Abstract
The success of nanomedicine as a new strategy for drug delivery and targeting prompted the interest in developing approaches toward basic and clinical neuroscience. Despite enormous advances on brain research, central nervous system (CNS) disorders remain the world’s leading cause of disability, in part due to the inability of the majority of drugs to reach the brain parenchyma. Many attempts to use nanomedicines as CNS drug delivery systems (DDS) were made; among the various non-invasive approaches, nanoparticulate carriers and, particularly, polymeric nanoparticles (NPs) seem to be the most interesting strategies. In particular, the ability of poly-lactide-co-glycolide NPs (PLGA-NPs) specifically engineered with a glycopeptide (g7), conferring to NPs’ ability to cross the blood brain barrier (BBB) in rodents at a concentration of up to 10% of the injected dose, was demonstrated in previous studies using different routes of administrations. Most of the evidence on NP uptake mechanisms reported in the literature about intracellular pathways and processes of cell entry is based on in vitro studies. Therefore, beside the particular attention devoted to increasing the knowledge of the rate of in vivo BBB crossing of nanocarriers, the subsequent exocytosis in the brain compartments, their fate and trafficking in the brain surely represent major topics in this field.
Highlights
Proper evaluation of the main advantages of drug delivery systems in terms of ability in controlling the release of loaded drugs, in being more biocompatible and able to interact with membranes or in terms of stability in bloodstream
To circumvent the multitude of barriers inhibiting central nervous system (CNS) penetration by potential therapeutic agents, numerous drug delivery strategies (DDS) were developed [1,2]. These strategies fall into one or more of the following three categories: (i) chemical approach; (ii) temporary disruption of the blood brain barrier (BBB) (an invasive strategy for enhanced CNS drug delivery involving the systemic administration of drugs in conjunction with transient BBB disruption (BBBD)); (iii) alternative approaches for drug delivery as a molecular Trojan horse
In previous papers [32], we clearly showed a real interaction of the g7-NPs to the surface of the BBB, confirming the involvement of the amphiphatic helices supposed by Polt et al after in vivo administration, we detected several ruffles, referable to macropinocytosis, were sometimes recognized when g7-NPs are near to the endothelial cells
Summary
The same mechanism that protects the brain against intrusive chemicals and exogenous toxic agents can frustrate therapeutic interventions. To circumvent the multitude of barriers inhibiting CNS penetration by potential therapeutic agents, numerous drug delivery strategies (DDS) were developed [1,2] These strategies fall into one or more of the following three categories: (i) chemical approach (lipophilic analogs, prodrugs); (ii) temporary disruption of the BBB (an invasive strategy for enhanced CNS drug delivery involving the systemic administration of drugs in conjunction with transient BBB disruption (BBBD)); (iii) alternative approaches for drug delivery as a molecular Trojan horse. In this view, this strategy (“Trojan horse”) has been widely applied for macromolecules themselves, allowing them to be selectively targeted to a desired site of action in their inactive form and, only in the correct place, to be activated. We think that this example, referring to one single kind of NPs which were analyzed from several points of view, and by several independent experiments, could be useful to plan future protocols and approaches for evaluation of the potentiality, the role and the fate of nanocarriers aimed to target the Central Nervous System
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