Khuloud Al Jamal
King’s College London, UK
Title: Double-targeting of glioma in mice using LRP1-targeting carbon nano-needles
Biography
Biography: Khuloud Al Jamal
Abstract
Statement of the Problem: Brain disorders are on the rise accounting for almost 12% of world mortalities every year. Despite extensive research in drug development, brain disorders are still largely untreated due to the inability to deliver current therapeutics to the brain across the BBB. Chemically functionalized carbon nanotubes (f-CNT) constitute a novel class of nanomaterials with attractive physical, chemical and electronic properties. One interesting characteristic of f-CNTs is their ability to translocate across plasma membranes and enter the cells either passively by direct translocation across membranes or actively via endocytosis. In this study, the brain uptake properties of multiwalled f-CNTs (f-MWNTs) were studied in in vitro and in vivo.
Methodology: An in vitro model consisting of PBEC and astrocytes were co-cultured in a Transwell™ system. Percentage of BBB crossing of radiolabelled [111In] DTPA-MWNTs was assessed at 37 °C up to 72 h or with an initial incubation at 4 °C for 4 h. Ultrathin sections of PBEC were imaged using electron microscopy. Brain uptake in vivo was evaluated by SPECT/CT imaging and gamma counting following intravenous injection of [111In] DTPA-MWNTs in mice.
Findings: The percentage transport of [111In] DTPA-MWNTs across PBEC (Figure A) increased over the course of 72 h. The initial 4 h-incubation at 4 â—¦C resulted in a slight but significantly lower % transport than that obtained at 37 â—¦C (P= 0.0005). This difference was abolished upon the re-incubation at 37 â—¦C at 72 h. The penetration process was captured by electron microscopy. The accumulation in mouse brain was confirmed by SPECT/CT imaging (Figure B). Superior brain uptake of ~2-5% ID/g was measured by gamma counting after whole body perfusion.
Conclusion & Significance: This is the first evidence of f-MWNTs translocation across the BBB. The significant reduction in BBB crossing at 4 °C confirmed the uptake was driven by an energy-dependent pathway. Electron micrographs revealed transcytosis of f-MWNTs and its sequence as a function of time. f-MWNT’s are able to access mice brain after i.v. injection.