title: Passive and active hepatoma tumor targeting of new N-(2-hydroxypropyl)methacrylamide copolymer conjugates: synthesis, characterization, and evaluation in vitro and in vivo.
abstract: 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.
authors.affiliation: Key Laboratory of Eco-Environment-Related Polymer Materials of Ministry of Education, College of Chemistry & Chemical Engineering, Northwest Normal University, Lanzhou 730070, China. jianchaoyuan@nwnu.edu.cn
authors.forename: Jianchao
authors.initials: J
authors.lastname: Yuan
authors.forename: Bingnian
authors.initials: B
authors.lastname: Yuan
authors.forename: Hongyun
authors.initials: H
authors.lastname: Guo
authors.forename: Xianwu
authors.initials: X
authors.lastname: Zeng
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Wang
authors.forename: Shiqi
authors.initials: S
authors.lastname: Liao
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Zong
authors.initials: Z
authors.lastname: Jia
authors.forename: Fengying
authors.initials: F
authors.lastname: Song
authors.forename: Fuzhou
authors.initials: F
authors.lastname: Wang
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000378:metabolism; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011109:Polymethacrylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013667:Technetium; D014018:Tissue Distribution
chemical_list: D000178:Acrylamides; D011109:Polymethacrylic Acids; D019275:Radiopharmaceuticals; C585283:poly(N-(2-hydroxypropyl methacrylamide)-co-sulfapyridine-co-diethylenetriaminepentaacetic acid); D013667:Technetium; D004369:Pentetic Acid; C032976:N-(2-hydroxypropyl)methacrylamide