Novel Monodisperse PEG-Dendrons as New Tools for Targeted Drug Delivery: Synthesis, Characterization and Cellular Uptake

详细信息    查看全文

• 作者：Manuela Berna ; Daniele Dalzoppo ; Gianfranco Pasut ; Maria Manunta ; Lorella Izzo ; Arwyn T. Jones ; Ruth Duncan ; and Francesco M. Veronese
• 刊名：Biomacromolecules
• 出版年：2006
• 出版时间：January 2006
• 年：2006
• 卷：7
• 期：1
• 页码：146 - 153
• 全文大小：323K
• 年卷期：v.7,no.1(January 2006)
• ISSN：1526-4602

文摘

Dendrimers, dendrons, and hyperbranched polymers are gaining popularity as novel drugs, imaging agents, anddrug delivery systems. They present advantages of well-defined molecular weight, multivalent surfaces, and highdrug carrying capacity. Moreover, it is emerging that such architectures can display unique endocytic properties.As poly(ethylene glycol) (PEG) is widely used for protein and drug conjugation, the aim of this study was for thefirst time to synthesize novel, branched PEG-based architectures, to define their cytotoxicity and, via preparationof Oregon green (OG) conjugates define the effect of structure on their cellular uptake. Five PEG-based dendronswere synthesized using monodisperse Fmoc-amino PEG propionic acid (M_w = 840) as a monomer, and cadaverine,tris(2-aminoethyl)amine or lysine as the branching moieties. These were diamino,bisPEG (M_w = 1300); triamino,trisPEG (Mw = 1946); tetraamino,tetraPEG (M_w = 3956); monocarboxy,diamino,bisPEG (M_w = 1346);and monocarboxy,tetraamino,tetraPEG (M_w = 3999). These products had NH₂ or both NH₂ and COOH terminalgroups and the identity was verified by amino group analysis and ESI-TOF mass spectroscopy. Purity wasdetermined by HPLC. Representative structures were not toxic towards an endothelial-like cell line (ECV304) atconcentrations up to 4 mg/mL (over 72 h). At 37 C, all of the OG-labeled PEG dendrons showed progressiveuptake by ECV304 cells, but tetraamino,tetraPEG showed the greatest rate of internalization over the first 20min. Cellular uptake was inhibited at 4 C, and PEG dendron localization to perinuclear vesicles was confirmedby fluorescence microscopy. These well-defined novel architectures have potential for further development astargetable drug delivery systems or tools for construction of structurally defined modified surfaces.