Sweet Deborah M, Kolhatkar Rohit B, Ray Abhijit, Swaan Peter, Ghandehari Hamidreza
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
J Control Release. 2009 Aug 19;138(1):78-85. doi: 10.1016/j.jconrel.2009.04.022. Epub 2009 Apr 22.
The purpose of this work was to assess the impact of PEGylation on transepithelial transport of anionic poly(amidoamine) dendrimers. Cytotoxicity, uptake and transport across Caco-2 cells of PEGylated G3.5 and G4.5 PAMAM dendrimers were studied. Methoxy polyethylene glycol (750 Da) was conjugated to carboxylic acid-terminated PAMAM dendrimers at feed ratios of 1, 2 and 4 PEG per dendrimer. Compared to the control, PEGylation of anionic dendrimers did not significantly alter cytotoxicity up to a concentration of 0.1 mM. PEGylation of G3.5 dendrimers significantly decreased cellular uptake and transepithelial transport while PEGylation of G4.5 dendrimers led to a significant increase in uptake, but also a significant decrease in transport. Dendrimer PEGylation reduced the opening of tight junctions as evidenced by confocal microscopy techniques. Modulation of the tight junctional complex correlated well with changes in PEGylated dendrimer transport and suggests that anionic dendrimers are transported primarily through the paracellular route. PEGylated dendrimers show promise in oral delivery applications where increased functionality for drug conjugation and release is desired.
这项工作的目的是评估聚乙二醇化对阴离子型聚（酰胺胺）树枝状大分子跨上皮转运的影响。研究了聚乙二醇化的G3.5和G4.5 PAMAM树枝状大分子对Caco-2细胞的细胞毒性、摄取和转运情况。将甲氧基聚乙二醇（750 Da）以每个树枝状大分子1、2和4个聚乙二醇的进料比例与羧酸封端的PAMAM树枝状大分子共轭。与对照相比，在浓度高达0.1 mM时，阴离子树枝状大分子的聚乙二醇化并未显著改变细胞毒性。G3.5树枝状大分子的聚乙二醇化显著降低了细胞摄取和跨上皮转运，而G4.5树枝状大分子的聚乙二醇化导致摄取显著增加，但转运也显著降低。共聚焦显微镜技术表明，树枝状大分子的聚乙二醇化减少了紧密连接的开放。紧密连接复合物的调节与聚乙二醇化树枝状大分子转运的变化密切相关，这表明阴离子树枝状大分子主要通过细胞旁途径转运。聚乙二醇化树枝状大分子在需要增加药物共轭和释放功能的口服给药应用中显示出前景。
