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.
Highlights
Neurological disorders are undoubtedly among the most alarming diseases well-known biological obstacle: the bloodbrain barrier (BBB)
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 dendronized streptavidin (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
Showing for the first time a biocompatible and multifunctional PAMAM dendrimer bioconjugate which can efficiently target the brain via crossing the intact BBB, significantly expands the existing potential of dendrimer-based drug delivery systems to may be translated into future trials involving central nervous system (CNS) pharmacotherapies
Summary
Neurological disorders are undoubtedly among the most alarming diseases well-known biological obstacle: the bloodbrain barrier (BBB). A new strategy for implementing therapeutic 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. 1. Introduction side effects.[5] Possible approaches are, for example, opening of the tight junctions by osmotic disruption[6] or ultrasound[7] and Neurological diseases are a growing challenge in health care direct intracerebral infusion or implantation.[8] In rare cases, since, with prolonged aging, the number of patients will such as traumatic brain injury or cancer, the pathological increase, with consequent high social impact due to severe mechanisms by themselves, affecting BBB integrity, might morbidity and mortality.[1] the scientific achievements offer the possibility to access the CNS.[9].
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