Key Laboratory of Eco-Environment-Related Polymer Materials of Ministry of Education, College of Chemistry & Chemical Engineering, Northwest Normal University, Lanzhou 730070, China.
J Biomater Sci Polym Ed. 2013;24(12):1472-83. doi: 10.1080/09205063.2013.768944. Epub 2013 Feb 11.
Human hepatocellular carcinoma (HCC) is one of the major causes of death worldwide. To investigate the relative importance of active and passive targeting strategies, the synthesis, characterization, in vitro uptake, and in vivo biodistribution of specific sulfapyridine HPMA (HPMA: N-(2-hydroxypropyl methacrylamide)) copolymer (sulfapyridine: SPD) conjugates, nonspecific HPMA copolymer conjugates, and DTPA are described in this study. The poly(HPMA)-SPD-DTPA (DTPA: diethylenetriaminepentaacetic acid), poly(HPMA)-DTPA, and DTPA conjugates were radiolabeled with the radionuclide (99m)Tc and tested for uptake by cultured H22 cells. The cellular accumulation of poly(HPMA)-SPD-DTPA-(99m)Tc complex was found to be time-dependent. The poly(HPMA)-SPD-DTPA-(99m)Tc tracer exhibited rapid uptake kinetics in cell culture with a t(1/2) of ~5 min. The uptake of poly(HPMA)-SPD-DTPA-(99m)Tc was significantly higher than that of poly(HPMA)-DTPA-(99m)Tc, indicating that the uptake of the poly(HPMA)-SPD-DTPA-(99m)T was active binding. The uptake of poly(HPMA)-DTPA-(99m)Tc was significantly higher than that of DTPA-(99m)Tc, suggesting that the uptake of the poly(HPMA)-DTPA-(99m)T was passive binding. Twenty-four hour necropsy data in the hepatocellular carcinoma tumor model showed significantly higher (p < 0.001) tumor localization for poly(HPMA)-SPD-DTPA-(99m)Tc (4.98 ± 0.48%ID/g [percentage injected dose per gram tissue]) compared with poly(HPMA)-DTPA-(99m)Tc (2.69 ± 0.15% ID/g) and DTPA-(99m)Tc (0.83 ± 0.03%ID/g). Moreover, higher T/B for poly(HPMA)-SPD-DTPA-(99m)Tc indicated reduced extravazation of the targeted polymeric conjugates in normal tissues. Specific molecular targeting and nonspecific vascular permeability are both significant in the relative tumor localization of poly(HPMA)-SPD-DTPA-(99m)Tc. Extravascular leak in nonspecific organs appears to be a major factor in reducing the T/B for the sulfapyridine molecules. Thus, the poly(HPMA)-SPD-DTPA is expected to be used as the potential macromolecular targeting carrier for hepatoma carcinoma in mice.
人肝癌（HCC）是全球主要死亡原因之一。为了研究主动和被动靶向策略的相对重要性，本研究描述了特异性磺胺嘧啶 HPMA（HPMA：N-（2-羟丙基）甲基丙烯酰胺）共聚物（磺胺嘧啶：SPD）缀合物、非特异性 HPMA 共聚物缀合物和 DTPA 的合成、表征、体外摄取和体内分布。聚（HPMA）-SPD-DTPA（DTPA：二乙三胺五乙酸）、聚（HPMA）-DTPA 和 DTPA 缀合物用放射性核素（99m）Tc 标记，并测试其在培养的 H22 细胞中的摄取。发现聚（HPMA）-SPD-DTPA-（99m）Tc 复合物的细胞积累是时间依赖性的。聚（HPMA）-SPD-DTPA-（99m）Tc 示踪剂在细胞培养中表现出快速摄取动力学，t（1/2）约为 5 分钟。聚（HPMA）-SPD-DTPA-（99m）Tc 的摄取明显高于聚（HPMA）-DTPA-（99m）Tc，表明聚（HPMA）-SPD-DTPA-（99m）Tc 的摄取是主动结合。聚（HPMA）-DTPA-（99m）Tc 的摄取明显高于 DTPA-（99m）Tc，表明聚（HPMA）-DTPA-（99m）Tc 的摄取是被动结合。在肝癌肿瘤模型的 24 小时尸检数据中，与聚（HPMA）-DTPA-（99m）Tc（2.69 ± 0.15%ID/g [组织每克注射剂量的百分比]）和 DTPA-（99m）Tc（0.83 ± 0.03%ID/g）相比，聚（HPMA）-SPD-DTPA-（99m）Tc 的肿瘤定位明显更高（p < 0.001）（4.98 ± 0.48%ID/g）。此外，聚（HPMA）-SPD-DTPA-（99m）Tc 的 T/B 更高，表明靶向聚合物缀合物在正常组织中的外渗减少。特异性分子靶向和非特异性血管通透性在聚（HPMA）-SPD-DTPA-（99m）Tc 的相对肿瘤定位中均具有重要意义。非特异性器官中的血管外渗漏似乎是降低磺胺嘧啶分子 T/B 的主要因素。因此，聚（HPMA）-SPD-DTPA 有望作为小鼠肝癌的潜在大分子靶向载体。
