University of Michigan, Department of Biomedical Engineering, 1101 Beal Avenue, Lurie Biomedical Engineering Building, Room 2150, Ann Arbor, MI 48109, USA, Web: www.bme.umich.edu/centlab.php.
Adv Healthc Mater. 2013 Oct;2(10):1337-50. doi: 10.1002/adhm.201200406. Epub 2013 Apr 3.
Poly(amidoamine) (PAMAM) dendrimers are branched water-soluble polymers defined by consecutive generation numbers (Gn) indicating a parallel increase in size, molecular weight, and number of surface groups available for conjugation of bioactive agents. In this article, we compare the biodistribution of N-acetylgalactosamine (NAcGal)-targeted [(14) C]1 -G5-(NH2 )5 -(Ac)108 -(NAcGal)14 particles to non-targeted [(14) C]1 -G5-(NH2 )127 and PEGylated [(14) C]1 -G5-(NH2 )44 -(Ac)73 -(PEG)10 particles in a mouse hepatic cancer model. Results show that both NAcGal-targeted and non-targeted particles are rapidly cleared from the systemic circulation with high distribution to the liver. However, NAcGal-targeted particles exhibited 2.5-fold higher accumulation in tumor tissue compared to non-targeted ones. In comparison, PEGylated particles showed a 16-fold increase in plasma residence time and a 5-fold reduction in liver accumulation. These results motivated us to engineer new PEGylated G5 particles with PEG chains anchored to the G5 surface via acid-labile cis-aconityl linkages where the free PEG tips are functionalized with NAcGal or SP94 peptide to investigate their potential as targeting ligands for hepatic cancer cells as a function of sugar conformation (α versus β), ligand concentration (100-4000 nM), and incubation time (2 and 24 hours) compared to fluorescently (Fl)-labeled and non-targeted G5-(Fl)6 -(NH2 )122 and G5-(Fl)6 -(Ac)107 -(cPEG)15 particles. Results show G5-(Fl)6 -(Ac)107 -(cPEG[NAcGalβ ])14 particles achieve faster uptake and higher intracellular concentrations in HepG2 cancer cells compared to other G5 particles while escaping the non-specific adsorption of serum protein and phagocytosis by Kupffer cells, which make these particles the ideal carrier for selective drug delivery into hepatic cancer cells.
聚（酰胺-胺）（PAMAM）树枝状聚合物是通过连续的代（Gn）数定义的支化水溶性聚合物，表明大小、分子量和表面可用于结合生物活性剂的基团数量呈平行增加。在本文中，我们将比较 N-乙酰半乳糖胺（NAcGal）靶向的 [(14)C]1-G5-(NH2)5-(Ac)108-(NAcGal)14 颗粒与非靶向的 [(14)C]1-G5-(NH2)127 和 PEG 化的 [(14)C]1-G5-(NH2)44-(Ac)73-(PEG)10 颗粒在小鼠肝癌模型中的分布。结果表明，NAcGal 靶向和非靶向颗粒都从体循环中迅速清除，肝脏分布高。然而，与非靶向颗粒相比，NAcGal 靶向颗粒在肿瘤组织中的积累增加了 2.5 倍。相比之下，PEG 化颗粒在血浆中的停留时间增加了 16 倍，在肝脏中的积累减少了 5 倍。这些结果促使我们设计新的 PEG 化 G5 颗粒，PEG 链通过酸不稳定的顺式丙烯酰基连接锚定在 G5 表面上，其中游离的 PEG 末端用 NAcGal 或 SP94 肽官能化，以研究它们作为肝癌细胞的靶向配体的潜力，作为糖构象（α 与 β）、配体浓度（100-4000 nM）和孵育时间（2 和 24 小时）的函数，与荧光标记的和非靶向的 G5-(Fl)6-(NH2)122 和 G5-(Fl)6-(Ac)107-(cPEG)15 颗粒相比。结果表明，与其他 G5 颗粒相比，G5-(Fl)6-(Ac)107-(cPEG[NAcGalβ])14 颗粒在 HepG2 癌细胞中的摄取更快，细胞内浓度更高，同时逃避了血清蛋白的非特异性吸附和枯否细胞的吞噬作用，这使得这些颗粒成为选择性递送至肝癌细胞的理想载体。
