Radiation and adjuvant drug-loaded liposomes target glioblastoma stem cells and trigger in-situ immune response.

Marco Pizzocri,Federica Ungaro,Massimo Masserini,Michela Matteoli,Elisabetta Stanzani,Beatrice Formicola,Francesco Dimeco,Maria Gregori,Eliana Lauranzano,Lorena Passoni,Maura Francolini,Francesca Re,Alessandro Perin,Simona Rodighiero,Matteo Tamborini

doi:10.1093/noajnl/vdab076

Abstract

BackgroundThe radio- and chemo-resistance of glioblastoma stem-like cells (GSCs), together with their innate tumor-initiating aptitude, make this cell population a crucial target for effective therapies. However, targeting GSCs is hardly difficult and complex, due to the presence of the blood–brain barrier (BBB) and the infiltrative nature of GSCs arousing their dispersion within the brain parenchyma.MethodsLiposomes (LIPs), surface-decorated with an Apolipoprotein E-modified peptide (mApoE) to enable BBB crossing, were loaded with doxorubicin (DOXO), as paradigm of cytotoxic drug triggering immunogenic cell death (ICD). Patient-derived xenografts (PDXs) obtained by GSC intracranial injection were treated with mApoE-DOXO-LIPs alone or concomitantly with radiation.ResultsOur results indicated that mApoE, through the engagement of the low-density lipoprotein receptor (LDLR), promotes mApoE-DOXO-LIPs transcytosis across the BBB and confers target specificity towards GSCs. Irradiation enhanced LDLR expression on both BBB and GSCs, thus further promoting LIP diffusion and specificity. When administered in combination with radiations, mApoE-DOXO-LIPs caused a significant reduction of in vivo tumor growth due to GSC apoptosis. GSC apoptosis prompted microglia/macrophage phagocytic activity, together with the activation of the antigen-presenting machinery crucially required for anti-tumor adaptive immune response.ConclusionsOur results advocate for radiotherapy and adjuvant administration of drug-loaded, mApoE-targeted nanovectors as an effective strategy to deliver cytotoxic molecules to GSCs at the surgical tumor margins, the forefront of glioblastoma (GBM) recurrence, circumventing BBB hurdles. DOXO encapsulation proved in situ immune response activation within GBM microenvironment.

Highlights

Glioblastoma (GBM) is the most common and aggressive primary human brain tumor, associated with very poor prognosis and survival (5-year survival rate less than 5%)[1]
M Glioblastoma Stem-like Cells (GSCs) intracranial injection were treated with mApoE-DOXO-LIPs alone or concomitantly d with radiation. te Results p Our results indicated that mApoE, through the engagement of the Low-Density Lipoprotein e Receptor (LDLR), promotes mApoE-DOXO-LIPs transcytosis across the Blood Brain Barrier (BBB) and confers c target specificity towards GSCs
Our results advocate for radiotherapy and adjuvant administration of drug-loaded, mApoEtargeted nanovectors as an effective strategy to deliver cytotoxic molecules to GSCs at the surgical tumor margins, the forefront of GBM recurrence, circumventing BBB hurdles

Summary

Introduction

Glioblastoma (GBM) is the most common and aggressive primary human brain tumor, associated with very poor prognosis and survival (5-year survival rate less than 5%)[1]. 3. RESULTS mApoE-DOXO-LIP are able to cross the BBB in vitro and affect GBM cell viability T mApoE-DOXO-LIP ability to cross the BBB and target GBM cells was investigated in ip vitro using a transwell system integrated with a human brain capillary endothelial cell r monolayer (hCMEC/D3), as a model of BBB (Fig. 1B).

Results

Conclusion