Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

Abstract

Neurological disorders are undoubtedly among the most alarming diseases humans might face. In treatment of neurological disorders, the blood‐brain barrier (BBB) is a challenging obstacle preventing drug penetration into the brain. Advances in dendrimer chemistry for central nervous system (CNS) treatments are presented here. A poly(amido)amine (PAMAM) dendrimer bioconjugate with a streptavidin adapter for the attachment of dendrons or any biotinylated drug is constructed. In vitro studies on porcine or murine models and in vivo mouse studies are performed and reveal the permeation of dendronized streptavidin (DSA) into the CNS. The bioconjugate is taken up mainly by the caveolae pathway and transported across the BBB via transcytosis escaping from lysosomes. After transcytosis DSA are delivered to astrocytes and neurons. Furthermore, DSA offer high biocompatibility in vitro and in vivo. In summary, a new strategy for implementing therapeutic PAMAM function as well as drug delivery in neuropathology is presented here.

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

“…We hypothesise that the dendrimers cross the BBB by both adsorptive transcytosis as well as by paracellular transport, though this last mechanism might be less significant due to the tight barrier established. This is in line to what was stated by Komarova and Malik where interdependence between both pathways results in the maintenance of tissue fluid homeostasis [51] and to a report from Moscariello and colleagues, where a PAMAM dendrimer bioconjugate was shown to cross an in vitro BBB by transcytosis [52]. It is known that adsorption of nanoparticles to the endothelial cell layer creates a concentration gradient that enhances their transport, important for drug delivery [53].…”

“…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].…”

Routing Nanomolar Protein Cargoes to Lipid Raft‐Mediated/Caveolar Endocytosis through a Ganglioside GM1‐Specific Recognition Tag

“…A frequent feature of these natural cargoes is theability to bind and cluster mono‐, di‐, and trisialotetrahexosylgangliosides (GM1, GD1a, GT1b) during their attachment to caveolar pits, which induces endocytosis . Entry through ganglioside recognition is an attractive strategy because progression of the internalized caveolae to endosomes and later to lysosomes is slow or absent, allowing time for delivery of the contents to cell organelles and the cytosol or transcytosis . Selection of the ganglioside‐mediated pathway addresses many of the challenges associated with the endocytic delivery of therapeutic macromolecules by allowing carrier‐triggered internalization at low concentrations and avoiding endosomal entrapment.…”

“…The mammalian cell membrane is a major obstacle in drug development because it represents a barrier that is mostly or absent, allowing time for delivery of the contents to cell organelles and the cytosol [11] or transcytosis. [12,13] Selection of the ganglioside-mediated pathway addresses many of the challenges associated with the endocytic delivery of therapeutic macromolecules [14] by allowing carrier-triggered internalization at low concentrations and avoiding endosomal entrapment. For this reason, there is increasing interest in reading the glycan code through which gangliosides trigger lipid raft-mediated/ caveolar endocytosis.…”

Dendrimer-based nanoparticles in cancer chemotherapy and gene therapy

“…Dendrimers with rich terminal reactive groups and excellent solubility can be easily modified with multiple ligands for specific therapies [41]. And more importantly, the interior hydrophobic cavity of dendrimers can load poor solubility drugs via noncovalent interactions, while the surface functional groups can be conjugated with drugs by covalent bond [42][43][44]. The cationic groups on the surface of dendrimers also can condense nucleic acids into nano-vehicle for efficient gene delivery [45,46].…”