Date Published: February 23, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Pierpaolo Moscariello, David Y. W. Ng, Malin Jansen, Tanja Weil, Heiko J. Luhmann, Jana Hedrich.
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.
Neurological diseases are a growing challenge in health care since, with prolonged aging, the number of patients will increase, with consequent high social impact due to severe morbidity and mortality.1 Although the scientific achievements are constantly providing possible therapeutic molecules,2 adequate treatments are still an unmet medical need, because systemically administered drugs are often ineffective due to a well‐known biological obstacle: the blood‐brain barrier (BBB). The BBB consists of brain capillary endothelial cells, pericytes, astrocytes, and neurons all referred to as the neurovascular unit (NVU).3 It represents a multicellular interface separating bloodstream and brain parenchyma, maintaining a constant homeostatic brain environment. After intravenous injection, only some lipophilic molecules penetrate to the brain parenchyma in therapeutically relevant concentrations, and 98% of neuroactive drugs cannot pass the BBB.4 Currently, therapeutics can be delivered to the central nervous system (CNS) via several ways. Either the drug can circumvent the BBB after systemic administration or it has to be applied by invasive methods involving a high risk of severe side effects.5 Possible approaches are, for example, opening of the tight junctions by osmotic disruption6 or ultrasound7 and direct intracerebral infusion or implantation.8 In rare cases, such as traumatic brain injury or cancer, the pathological mechanisms by themselves, affecting BBB integrity, might offer the possibility to access the CNS.9
Combining in vitro and in vivo approaches by using BBB models, NVU cell cultures as well as intravenous injection and analysis on tissue of mice, we demonstrated that DSA (I) are taken up by neurovascular unit cells, (II) are transported from the bloodstream to the brain via transcytosis, (III) are biocompatible for NVU cells, and (IV) do not impair BBB integrity.
Ethical Approval: All experimental procedures were approved by the ethical committee of the “Landesuntersuchungsamt Rheinland‐Pfalz” and the authority “Landesuntersuchungsamt Rheinland‐Pfalz” protocol number: “Aktenzeichen “23 177‐07/G 16‐1‐024.” Principles of laboratory animal care (European, national and international laws) were followed.
The authors declare no conflict of interest.