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

ABSTRACT: Interest of tumor targeting through EPR effect is still controversial due to intrinsic low targeting efficacy and rare translation to human cancers. Moreover, due to different reasons, it has generally been described for relatively large nanoparticles (NPs) (hydrodynamic diameter > 10 nm). In this review EPR effect will be discussed for ultrasmall NPs using the example of the AGuIX® NP (Activation and Guiding of Irradiation by X-ray) recently translated in clinic. AGuIX® NP is a 4 ± 2 nm hydrodynamic diameter polysiloxane based NP. Since AGuIX® NP biodistribution is monitored by magnetic resonance imaging (MRI) and its activation is triggered by irradiation upon X-rays, this NP is well adapted for a theranostic approach of radiotherapy cancer treatment. Here we show that AGuIX® NP is particularly well suited to benefit from EPR-mediated tumor targeting thanks to an ultrasmall size and efficacy under irradiation at small dose. Indeed, intravenously-injected AGuIX® NP into rodent cancer models passively reached the tumor and revealed no toxicity, favoured by renal clearance. Moreover, translation of AGuIX® NP accumulation and retention into humans carrying brain metastases was validated during a first-in-man phase Ib trial taking advantage of easy biodistribution monitoring by MRI.

SUBMITTER: Bort G

PROVIDER: S-EPMC6956799 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Bort Guillaume G Lux François F Dufort Sandrine S Crémillieux Yannick Y Verry Camille C Tillement Olivier O

Theranostics 20200101 3

Interest of tumor targeting through EPR effect is still controversial due to intrinsic low targeting efficacy and rare translation to human cancers. Moreover, due to different reasons, it has generally been described for relatively large nanoparticles (NPs) (hydrodynamic diameter > 10 nm). In this review EPR effect will be discussed for ultrasmall NPs using the example of the AGuIX® NP (Activation and Guiding of Irradiation by X-ray) recently translated in clinic. AGuIX® NP is a 4 ± 2 nm hydrody ...[more]

PMID: 31938067

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Project description:BackgroundLocal 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).MethodsThe 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.ResultsThe 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 non-invasive 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.ConclusionPost-VTP follow-ups demonstrated promising tumor responses with a prolonged delay in tumor growth accompanied by a decrease in tumor metabolism.

Project description:Aberrant expression of miRNAs in pancreatic islets is closely related to the development of type 1 diabetes (T1D). The aim of this study was to identify key miRNAs dysregulated in pancreatic islets during T1D progression and to develop a theranostic approach to modify their expression using an MRI-based nanodrug consisting of iron oxide nanoparticles conjugated to miRNA-targeting oligonucleotides in a mouse model of T1D. Isolated pancreatic islets were derived from NOD mice of three distinct age groups (3, 8 and 18-week-old). Total RNA collected from cultured islets was purified and global miRNA profiling was performed with 3D-Gene global miRNA microarray mouse chips encompassing all mouse miRNAs available on the Sanger miRBase V16. Of the miRNAs that were found to be differentially expressed across three age groups, we identified one candidate (miR-216a) implicated in beta cell proliferation for subsequent validation by RT-PCR. Alterations in miR-216a expression within pancreatic beta cells were also examined using in situ hybridization on the frozen pancreatic sections. For in vitro studies, miR-216a mimics/inhibitors were conjugated to iron oxide nanoparticles and incubated with beta cell line, ?TC-6. Cell proliferation marker Ki67 was evaluated. Expression of the phosphatase and tensin homolog (PTEN), which is one of the direct targets of miR-216a, was analyzed using western blot. For in vivo study, the miR-216a mimics/inhibitors conjugated to the nanoparticles were injected into 12-week-old female diabetic Balb/c mice via pancreatic duct. The delivery of the nanodrug was monitored by in vivo MRI. Blood glucose of the treated mice was monitored post injection. Ex vivo histological analysis of the pancreatic sections included staining for insulin, PTEN and Ki67. miRNA microarray demonstrated that the expression of miR-216a in the islets from NOD mice significantly changed during T1D progression. In vitro studies showed that treatment with a miR-216a inhibitor nanodrug suppressed proliferation of beta cells and increased the expression of PTEN, a miR-216a target. In contrast, introduction of a mimic nanodrug decreased PTEN expression and increased beta cell proliferation. Animals treated in vivo with a mimic nanodrug had higher insulin-producing functionality compared to controls. These observations were in line with downregulation of PTEN and increase in beta cell proliferation in that group. Our studies demonstrated that miR-216a could serve as a potential therapeutic target for the treatment of diabetes. miR-216a-targeting theranostic nanodrugs served as exploratory tools to define functionality of this miRNA in conjunction with in vivo MR imaging.

Dataset Information

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

Publications

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

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