karuri NW, Liliensiek S,Teixeira AI, et al.Biological length scale topography enhances cell-sustratum adhesion of human corneal epithelial cells. J Cell Sci.2004, 117:3153-3164.
[11]Karuri N, Nealey PF, Campbell S, et al.Fluid shear induced detachment of SV-40 corneal epithelial cells from planar and nano-structured substrates. Invest Ophthalmol Vis Sci.2002,43:1690.
[12]Anthony B, William R. Evolving and experimental technologies in medical imaging. Radiology.2006,238:16-39.
[13]Kokate A, Li X, Jasti BR, et al.Physiological and biochemical barriers to drug delivery. In Design of Controlled Release Drug Delivery Systems.2006,12:41-73.
[14]Ravivarapu H, Li X, Jasti BR, et al.Biodegradable polymeric delivery systems. In Design of Controlled Release Drug Delivery Systems.2006,12:271-303.
[15]Yasukawa T. Drug delivery systems for vitreoretinal diseases. Prog Retin Eye Res.2004,23:253-281.
[16]Wong CG. et al. Intravitreal VEGF and bFGF produce florid retinal neovascularization and hemorrhage in the rabbit. Curr Eye Res.2001,22:140-147.
[17]Zimmer A, Kreuter J. Microspheres and nanoparticles used in ocular delivery systems. Adv Drug Deliv Rev.1995,16:61-73.
[18]Bourges JL, Gautier SE, Delie F, et al.Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Ophthalmol Vis Sci.2003,44:3562-3569.
[19]Park EK, Lee SB,Lee YM.Preparation and characterization of methoxy poly(ethylene glycol)/poly(ε-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folat-mediated targeting of anticancer drugs. Biomaterials.2005,26:1053-1061.
[20]张良珂,侯世祥,毛声俊,等.受体介导米托葸醌白蛋白纳米粒肿瘤细胞靶向性研究.四川大学学报(医学版).2006,37：77-79.
[21]Kaul G, Amiji M.Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles:in vitro and in vivo studies.Pharm Res.2005, 22:951-961.
[22]李筱荣,刘新玲，常津,等.靶向5-氟尿嘧啶纳米微球对体外培养的人晶状体上皮细胞作用的研究.中华眼科杂志.2006,42：526-530.
[23]Zimmer A, Kreuter J, Robinson JR. Studies on the transport pathway of PBCA nanoparticles in ocular tissues.J Microencapsul.1991,8:497-504.
[24]Pilar C, Charles T, Maria J, et al.Study of the mechanism of interaction of poly (-caprolactone) nanocapsules with the cornea by confocal laser scanning microscopy. Int J Pharma.1994,103:283-291.
[25]Calvo P, Thomas C, Alonso MJ, et al.Study of the mechanism of interaction of poly(epsilon-caprolactone) nanocapsules with the cornea by confocal laser scanning microscopy. Int J Pharm.1994,103:283-291.
[26]De Campos AM, Sanchez A, Gref R, et al.The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa. Eur J Pharm Sci.2003,20:73.
[27]Le Bourlais CA, Chevanne F, Turlin B,et al.Effect of cyclosporine A formulations on bovine corneal absorption:ex-vivo study. J Microencapsul.1997,14: 457-467.
[28]Qaddoumi MG, Gukasyan HJ, Davda J, et al.Clathrin and caveolin-1 expression in primary pigmented rabbit conjunctival epithelia cells:role in PLGA nanoparticle endocytosis.Mol Vis.2003,15:559-568.
[29]Wood RW, Li VHK, Kreuter J, et al.Ocular disposition of polyhexyl-2-cyano [3-14C] acrylate nanoparticles in the albino rabbit. Int J Pharm.1985,23:175-183.
[30]Calvo P, Vila-Jato JL, Alonso MJ.Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers.Int J Pharm.1997,153:41-50.
[31]Giannavola C, Bucolo C, Paolino D, et al.Influence of preparation conditions on acyclovir-loaded poly-d,1-lactic acid nanospheres and effect of PEG coating on drug bioavailability. Pharm Res.2003,20:584-590.
[32]Aukunuru JV, Kompella UB, Delivery of nano-and micro-particles to human rentinal pigment epithelial(ARPE-19)cells.Drug Del Tech.2002,2:50.
[33]Bejjani RA, BenEzra D, Bourges JL. Phagocytosis of polylactides (PLA) nanoparticles by bovine and human RPE cells in vitro. Invest Ophthalmol Vis Sci. 2002,43:2295.
[34]李越,王雨生,宋存先,等.地塞米松-PLGA纳米粒兔眼玻璃体内注射的药 物代谢动力学.眼科新进展.2005,25：229-231.
[35]李筱荣,刘新玲,常津,等.靶向5-氟尿嘧啶纳米微球对体外培养的人晶状体上皮细胞作用的研究.中华眼科杂志.2006,42：526-530.
[36]Pignatello R, Bucolo C, Spedalieri G, et al.Flurbipro-fen-loaded aerylate polymer nanosuspensions for ophthalmic application. Biomaterials.2002,23:3247-3255.
[37]Gupta AK, Madan S,Majumdar DK, et al.Ketorolac entrapped in polymeric micelles:preparation, characterisation and ocular anti-inflammatory studies.Int J Pharm.2000,209:1-14.
[38]Marchal-Heussler L, Maincent P, Hoffman M, et al.Antiglaucomatous activity of hetaxolol chlorhydrate sorbed onto different isobutylcyanoacrylate nanoparticle preparations.Int J Pharm.1990,58:115-122.
[39]Hsiue GH, Hsu SH, Yang ChC, et al.Preparation of controlled release ophthalmic drops, for glaucoma therapy using thermosensitive poly-N-isoptopylaerylamide. Biomaterials.2002,23:457-462.
[40]Chu TC, He Q, David EP. Biodegradable calcium phosphate nanoparticles as a new vehicle for delivery of a potential ocular hypotensive agent. J Ocul Pharmacol Ther.2002,18:507-514.
[41]Chiang CH, Tung SM, Lu DW, et al.In vitro and vivo evaluation of an ocular delivery system of 5-fluorouracil microspheres[J].J Ocul Phama col Ther.2001.17(6): 545.
[42]Herrero-Vanrell R, Alvarez-Santiago C, Barcia E.Biodegradable microspheres loaded with dexamethasone for intravitreal administration.Invest Ophthalmol Vis Sci. 1999,40:84.
[43]Kompella UB,Bandi N, Ayalasomayajula SP. Subconjunctival nano-and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci.2003,44:1192-1201.
[44]Giannavola C, Bucolo C, Paolino D, et al.Influence of preparation conditions on acyclovir-loaded poly-d,1-lactic acid nanospheres and effect of PEG coating on drug bioavailability. Pharm Res.2003,20:584-590.
[45]Pignatello R, Bucolo C, Spedalieri G, et al.Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials.2002,23:3247-3255.
[46]Vega E, Gamisans F, Garcia ML, et al. PLGA nanospheres for the ocular delivery of flurbiprofen:drug release and ineractions. Journal of Pharmaceutical Sciences. 2008,97:5306-5317.
[47]De Campos AM, Sanchez A, Alonso MJ.Chitosan nanoparticles:a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporine A. Int J Pharm.2001,224:159.
[48]Lallemand F, Felt-baeyens O, Besseghir K, et al.Cyclosporine a delivery to the eye:a pharmaceutical challenge.Eur J Pharm Bio.2003,56:307-318.
[49]费文雷,陈家祺,庞志清,等.FK506纳米粒对大鼠角膜移植排斥反应的影响.眼科研究.2006,24：156-159.
[50]费文雷,陈家祺,钟诗龙,等.FK506及其纳米粒的房水药代动力学的实验研究.中华眼科杂志.2006,42：305-308.
[51]平其能.纳米药物和纳米载体系统.中国新药杂志.2002,11(1)：42-46.
[52]张晓佳,梁慷,卞春及,等.维甲酸纳米粒混悬剂预防实验性增生性玻璃体视网膜病变.眼科研究.2005,23：34-36.
[53]栾洁,张瑞,夏强,等.维甲酸纳米粒的视网膜毒性实验研究.眼科新进展.2003,23(5)：314-315.
[54]王梓,栾洁,李长生,等.维甲酸纳米粒滴眼液抑制后发性白内障的实验研究.东南大学学报(医学版).2005,24：147-150.
[55]Cavalli R, Gasco MR, Chetoni P, et al.Solid lipid nanoparticles (SLN)as ocular delivery system for tobramycin. Int J Pharm.2002,238:241-245.
[56]李剑波,魏锐利.加替沙星-羧甲基壳聚糖纳米粒的制备及其兔眼局部应用研究.第二军医大学.2007年硕士学位论文.
[57]Fresta M, Fontana G, Bucolo C, et al.Ocular tolerability and in vivo bio-availability of poly-(ethylene glycol)(PEG)-coated polyethyl-2-cyanoacrylate nanosphere-encapsulated acyclovir. J Pharm Sci.2001,90:288.
[58]Veloso AAS,Zhu Q, Herrero-Vanrell R, et al.Ganciclovir-loaded polymer microspheres in rabbit eyes inoculated with human cytomegalovirus. Invest Ophthal Vis Sci.1999,38:665.
[59]Merodio M, Irachea JM, Valamaneshb F, et al.Ocular disposition and tolerance of ganciclovir-loaded alhumin nanoparticles after intravitreal injection in rats. Biomaterials.2002,23;1587-1594.
[60]Sharma D, Chelvi TP, Kaur J, et al.Novel Taxol formulation:polyvinyl plyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy. Oncol Res.1996,8:282-286.
[61]杨凯,温玉明,李龙江,等.颈淋巴结靶向葫芦素BE聚乳酸纳米微粒冻干针 剂的研制.华西口腔医学杂志.2001,19：347-350.
[62]杨凯,温玉明,李龙江,等.颈淋巴结靶向葫芦素BE聚乳酸纳米微粒的急性毒性和局部刺激实验研究.华西口腔医学杂志.2001,19：380-382.
[63]常津.阿霉素免疫磁性毫微粒的体内磁靶向定位研究[J].中国生物医学工程学报.1996,15：216-221.
[64]Chiannilkulchai N,Driouich Z, Benoit JP,et al.Doxorubicin-loaded nanoparticles:increased efficiency in murine hepatic metastases.Sel Cancer Ther. 1989,5:1-11.
[65]Llobet MI, Egea MA, Valero J, et al. Methotrexate-loaded nanoparticles:analysis of drug content and study of the matrix structure. Drug development and industrial pharmacy.1995,21:1761-1771.
[66]Maincent P, Le Verge R, Couvreur P, et al.Disposition kinetics and oral bioavailability of vincamine-loaded polyalkylcyanoacrylate nanoparticles.J Pharm Sci.1986,75:955-958.
[67]Freitas RA.Exploratory design in medical nanotechnology:a mechanical artificial red cell.Artif Cell Blood Substit Immobil Biotechnol,1998,26:411-430.
[68]Ellis-Behnke RG, Liang YX, You SW, et al.Nano neuro knitting:Peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision. Proc Natl Acad Sci USA.2006,103:5054-5059.
[69]Seisuke K. Application of hydroxyapatite-solas drug carrier. Bio Med Mater and Eng.1994,4:283-290.
[70]姚晓明,邓宏伟,李玉宝,等.多孔纳米羟基磷灰石-聚乙烯醇水凝胶人工角膜的实验研究.中国实用眼科杂志.2004,22：667-669.
[71]许凤兰,李玉宝,姚晓明,等.纳米羟基磷灰石／聚乙烯醇复合人工角膜材料.复合材料学报.2005,22：27-31.
[72]Bourlais CL. Ophthalmic drug delivery systems-recent advances. Prog Retin Eye Res.1998,17:33-58.
[73]McNamara NA. Tear mixing under a soft contact lens:effects of lens diameter. Am J Ophthalmol.1999,127:659-665.
[74]Anderson SA, Rader RK, Westlin WF, et al.Magnetic resonance contrast enhancement of neovasculature with alpha(v)beta(3)-targeted nanoparticles.Magn Reson Med.2000,44:433-439.
[75]Krause M, Kwong KK, Xion J, et al.MRI of blood volume and cellular up take of super paramagnetic iron in animal model of choroidal melanoma. Ophthalmic Res. 2002,34:241-250.
[76]Davis PB,Cooper MJ.Vectors for airway gene delivery. The AAPS Journal. 2007,9:11-17.
[77]Jackson DA, Juranek S,Lipps HJ.Designing nonviral vectors for efficient gene transfer and long-term gene expression. Molecular Therapy.2006,14:613-626.
[78]Thomas CE, Ehrhardt A, Kay MA.Progress and problems with the use of viral vectors for gene therapy. Nature Reviews Genetics.2003,4:346-358.。
[79]Andrieu-Soler C, Bejjani RA,de Bizemont T, et al.Ocular gene therapy:A review of nonviral strategies. Molecular Vision.2006,12:1334-1347.
[80]Hayes ME, Drummond DC, Kirpotin DB, et al.Genospheres:Self-assembling nucleic acid-lipid nanoparticles suitable for targeted gene delivery. Gene Therapy. 2006,13:646-651.
[81]Cai X, Conley S,Naash M. Nanoparticle applications in ocular gene therapy. Vision Research.2008,48:319-324.
[82]Lee D, Zhang W,Shirley SA, et al.Thiolated chitosan/DNA nanocomplexes exhibit enhanced and sustained gene delivery. Pharmaceutical Research.2007,24: 157-167.
[83]Zhang Y, Zhang Y, Chen J, et al.Polybutylcyanoacrylate nanoparticles as novel vectors in cancer gene therapy. Nanomedicine.2007,3:144-153.
[84]Ziady AG, Gedeon CR, Miller T, et al.Transfection of airway epithelium by stable PEGylated poly-L-lysineDNAnanoparticles invivo.Molecular Therapy.2003,8: 936-947.
[85]Bondi ML, Azzolina A, Craparo EF, et al.Novel cationic solid-lipid nanoparticles as non-viral vectors for gene delivery. Journal of Drug Targeting.2007, 15:295-301.
[86]Walsh M, Tangney M, O'Neill MJ, et al.Evaluation of cellular uptake and gene transfer efficiency of pegylated poly-L-lysine compacted DNA:Implications for cancer gene therapy. Molecular Pharmacology.2006,3:644-653.
[87]Harush-Frenkel O, Debotton N, Benita S,et al.Targeting of nanoparticles to the clathrin-mediated endocytic pathway. Biochemical and Biophysical Research Communications.2007,353:26-32.
[88]Liu G,Li D, Pasumarthy MK, et al.Nanoparticles of compacted DNA transfect postmitotic cells. The Journal of Biological Chemistry.2003,278;32578-32586.
[89]Yurek DM, Fletcher-Turner A, Cooper MJ.Comepacted DNA nanoparticles effectively transfect brain cells in vitro and in vivio.Molecular Therapy.2005,11:253.
[90]Guo P. RNA nanotechnology:Engineering, assembly and applications in detection, gene delivery and therapy. Journal of Nanoscience and Nanotechnology. 2005,5:1964-1982.
[91]Sesenoglu-Laird O, Svenson AG, Tyr O, et al.Nuclease stability of siRNA and DNA condensed with PEGylated polylysine. Molecular Therapy.2007,15:S200.
[92]Chavany C, Le Doan T, Convreur P, et al.Plyalkylcyanoacrylate nanoparticles as polymeric carriers for antisense oligonucleotides [J].Pharm Res.1992,9:441-449.
[93]Chavany C, Saison BT, Le DT, et al.Absorption of oligonucleotides onto polyisohexylcyanoacrylate nanoparticles protects them against nucleases and increases their cellular uptake [J].Pharm Res.1996,11:1370-1378.
[94]Fink TL, Klepcyk PJ, Oette SM, et al.Plasmid size up to 20 kbp does not limit effective in vivo lung gene transfer using compacted DNA nanoparticles.Gene Therapy.2006,13:1048-1051.
[95]Farjo R, Skaggs J, Quiambao AB,et al.Efficient non-viral ocular gene transfer with compacted DNA nanoparticles.PLoS ONE.2006,1:e38.
[96]Konstan MW, Davis PB, Wagener JS,et al.Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Human Gene Therapy.2004,15:1255-1269.
[97]Li SD, Huang L. Surface-modified LPD nanoparticles for tumor targeting. Annals of the New York Academy of Sciences.2006,1082:1-8.
[98]Peeters L, Sanders N, Braeckmans K, et al.Vitreous:A barrier to nonviral ocular gene therapy. Invest Ophthalmol Vis Sci.2005,46:3553-3561.
[99]Bejjani RA, BenEzra D, Cohen H, et al.Targeted non-viral gene transfer into RPE cells.Invest Ophthalmol Vis Sci.2003,44:2333.
[100]Hood JD, Bedna, Frausto R, el al.Tumor regression by targeted gene delivery to the neovasculature[J].Science.2002,296(5577):2404-2407.
[101]Reynolds AR, Moein MS, Hodivala DK. Nanoparticle-mediated gene delivery to tumor neovasculature. Trends Mol Med.2003,9:2-4.
[102]Ito A,Shinkai M,Honda H, et al.Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy[J].Cancer Gene Ther.2001,8(9):649-654.
[103]Costas M, Edwin K, Wei XB, et al.Selective cell targeting with light-absorbing microparticles and nanoparticles.Biophy J.2003,84:4023-4032.
[104]Yesin KB,Karl Vollmers, Bradley J, et al.Modeling and control of untethered biomicrorobots in a fluidic environment using electromagnetic fields.Inter J Robot Res.2006,25:527-536.
[105]Gourley PL. Brief overview of bio micro nanotechnologies.Biotechnol Prog. 2005,21:2-10.
[106]Orosz KE, Gupta S,Hassink M, et al.Delivery of antiangiogenic and antioxidant drugs of ophthalmic interest through a nanoporous inorganic filter. Mol Vis.2004,10:555-565.
[107]Nanotechnology in ocular drug delivery. Drug discovery today.2008,13:144-151.
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