PAMAM Dendrimers Cross the Blood–Brain Barrier When Administered through the Carotid Artery in C57BL/6J Mice

Abstract

Drug delivery into the central nervous system (CNS) is challenging due to the blood-brain barrier (BBB) and drug delivery into the brain overcoming the BBB can be achieved using nanoparticles such as dendrimers. The conventional cationic dendrimers used are highly toxic. Therefore, the present study investigates the role of novel mixed surface dendrimers, which have potentially less toxicity and can cross the BBB when administered through the carotid artery in mice. In vitro experiments investigated the uptake of amine dendrimers (G1-NH 2 and G4-NH 2 ) and novel dendrimers (G1-90/10 and G4-90/10) by primary cortical cultures. In vivo experiments involved transplantation of G4-90/10 into mice through (1) invasive intracranial injections into the striatum; and (2) less invasive carotid injections. The animals were sacrificed 24-h and 1-week post-transplantations and their brains were analyzed. In vivo experiments proved that the G4-90/10 can cross the BBB when injected through the carotid artery and localize within neurons and glial cells. The dendrimers were found to migrate through the corpus callosum 1-week post intracranial injection. Immunohistochemistry showed that the migrating cells are the dendrimer-infected glial cells. Overall, our results suggest that poly-amidoamine (PAMAM) dendrimers may be used as a minimally invasive means to deliver biomolecules for treating neurological diseases or disorders Keywords: PAMAM dendrimer nanoparticle; blood-brain barrier; non-invasive delivery; bio-distribution and uptake; neurodegenerative diseases Int.

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

“…A comparable mechanism might be responsible for the migration of pure PAMAM dendrimers through the corpus callosum one‐week post intracranial injection described by Srinageshwar et al52 In order to quantify the amount of G3‐DSA reaching the brain after intravenous injection, the percentage of injected dose (% ID) as well as the concentration of G3‐DSA expressed in µg/g of brain tissue was calculated. The results show that 0.03% ± 0.0% ID ( n = 3) and 0.44% ± 0.03 µg g −1 of brain tissue ( n = 3) of G3‐DSA efficiently overcome the BBB and reach the brain in vivo.…”

DendriPeps: Expanding Dendrimer Functionality by Hybridizing Poly(amidoamine) (PAMAM) Scaffolds with Peptide Segments

“…For example, drug‐delivery research using PAMAM dendrimers presents an opportunity for improvement. Traditionally, drugs are either covalently bound to the terminal groups of the dendrimer's branches or noncovalently entrapped within the internal cavities of the PAMAM architecture . Both approaches present disadvantages.…”

PAMAM dendrimers: blood-brain barrier transport and neuronal uptake after focal brain ischemia

“…PEGylation is expected to modulate this interaction by partially masking positive charges, enhancing the intra-and inter-cellular crossing at the BBB. Other reports have shown a clathrin-mediated endocytosis of PAMAM [54] as well as the BBB crossing of PAMAM by passive diffusion through the tight junctions, where PAMAM was functionalized with hydroxyl groups (mixed surface dendrimers) to reduce the positive charge [55]. These authors concluded that such dendrimers can be used to carry drugs that otherwise would not cross the blood-brain barrier.…”

“…A closer inspection of the astrocytes shows a higher intracellular presence of PAMAM when OGD was induced. It has been Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 previously reported that PAMAM dendrimers can cross the BBB [52,55,63]. Here, we report an increase in dendrimer traffic through the barrier subjected to hypoxia, that can be explained by the increase of the paracellular transport [64].…”