Lakshmi Pallavi Ganipineni1, Bernard Ucakar1, Nicolas Joudiou2, Raphaël Riva3, Christine Jérôme3, Bernard Gallez2, Fabienne Danhier1, Véronique Préat1. 1. a Université Catholique de Louvain, Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute , Brussels , Belgium. 2. b Université Catholique de Louvain, Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute , Brussels , Belgium. 3. c University of Liège, Center for Education and Research on Macromolecules (CERM), CESAM Research Unit , Liège , Belgium.
Abstract
INTRODUCTION: We hypothesised that the active targeting of αvβ3 integrin overexpressed in neoangiogenic blood vessels and glioblastoma (GBM) cells combined with magnetic targeting of paclitaxel- and SPIO-loaded PLGA-based nanoparticles could improve accumulation of nanoparticles in the tumour and therefore improve the treatment of GBM. METHODS: PTX/SPIO PLGA nanoparticles with or without RGD-grafting were characterised. Their in vitro cellular uptake and cytotoxicity was evaluated by fluorospectroscopy and MTT assay. In vivo safety and anti-tumour efficacy of different targeting strategies were evaluated in orthotopic U87MG tumour model over multiple intravenous injections. RESULTS: The nanoparticles of 250 nm were negatively charged. RGD targeted nanoparticles showed a specific and higher cellular uptake than untargeted nanoparticles by activated U87MG and HUVEC cells. In vitro IC50 of PTX after 48 h was ∼1 ng/mL for all the PTX-loaded nanoparticles. The median survival time of the mice treated with magnetic targeted nanoparticles was higher than the control (saline) mice or mice treated with other evaluated strategies. The 6 doses of PTX did not induce any detectable toxic effects on liver, kidney and heart when compared to Taxol. CONCLUSION: The magnetic targeting strategy resulted in a better therapeutic effect than the other targeting strategies (passive, active).
INTRODUCTION: We hypothesised that the active targeting of αvβ3 integrin overexpressed in neoangiogenic blood vessels and glioblastoma (GBM) cells combined with magnetic targeting of paclitaxel- and SPIO-loaded PLGA-based nanoparticles could improve accumulation of nanoparticles in the tumour and therefore improve the treatment of GBM. METHODS:PTX/SPIO PLGA nanoparticles with or without RGD-grafting were characterised. Their in vitro cellular uptake and cytotoxicity was evaluated by fluorospectroscopy and MTT assay. In vivo safety and anti-tumour efficacy of different targeting strategies were evaluated in orthotopic U87MG tumour model over multiple intravenous injections. RESULTS: The nanoparticles of 250 nm were negatively charged. RGD targeted nanoparticles showed a specific and higher cellular uptake than untargeted nanoparticles by activated U87MG and HUVEC cells. In vitro IC50 of PTX after 48 h was ∼1 ng/mL for all the PTX-loaded nanoparticles. The median survival time of the mice treated with magnetic targeted nanoparticles was higher than the control (saline) mice or mice treated with other evaluated strategies. The 6 doses of PTX did not induce any detectable toxic effects on liver, kidney and heart when compared to Taxol. CONCLUSION: The magnetic targeting strategy resulted in a better therapeutic effect than the other targeting strategies (passive, active).
Authors: Jason V Gregory; Padma Kadiyala; Robert Doherty; Melissa Cadena; Samer Habeel; Erkki Ruoslahti; Pedro R Lowenstein; Maria G Castro; Joerg Lahann Journal: Nat Commun Date: 2020-11-10 Impact factor: 14.919