Biodegradable polymeric nanoparticles administered in the cerebrospinal fluid: Brain biodistribution, preferential internalization in microglia and implications for cell-selective drug release

Abstract

Cell-selective drug release Modulation of neuroinflammation in the central nervous system (CNS) holds great promise for the treatment of several neurodegenerative diseasesmany CNS disorders but it is still challenging. However, selective cell targeting remains challenging. We previously exploited demonstrated that polymeric nanoparticles (NPs) injected intra-parenchyma in the brain can be internalized specifically in to obtain cell specific uptake in microglia/macrophages surrounding the injection site, upon intra-parenchyma administration in mice. Here, we explored NPs administration in the cerebrospinal fluid (CSF) to achieve a wider spreading and increased cell targeting throughout the CNS, generated new NPs variants and studied the effect of modifying size and surface charge on NPs biodistribution and cellular uptake. As hypothesized, intra-cerebroventricular administration resulted in a widespread NPs brain distribution throughout the CNS with prevalent localization in proximity to stemcell niches, such as around the lateral ventricles, the subventricular zone and the rostral migratory stream. Formattato: Non Evidenziato Formattato: Non Evidenziato Formattato: Non Evidenziato Formattato: Non Evidenziato Formattato: Non Evidenziato Formattato: Non EvidenziatoNPs dimensions of 37-39 nm allowed extensive penetration in the brain parenchyma and targeting of up to 15% of microglia. Transient Ddisruption of the blood-brain barrier with mannitol improved NPs brain penetration leading to their internalization in up to 25% of microglia cells. A fraction of the targeted cells was positive for markers of proliferation or stained positive for stemness / progenitor-cell markers such as Nestin, c-kit, or NG2. Interestingly, through these newly formulated NPs we obtained controlled and selective release of chemotherapeutics otherwise difficult to formulate (such as busulfan and etoposide) toloaded drugs (such as the chemotherapeutics busulfan or etoposide) efficiently and could release them selectivity in the target cells, preventing unwanted side effects and the toxicity obtained by direct brain delivery of the same not encapsulated drugs. Overall, these data provide proof of concept of the applicability of these novel NP-based drug formulationss for targeting not only mature microglia but also possibly progenitor cells in the brain and paves the way for brain-restricted microglia-targeted drug delivery regimens.

Neuroinflammation Treatment via Targeted Delivery of Nanoparticles

“…The size of nanoparticles influences biodistribution, and generally smaller nanoparticles penetrate the CNS faster and with higher specificity than larger ones (Mahmoud et al, 2020). In addition to CNS penetration, nanoparticle properties also have an impact on cell targeting (Peviani et al, 2019). For instance, ligand-free 4 nm polyamidoamine dendrimers selectively accumulate in activated microglia and astrocytes in a model of cerebral palsy (Dai et al, 2010).…”

Synthesis and Characterization of a “Clickable” PBR28 TSPO-Selective Ligand Derivative Suitable for the Functionalization of Biodegradable Polymer Nanoparticles

“…This is not surprising and is in line with what has been reported by other authors (where only partial co-localization between TSPO-targeted NPs and mitochondria was reported [ 9 , 30 ]). In previous studies, we reported that our polymeric NPs can be internalized in microglia cells even without surface functionalization, through the interaction with scavenger receptors that are highly expressed by microglia/macrophages [ 22 ]. Based on the results of the confocal analyses performed with 6PBR30, and since TSPO is mainly localized on mitochondria, it can be hypothesized that the 6PBR30 NPs (as most likely also other TSPO-ligand functionalized NPs), are retained on the mitochondria network through the interaction of TSPO after cellular internalization through other mechanisms.…”

“…Recently, we reported the synthesis of zwitterionic biodegradable NPs whose properties can be readily modulated during the synthesis thus providing versatile platforms for the loading of poorly water-soluble drugs with minimal use of toxic organic solvents and providing enhanced stability to the formulation [17,20,21]. We showed that these NPs are able to be preferentially internalized in the microglia after administration into the spinal cord or in the cerebral lateral ventricles [20,22]. On the other hand, they were unable to differentiate between active and non-active microglia.…”

Delivery Platforms for CRISPR/Cas9 Genome Editing of Glial Cells in the Central Nervous System

“…Over the last 5 years, several contributions in the field (Elzoghby et al, 2016 ; Patel and Patel, 2017 ; Peviani et al, 2019 ; Birolini et al, 2021 ) highlighted that the size and surface charge of the NPs are critical features that must be controlled in order to achieve good NP biodistribution in the brain as well as selective cell targeting.…”