Locoregional Confinement and Major Clinical Benefit of ¹⁸⁸Re-Loaded CXCR4-Targeted Nanocarriers in an Orthotopic Human to Mouse Model of Glioblastoma

Abstract

Purpose: Gold standard beam radiation for glioblastoma (GBM) treatment is challenged by resistance phenomena occurring in cellular populations well prepared to survive or to repair damage caused by radiation. Among signals that have been linked with radio-resistance, the SDF1/CXCR4 axis, associated with cancer stem-like cell, may be an opportune target. To avoid the problem of systemic toxicity and blood-brain barrier crossing, the relevance and efficacy of an original system of local brain internal radiation therapy combining a radiopharmaceutical with an immuno-nanoparticle was investigated.Experiment design: The nanocarrier combined lipophilic thiobenzoate complexes of rhenium-188 loaded in the core of a lipid nanocapsule (LNC188Re) with a function-blocking antibody, 12G5 directed at the CXCR4, on its surface. The efficiency of 12G5-LNC188Re was investigated in an orthotopic and xenogenic GBM model of CXCR4-positive U87MG cells implanted in the striatum of Scid mice.Results: We demonstrated that 12G5-LNC188Re single infusion treatment by convection-enhanced delivery resulted in a major clinical improvement in median survival that was accompanied by locoregional effects on tumor development including hypovascularization and stimulation of the recruitment of bone marrow derived CD11b- or CD68-positive cells as confirmed by immunohistochemistry analysis. Interestingly, thorough analysis by spectral imaging in a chimeric U87MG GBM model containing CXCR4-positive/red fluorescent protein (RFP)-positive- and CXCR4-negative/RFP-negative-GBM cells revealed greater confinement of DiD-labeled 12G5-LNCs than control IgG2a-LNCs in RFP compartments.Main conclusion: These findings on locoregional impact and targeting of disseminated cancer cells in tumor margins suggest that intracerebral active targeting of nanocarriers loaded with radiopharmaceuticals may have considerable benefits in clinical applications.

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Although this does not necessarily modify the diagnosis as it is perceived today, it could be useful as regards the consideration of patient management and escape or not to new well identified therapies. The presence of TAMs has already been well described in GB (Saha et al, 2017;Séhédic et al, 2017;Roesch et al, 2018). In a mouse model, TAMs were observed in perivascular areas in the tumor and seem to be implicated in gliomagenesis Feng et al, 2015.…”

Development of a non-toxic and non-denaturing formulation process for encapsulation of SDF-1α into PLGA/PEG-PLGA nanoparticles to achieve sustained release

“…The bioactivity of the precipitated and released SDF-1α was assessed using the agarose drop migration assay as adapted from Milner et al [39]. Briefly, U87-MG cells (American Tissue Culture Collection, Rockville, Maryland, USA), previously transfected to express CXCR4 receptor by Séhédic et al [40], were seeded into a 24…”

Possibility of cancer-stem-cell-targeted radioimmunotherapy for acute myelogenous leukemia using 211At-CXCR4 monoclonal antibody

“…CXCR4-directed therapies using either alternative small-molecule CXCR4 antagonists 26,27 , CXCL12 inhibitors 28 , or anti-CXCR4 antibodies 29,30 have resulted in prolonged overall survival in preclinical studies. The use of gold nanoparticles labeled with 188 Re targeting CXCR4 has been studied to reverse chemoresistance of CSC in glioblastoma 31 .…”