Abstract
The interaction of biotinylated G4 poly(amidoamine) (PAMAM) dendrimer conjugates and G4 PAMAM dendrimers with in vitro models of the blood brain barrier (BBB) was evaluated using Langmuir Blodgett monolayer techniques, atomic force microscopy (AFM) and lactate dehydrogenase measures of cell membrane toxicity. Results indicate that both G4 and G4 biotinylated PAMAM dendrimers disrupt the composition of the liquid condensed (LC) and liquid expanded (LE) phases of the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid monolayer. The disruption is concentration dependent and more marked for G4 biotinylated PAMAMs. Lactate dehydrogenase (LDH) assays using endothelial cell culture models of the BBB indicate that biotinylation results in higher levels of toxicity than non-biotinylation. This approach provides valuable information to assess nanoparticle toxicity for drug delivery to the brain.
Highlights
Central nervous system (CNS) diseases, disorders and injuries affect over 1.5 billion people worldwide and diagnosis and treatment of CNS disorders represent a considerable challenge
Increasing amounts of G4 and G4 biotinylated PAMAM dendrimers seem to have a greater effect on the disappearance of the DPPC liquid expanded (LE)-liquid condensed (LC) phase transition
The findings presented here show the potential toxicity of G4 and G4 biotinylated PAMAM dendrimers and how biophysical measurements with model lipid systems can be correlated with cell toxicity analysis to provide information on nanoparticle toxicity
Summary
Central nervous system (CNS) diseases, disorders and injuries affect over 1.5 billion people worldwide and diagnosis and treatment of CNS disorders represent a considerable challenge. The complexity of the BBB comes from the variety and number of transporters within the BBB, including p-glycoprotein-1, glucose-related transporters, nucleoside transporters, receptors for transferrin, insulin, leptin, lectins, IGFs, various ATPases and many, many more that are taken up via receptor mediated endocytosis [4] This complexity makes developing in vitro models of the BBB challenging. Evaluation of Biotinylated PAMAM Dendrimer Toxicity in Models of the Blood Brain Barrier:. A detailed characterization of dendrimer toxicity is important for the design and use of dendrimers in brain drug delivery. Toxicity of both the functional group and generation of the dendrimer must be taken into consideration. Biotinylated PAMAM dendrimers may have the potential for delivering therapeutic drugs to the brain [24,29]. The results provide important insights into strategies for developing nanoparticle systems for brain drug delivery
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