Analysis of Biotinylated Generation 4 Poly(amidoamine) (PAMAM) Dendrimer Distribution in the Rat Brain and Toxicity in a Cellular Model of the Blood-Brain Barrier

Abstract

Dendrimers are highly customizable nanopolymers with qualities that make them ideal for drug delivery. The high binding affinity of biotin/avidin provides a useful approach to fluorescently label synthesized dendrimer-conjugates in cells and tissues. In addition, biotin may facilitate delivery of dendrimers through the blood-brain barrier (BBB) via carrier-mediated endocytosis. The purpose of this research was to: (1) measure toxicity using lactate dehydrogenase (LDH) assays of generation (G)4 biotinylated and non-biotinylated poly(amidoamine) (PAMAM) dendrimers in a co-culture model of the BBB, (2) determine distribution of dendrimers in the rat brain, kidney, and liver following systemic administration of dendrimers, and (3) conduct atomic force microscopy (AFM) on rat brain sections following systemic administration of dendrimers. LDH measurements showed that biotinylated dendrimers were toxic to cell co-culture after 48 h of treatment. Distribution studies showed evidence of biotinylated and non-biotinylated PAMAM OPEN ACCESSMolecules 2013, 18 11538 dendrimers in brain. AFM studies showed evidence of dendrimers only in brain tissue of treated rats. These results indicate that biotinylation does not decrease toxicity associated with PAMAM dendrimers and that biotinylated PAMAM dendrimers distribute in the brain. Furthermore, this article provides evidence of nanoparticles in brain tissue following systemic administration of nanoparticles supported by both fluorescence microscopy and AFM.

Different patterns of nuclear and mitochondrial penetration by the G3 PAMAM dendrimer and its biotin–pyridoxal bioconjugate BC-PAMAM in normal and cancer cells in vitro

“…36 Biotin conjugates are therefore considered to be biocompatible carriers for delivering anticancer drugs, and they can be transferred through the blood-brain barrier. [37][38][39] Pyridoxal (PL) and its 5′ phosphorylated derivative are active forms of vitamin B6 that play a critical role in cellular metabolism and stress response. 40,41 Recent studies have highlighted the importance of the protective role of vitamin B6 in carcinogenesis, especially colon carcinogenesis, by reducing cell proliferation, oxidative stress, NO production, and angiogenesis.…”

Selective aggregation of PAMAM dendrimer nanocarriers and PAMAM/ZnPc nanodrugs on human atheromatous carotid tissues: a photodynamic therapy for atherosclerosis

“…Studies of PAMAM distribution on biological samples are rather scarce [79][80][81][82]. For example, Dobrovolskaia et al [79] reported in in vitro studies the effects of the size and surface terminal groups of PAMAM dendrimers on healthy human platelets.…”

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

“…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].…”