Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target ...Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.展开更多
目的研究在外加磁场作用下^(131)I-VEGF si RNA/SPIO在人肝细胞癌移植瘤裸鼠体内的血液清除动力学及生物分布特性。方法以Bolton-Hunter法使VEGF si RNA标记上^(131)I,以氧化铁超顺磁性纳米颗粒(superparamagneticiron oxide nanopartic...目的研究在外加磁场作用下^(131)I-VEGF si RNA/SPIO在人肝细胞癌移植瘤裸鼠体内的血液清除动力学及生物分布特性。方法以Bolton-Hunter法使VEGF si RNA标记上^(131)I,以氧化铁超顺磁性纳米颗粒(superparamagneticiron oxide nanoparticles,SPIO)包裹^(131)I-VEGF si RNA。以人肝细胞癌细胞株Hep G2细胞悬液臀部皮下注射建立人肝细胞癌移植瘤裸鼠模型。45只人肝细胞癌移植瘤裸鼠随机分成外加磁场组(尾静脉注射^(131)I-VEGF si RNA/SPIO+肿瘤部位外加磁场)、非外加磁场组(尾静脉注射^(131)I-VEGF si RNA/SPIO+肿瘤部位无外加磁场)及对照组(尾静脉注射^(131)I-VEGF si RNA+肿瘤部位无外加磁场)。然后进行:(1)血液清除动力学研究:三组人肝细胞癌移植瘤裸鼠(每组5只)尾静脉给药后,分别于0.5 h、1.0 h、1.5 h、2.0 h、3.0 h、4.0 h、6.0 h、8.0 h、10.0 h、12.0 h时间点尾静脉采血20μL,测量血样每分钟放射性计数(counts per minute,cpm)值并绘制放射性-时间曲线,计算血液半衰期;(2)体内生物分布研究:三组人肝细胞癌移植瘤裸鼠尾静脉给药1 h后进行SPECT显像(每组5只)及MRI显像(每组5只),SPECT及MRI显像完毕,依次摘取移植瘤裸鼠肿瘤、皮肤、肌肉、骨、甲状腺、胃、小肠、大肠、肺、脾、性腺、肝、心、肾、膀胱等脏器称重并测量cpm值,然后计算各离体组织的%ID/g[即组织的放射性比活度(cpm/g)/注入标记物的放射性比活度(cpm/g)]。结果本研究分别以薄层层析硅胶板为载体、1∶1丙酮-生理盐水为展开剂和以新华一号滤纸为载体、1∶1甲醇-5%醋酸铵为展开剂测定^(131)I标记VEGF si RNA的放化纯分别为81.15%和84.05%。外加磁场组、非外加磁场组及对照组移植瘤裸鼠的血液半衰期分别约为(2.27±0.14)h、(2.93±0.20)h和(3.06±0.23)h,外加磁场组半衰期小于其它两组(差异有统计学意义,P<0.01)。SPECT显像显示外加磁场组肿瘤局部明显放射性增浓,非外加磁场组及对照组肿瘤局部未见明显放射性增浓;尾静脉给药前后MRI T1WI显示外加磁场组肿瘤局部信号明显强化,非外加磁场组及对照组肿瘤局部信号未见明显强化;外加磁场组肿瘤组织的%ID/g分布较非外加磁场组及对照组的均明显增高(P<0.01)。结论在外加磁场的作用下,以SPIO作为si RNA载体能够较成功地将^(131)I-VEGF si RNA转导至人肝细胞癌移植瘤裸鼠臀部皮下的肿瘤部位,对进一步研究肝细胞癌的VEGF靶向治疗、基因治疗以及示踪体内基因转导均有重要的意义。展开更多
基金supported by Guangdong Basic and Applied Basic Research Foundation(2023A1515010969)Natural Science Foundation of Top Talent of SZTU(GDRC202305).
文摘Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.
文摘目的研究在外加磁场作用下^(131)I-VEGF si RNA/SPIO在人肝细胞癌移植瘤裸鼠体内的血液清除动力学及生物分布特性。方法以Bolton-Hunter法使VEGF si RNA标记上^(131)I,以氧化铁超顺磁性纳米颗粒(superparamagneticiron oxide nanoparticles,SPIO)包裹^(131)I-VEGF si RNA。以人肝细胞癌细胞株Hep G2细胞悬液臀部皮下注射建立人肝细胞癌移植瘤裸鼠模型。45只人肝细胞癌移植瘤裸鼠随机分成外加磁场组(尾静脉注射^(131)I-VEGF si RNA/SPIO+肿瘤部位外加磁场)、非外加磁场组(尾静脉注射^(131)I-VEGF si RNA/SPIO+肿瘤部位无外加磁场)及对照组(尾静脉注射^(131)I-VEGF si RNA+肿瘤部位无外加磁场)。然后进行:(1)血液清除动力学研究:三组人肝细胞癌移植瘤裸鼠(每组5只)尾静脉给药后,分别于0.5 h、1.0 h、1.5 h、2.0 h、3.0 h、4.0 h、6.0 h、8.0 h、10.0 h、12.0 h时间点尾静脉采血20μL,测量血样每分钟放射性计数(counts per minute,cpm)值并绘制放射性-时间曲线,计算血液半衰期;(2)体内生物分布研究:三组人肝细胞癌移植瘤裸鼠尾静脉给药1 h后进行SPECT显像(每组5只)及MRI显像(每组5只),SPECT及MRI显像完毕,依次摘取移植瘤裸鼠肿瘤、皮肤、肌肉、骨、甲状腺、胃、小肠、大肠、肺、脾、性腺、肝、心、肾、膀胱等脏器称重并测量cpm值,然后计算各离体组织的%ID/g[即组织的放射性比活度(cpm/g)/注入标记物的放射性比活度(cpm/g)]。结果本研究分别以薄层层析硅胶板为载体、1∶1丙酮-生理盐水为展开剂和以新华一号滤纸为载体、1∶1甲醇-5%醋酸铵为展开剂测定^(131)I标记VEGF si RNA的放化纯分别为81.15%和84.05%。外加磁场组、非外加磁场组及对照组移植瘤裸鼠的血液半衰期分别约为(2.27±0.14)h、(2.93±0.20)h和(3.06±0.23)h,外加磁场组半衰期小于其它两组(差异有统计学意义,P<0.01)。SPECT显像显示外加磁场组肿瘤局部明显放射性增浓,非外加磁场组及对照组肿瘤局部未见明显放射性增浓;尾静脉给药前后MRI T1WI显示外加磁场组肿瘤局部信号明显强化,非外加磁场组及对照组肿瘤局部信号未见明显强化;外加磁场组肿瘤组织的%ID/g分布较非外加磁场组及对照组的均明显增高(P<0.01)。结论在外加磁场的作用下,以SPIO作为si RNA载体能够较成功地将^(131)I-VEGF si RNA转导至人肝细胞癌移植瘤裸鼠臀部皮下的肿瘤部位,对进一步研究肝细胞癌的VEGF靶向治疗、基因治疗以及示踪体内基因转导均有重要的意义。
