Covalent assembly of nanoparticles as a peptidase-degradable platform for molecular MRI

Perez‐Balderas, Francisco; Kasteren, Sander I. van; Aljabali, Alaa A. A.; Wals, Kim; Serres, Sébastien; Jefferson, Ann; Soto, Manuel Sarmiento; Khrapitchev, Alexandre A.; Larkin, James R.; Bristow, Claire; Lee, Seung Seo; Bort, Guillaume; Simone, Filippo De; Campbell, Sandra J.; Choudhury, Robin P.; Anthony, Daniel C.; Sibson, Nicola R.; Davis, Benjamin G.

doi:10.1038/ncomms14254

Cited by 47 publications

(53 citation statements)

References 37 publications

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“…We have recently developed a nonimmunogenic, fully humanized anti-VCAM-1 antibody and biodegradable multimeric MPIO (mMPIO; ref. 34) to enhance the safety profile of the targeted contrast agent for human use. The mMPIO have the additional advantage of exhibiting approximately three times greater T 2 relaxivities compared with commercially available polystyrene-coated MPIO; thus potentiating the contrast effect in human application (34).…”

Section: Discussionmentioning

confidence: 99%

“…34) to enhance the safety profile of the targeted contrast agent for human use. The mMPIO have the additional advantage of exhibiting approximately three times greater T 2 relaxivities compared with commercially available polystyrene-coated MPIO; thus potentiating the contrast effect in human application (34). Following preclinical toxicology studies, it is anticipated that this agent will go forward to phase I/IIa clinical trial.…”

Section: Discussionmentioning

confidence: 99%

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VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

Cheng

Soto

Khrapitchev

et al. 2019

Clinical Cancer Research

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Purpose: A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types.Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001), and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n ¼ 5-6/group) were injected intravenously with VCAM-1targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T 2 Ã -weighted MRI. Control groups of na€ ve mice injected with VCAM-MPIO and tumor-bearing mice injected with nontargeting IgG-MPIO were included.Results: All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time course. T 2 Ã -weighted MRI of all tumor-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (P < 0.001; twosided) than control cohorts, despite a lack of blood-brain barrier (BBB) impairment. Specific MPIO binding to VCAM-1-positive tumor-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumor types.Conclusions: VCAM-1-targeted MRI enables the detection of brain micrometastases from the three primary tumor types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

Cheng

Soto

Khrapitchev

et al. 2019

Clinical Cancer Research

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“…Magnetic resonance imaging (MRI) is well‐known as a clinical diagnosis tool for soft‐tissue injuries and diseases . Currently, 40–50% of clinical MRI examinations have used contrast agents to enhance the sensitivity, especially for diagnosis of tumors .…”

Section: R1 and R2 Measured Using Different Mri Scanner Systemsmentioning

confidence: 99%

Exceedingly Small Gadolinium Oxide Nanoparticles with Remarkable Relaxivities for Magnetic Resonance Imaging of Tumors

Shen

Fan

Yáng

et al. 2019

Small

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Gd chelates have occupied most of the market of magnetic resonance imaging (MRI) contrast agents for decades. However, there have been some problems (nephrotoxicity, non‐specificity, and low r1) that limit their applications. Herein, a wet‐chemical method is proposed for facile synthesis of poly(acrylic acid) (PAA) stabilized exceedingly small gadolinium oxide nanoparticles (ES‐GON‐PAA) with an excellent water dispersibility and a size smaller than 2.0 nm, which is a powerful T1‐weighted MRI contrast agent for diagnosis of diseases due to its remarkable relaxivities (r1 = 70.2 ± 1.8 mM−1 s−1, and r2/r1 = 1.02 ± 0.03, at 1.5 T). The r1 is much higher and the r2/r1 is lower than that of the commercial Gd chelates and reported gadolinium oxide nanoparticles (GONs). Further ES‐GON‐PAA is developed with conjugation of RGD2 (RGD dimer) (i.e., ES‐GON‐PAA@RGD2) for T1‐weighted MRI of tumors that overexpress RGD receptors (i.e., integrin αvβ3). The maximum signal enhancement (ΔSNR) for T1‐weighted MRI of tumors reaches up to 372 ± 56% at 2 h post‐injection of ES‐GON‐PAA@RGD2, which is much higher than commercial Gd‐chelates (<80%). Due to the high biocompatibility and high tumor accumulation, ES‐GON‐PAA@RGD2 with remarkable relaxivities is a promising and powerful T1‐weighted MRI contrast agent.

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“…The main limitation is the lack of direct clinical translatability of the particles and antibodies that were used in the present study. However, biodegradable MPIOs are now available( 27 ) and anti-human MAdCAM-1 antibodies are currently under clinical investigation( 28 ), opening the way for clinical translation of our imaging method by coupling the two constructs.…”

Section: Discussionmentioning

confidence: 99%

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Fournier

Lizarrondo

Rateau

et al. 2019

Preprint

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One Sentence Summary: Molecular magnetic resonance imaging allows non-invasive evaluation of mucosal inflammation in clinically relevant experimental models. ABSTRACTMucosal tissues line the digestive, respiratory, urinary, mammary and reproductive tracts and play critical roles in health and disease as the primary barrier between the external world and the inner body. Clinical evaluation of mucosal tissues is currently performed using endoscopy, such as ileocolonoscopy for the intestinal mucosa, that causes significant patient discomfort and can lead to organ damage. Here, we developed a new contrast agent for molecular magnetic resonance imaging (MRI) that is targeted to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), an adhesion molecule overexpressed by inflamed mucosal tissues. We investigated the diagnostic performance of molecular MRI of MAdCAM-1 to detect mucosal inflammation in several models of acute and chronic intestinal inflammation in mice. We demonstrated that molecular MRI of MAdCAM-1 reveals disease activity and can evaluate the response to inflammatory treatments along the whole intestinal mucosa in clinically relevant models of inflammatory bowel diseases. We also provide evidence that this new technique can detect low, subclinical levels of mucosal inflammation.Molecular MRI of MAdCAM-1 has thus potential applications in early diagnosis, longitudinal follow-up and therapeutic response monitoring in diseases affecting mucosal tissues, such as inflammatory bowel diseases.Recently, we and others reported the use of a new family of contrast agents for molecular MRI based on micro-sized particles of iron oxide (MPIO) that displays a dramatically higher sensitivity than classically used nano-sized particles(9-12). Thanks to an artefact known as the blooming effect, MPIO appear around 50 times larger than their actual size on iron sensitive T2*-weighted images (12). This characteristic of MPIO makes them particularly interesting for imaging mucosal tissues, since these tissues measure only a few hundred micrometers of thickness in physiological conditions and are thus hardly visible on unenhanced MRI. In the present study in mice, we developed a new MPIO-based contrast agent for MRI targeted to MAdCAM-1 (thereafter named MPIO-αMAdCAM-1). In three different models of intestinal inflammation, including lipopolysaccharides (LPS) induced endothelial activation, dextran sodium sulfate (DSS) induced colitis and trinitrobenzene sulfonic acid (TNBS) induced colitis(13), we demonstrated that this contrast agent allows detection of mucosal inflammation, quantification of disease activity and assessment of the mucosal response to anti-inflammatory treatments.

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Covalent assembly of nanoparticles as a peptidase-degradable platform for molecular MRI

Cited by 47 publications

References 37 publications

VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

Exceedingly Small Gadolinium Oxide Nanoparticles with Remarkable Relaxivities for Magnetic Resonance Imaging of Tumors

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

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