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• W2016026936 abstract "Factors limiting the pharmacological effectiveness of antisense oligonucleotides include serum stability and the fact that these agents are inefficiently transported to their sites of action in the cytoplasm and nucleus. Polyamidoamine (PAMAM) dendrimers are nonlinear polycationic cascade polymers composed of interconnected ethylenediamine molecules that are able to bind oligonucleotides electrostatically. This new complex potentially reduces metabolic degradation of phosphodiester oligonucleotides in the serum and in the lysosome. Dendrimers also have the potential to increase oligonucleotide cellular uptake, thus augmenting their pharmacological effectiveness. We studied various dendrimer generations and their ability to interact with phosphodiester oligonucleotides. Alterations in pH and in ionic strength were studied for their effects on the dendrimer–oligonucleotide complex. A fluorescent-labeled oligonucleotide was utilized to study these interactions through a fluorescence anisotropy method. Oligonucleotides complexed to dendrimers were shown to have increased metabolic stability compared with free oligonucleotides. Using tissue culture models, fluorescent-labeled oligonucleotides complexed to dendrimers were studied for their transport properties. Flow cytometry was used to monitor cell-associated fluorescence of oligonucleotides and dendrimer systems. The electrostatic oligodeoxynucleotide (ODN)–dendrimer interaction was found to be sensitive to pH and to ionic strength, with the maximal interaction occurring at low pH and ionic strength. Using fluorescent-labeled ODN, we demonstrated that the ODN–DEN complex accumulated to a greater extent than free oligonucleotides. In summary, dendrimers have the potential to increase the effectiveness of oligonucleotides by forming an electrostatic complex that is conducive to increasing metabolic stability and cellular accumulation. In this report we describe the interactions between phosphodiester ODNs and dendrimers with regard to their electrostatic interactions and their cellular uptake." @default.
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• W2016026936 date "1996-01-01" @default.
• W2016026936 modified "2023-10-18" @default.
• W2016026936 title "Dendrimer Delivery of Oligonucleotides" @default.
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• W2016026936 doi "https://doi.org/10.3109/10717549609029458" @default.
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