EPR-mediated tumor targeting using ultrasmall-hybrid nanoparticles: From animal to human with theranostic AGuIX nanoparticles

Bort, Guillaume; Lux, François; Dufort, Sandrine; Crémillieux, Yannick; Verry, Camille; Tillement, Olivier

doi:10.7150/thno.37543

Cited by 98 publications

(79 citation statements)

References 44 publications

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“…Bort and colleagues discuss studies on the use of ultrasmall nanoparticles for tumor targeting. These include polysiloxane-based nanoparticles with a hydrodynamic diameter of approximately 4 nm, which have been successfully tested in animal models and have recently entered a clinical trial for treating patients with brain metastases 20 . In a comparative study, Xu et al investigate the tumor targeting efficiency of ligand-modified nanoparticles of 3 and 30 nm, respectively.…”

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confidence: 99%

The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy

et al. 2020

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Following its discovery more than 30 years ago, the enhanced permeability and retention (EPR) effect has become the guiding principle for cancer nanomedicine development. Over the years, the tumor-targeted drug delivery field has made significant progress, as evidenced by the approval of several nanomedicinal anticancer drugs. Recently, however, the existence and the extent of the EPR effect - particularly in patients - have become the focus of intense debate. This is partially due to the disbalance between the huge number of preclinical cancer nanomedicine papers and relatively small number of cancer nanomedicine drug products reaching the market. To move the field forward, we have to improve our understanding of the EPR effect, of its cancer type-specific pathophysiology, of nanomedicine interactions with the heterogeneous tumor microenvironment, of nanomedicine behavior in the body, and of translational aspects that specifically complicate nanomedicinal drug development. In this virtual special issue, 24 research articles and reviews discussing different aspects of the EPR effect and cancer nanomedicine are collected, together providing a comprehensive and complete overview of the current state-of-the-art and future directions in tumor-targeted drug delivery.

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confidence: 99%

The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy

et al. 2020

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“…A ligand matching both criteria was a DOTA derivative, DOTAGA (GA for glutamic acid) . Reassuringly, studies have demonstrated the robust nature of Gd(III) complexes formed with this ligand, and no significant toxicity has been observed, even with compounds presenting multiple metal complexes …”

Section: Resultsmentioning

confidence: 98%

Gadolinium Complexes Attached to Poly Ethoxy Ethyl Glycinamide (PEE‐G) Dendrons: Magnetic Resonance Imaging Contrast Agents with Increased Relaxivity

et al. 2020

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A range of poly ethoxy ethyl glycinamide (PEE−G) dendron scaffolds with gadolinium (III) complexes attached were synthesized with a focus on product purity and high Gd(III) loading. The nuclear magnetic resonance relaxivity of these products was measured and compared with commercially available low‐molecular‐weight magnetic resonance imaging contrast agents. Over twice the relaxivity based on Gd(III) concentration, and up to 20‐fold increase in relaxivity were observed based on molecular concentration. Relaxivity properties were observed to increase with both increasing molecular weight and number of Gd(III) complexes attached, however a plateau was reached for molecular weight increase. T1 and T2 relaxivity properties were also investigated at two different magnetic fields. Transverse relaxivity is unaffected by magnetic field strength whereas increase in longitudinal relaxivity was not as pronounced at the higher field.

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“…13,14 Consequently, the heterogeneity of the accumulation of AGuIX nanoparticles due to the unpredictability of the EPR effect and sometimes their low tumor residence times, tend to consider active targeting, especially in the strategic infiltrative areas of GBM tumors. 15 Active targeting strategies using, for instance, specific ligands such as antibodies or peptides could be a solution to overcome these limitations.…”

Section: Introductionmentioning

confidence: 99%

<p>Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma</p>

Gries¹,

Thomas²,

Daouk³

et al. 2020

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Background: Local recurrences of glioblastoma (GBM) after heavy standard treatments remain frequent and lead to a poor prognostic. Major challenges are the infiltrative part of the tumor tissue which is the ultimate cause of recurrence. The therapeutic arsenal faces the difficulty of eradicating this infiltrating part of the tumor tissue while increasing the targeting of tumor and endogenous stromal cells such as angiogenic endothelial cells. In this aim, neuropilin-1 (NRP-1), a transmembrane receptor mainly overexpressed by endothelial cells of the tumor vascular system and associated with malignancy, proliferation and migration of GBM, highlighted to be a relevant molecular target to promote the anti-vascular effect of photodynamic therapy (VTP). Methods: The multiscale selectivity was investigated for KDKPPR peptide moiety targeting NRP-1 and a porphyrin molecule as photosensitizer (PS), both grafted onto original AGuIX design nanoparticle. AGuIX nanoparticle, currently in Phase II clinical trials for the treatment of brain metastases with radiotherapy, allows to achieve a real-time magnetic resonance imaging (MRI) and an accumulation in the tumor area by EPR (enhanced permeability and retention) effect. Using surface-plasmon resonance (SPR), we evaluated the affinities of KDKPPR and scramble free peptides, and also peptides-conjugated AGuIX nanoparticles to recombinant rat and human NRP-1 proteins. For in vivo selectivity, we used a cranial window model and parametric maps obtained from T2*-weighted perfusion MRI analysis. Results: The photophysical characteristics of the PS and KDKPPR molecular affinity for recombinant human NRP-1 proteins were maintained after the functionalization of AGuIX nanoparticle with a dissociation constant of 4.7 μM determined by SPR assays. Cranial window model and parametric maps, both revealed a prolonged retention in the vascular system of human xenotransplanted GBM. Thanks to the fluorescence of porphyrin by noninvasive imaging and the concentration of gadolinium evaluated after extraction of organs, we checked the absence of nanoparticle in the brains of tumor-free animals and highlighted elimination by renal excretion and hepatic metabolism. Conclusion: Post-VTP follow-ups demonstrated promising tumor responses with a prolonged delay in tumor growth accompanied by a decrease in tumor metabolism.

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EPR-mediated tumor targeting using ultrasmall-hybrid nanoparticles: From animal to human with theranostic AGuIX nanoparticles

Cited by 98 publications

References 44 publications

The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy

The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy

Gadolinium Complexes Attached to Poly Ethoxy Ethyl Glycinamide (PEE‐G) Dendrons: Magnetic Resonance Imaging Contrast Agents with Increased Relaxivity

<p>Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma</p>

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