Translocation of LRP1 targeted carbon nanotubes of different diameters across the blood–brain barrier in vitro and in vivo

Abstract

Brain glioblastoma and neurodegenerative diseases are still largely untreated due to the inability of most drugs to cross the blood–brain barrier (BBB). Nanoparticles have emerged as promising tools for drug delivery applications to the brain; in particular carbon nanotubes (CNTs) that have shown an intrinsic ability to cross the BBB in vitro and in vivo. Angiopep-2 (ANG), a ligand for the low-density lipoprotein receptor-related protein-1 (LRP1), has also shown promising results as a targeting ligand for brain delivery using nanoparticles (NPs). Here, we investigate the ability of ANG-targeted chemically-functionalised multi-walled carbon nanotubes (f-MWNTs) to cross the BBB in vitro and in vivo. ANG was conjugated to wide and thin f-MWNTs creating w-MWNT-ANG and t-MWNT-ANG, respectively. All f-MWNTs were radiolabelled to facilitate quantitative analyses by γ-scintigraphy. ANG conjugation to f-MWNTs enhanced BBB transport of w- and t-MWNTs-ANG compared to their non-targeted equivalents using an in vitro co-cultured BBB model consisting of primary porcine brain endothelial cells (PBEC) and primary rat astrocytes. Additionally, following intravenous administration w-MWNTs-ANG showed significantly higher whole brain uptake than the non-targeted w-MWNT in vivo reaching ~ 2% injected dose per g of brain (%ID/g) within the first hour post-injection. Furthermore, using a syngeneic glioma model, w-MWNT-ANG showed enhanced uptake in glioma brain compared to normal brain at 24 h post-injection. t-MWNTs-ANG, on the other hand, showed higher brain accumulation than w-MWNTs. However, no significant differences were observed between t-MWNT and t-MWNT-ANG indicating the importance of f-MWNTs diameter towards their brain accumulation. The inherent brain accumulation ability of f-MWNTs coupled with improved brain-targeting by ANG favours the future clinical applications of f-MWNT-ANG to deliver active therapeutics for brain glioma therapy.

Antidepressant effects of curcumin and HU-211 coencapsulated solid lipid nanoparticles against corticosterone-induced cellular and animal models of major depression

“…In our future research, a BBB model and inhibitors associated with the signaling pathways will be applied to further study the underling mechanism of its activity. 23,64 It is noteworthy that, in this study, the lowtoxic Cur/SLNs-HU-211 nanoparticles displayed excellent Figure 10 schematic representation of the mechanisms by which cur/slNs-hU-211 crosses the BBB for the cOrT-induced major depression model. Notes: after intraperitoneal injection of cur/slNs-hU-211 into the mice with major depression, the nanoparticles accumulated at brain.…”

Drug delivery approaches for breast cancer

“…[12][13][14] Recently, nextgeneration nano-formulated platinum-based drug delivery has been used in clinics for cancer. 15 The receptor (HER-2, epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor [VEGFR], insulin-like growth factor I receptor [IGF-IR])-based targeting is the approach which is correlated with the breast tumorigenesis and is undergoing clinical trials (Phases II and III).…”

Single domain antibodies for the knockdown of cytosolic and nuclear proteins

“…It might be very attractive to encapsule recombinant cytosolic sdAb or sdAb expression plasmids into nanoparticles decorated with an specific anti‐receptor nanobody (for example EGFR 122 to deliver cytosolic anti‐cancer single domain antibodies to tumor cells. Furthermore, nanoparticles/nanotubes coated with transferrin or Angiopep‐2, a ligand for the low‐density lipoprotein receptor‐related protein‐1 (LRP1), demonstrated translocation across the blood‐brain barrier . The delivery of cytosolic/nuclear single domain intrabodies into the brain (for example recognizing hungtington protein or α‐Synuclein) might be possible in the future.…”

“…Furthermore, nanoparticles/nanotubes coated with transferrin or Angiopep-2, a ligand for the low-density lipoprotein receptor-related protein-1 (LRP1), demonstrated translocation across the blood-brain barrier. 123,124 The delivery of cytosolic/ nuclear single domain intrabodies into the brain (for example recognizing hungtington protein or a-Synuclein) 71,72 might be possible in the future.…”