Sensitive Angiogenesis Imaging of Orthotopic Bladder Tumors in Mice Using a Selective Magnetic Resonance Imaging Contrast Agent Containing VEGF121/rGel

Cho, Eun Jin; Yang, Jaemoon; Mohamedali, Khalid A.; Lim, Eun‐Kyung; Kim, Eunjung; Farhangfar, Carol J.; Suh, Jin Suck; Haam, Seungjoo; Rosenblum, Michael G.; Huh, Yong Min

doi:10.1097/rli.0b013e3182174fad

Cited by 35 publications

(34 citation statements)

References 17 publications

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“…However, the oxidation is much facilitated in aqueous solutions (vide infra). In order to examine the pH-dependent stability of the formed MnO@Mn 3 O 4 nanourchin, we placed MnO nanourchins surface-modified with carboxylated amphiphilic polysorbate 80 molecules [10] in phosphate-buffered saline (PBS) solutions of various pH values. While the nanourchin is very stable at pH values above 7, the MnO core is easily dissolved at lower pH conditions (pH 4-6) to give a hollow Mn 3 O 4 nanourchin ( Figure S13 in the Supporting Information).…”

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confidence: 99%

Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T₁ Contrast Agents for Magnetic Resonance Imaging

et al. 2011

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The ultrasensitive detection of cancer in its earliest stage would greatly help the ensuing treatment process, and therefore various imaging modalities and image-enhancing methods are being developed.[1] In particular, metal oxide nanoparticles prove to be promising contrast agents in magnetic resonance imaging (MRI) for the ultrasensitive detection of cancer, and the principles for enhancing MRI contrast have been deciphered recently.[2] For example, it is advantageous to employ superparamagnetic metal oxide nanoparticles with high magnetization values (emu g À1 ) for improved T 2 image contrast.[3] In addition, clusters of superparamagnetic nanoparticles exhibit greater T 2 contrast abilities than individual nanoparticles.[4] Therefore, the clustering of magnetic nanoparticles with high magnetization values is advantageous because of both improved T 2 contrast and the frugal usage of targeting moieties. For enhanced T 1 contrast, nanoparticles should have numerous high-spin metal ions exposed on the surface for facilitated interactions with the surrounding water molecules. [5,6] This calls for the use of smaller nanoparticles with a high surface-to-volume ratio, but simply using a high number of small nanoparticles is not compatible with the frugal usage of targeting moieties. In the case of large nanoparticles, the non-exposed metal ions in the core cannot contribute to the MRI T 1 contrast; the T 1 -weighted image obtained with metal ions is much poorer than that from conventional ion-based contrast agents.We reasoned that the highest surface area for a nanoparticle of a given diameter would be provided by an urchinlike morphology as shown in Figure 1. As a model system to prove our concept, manganese oxides were investigated that had been previously used as an MRI T 1 contrast agent. This system is particularly interesting because of the easy conversion of MnO to Mn 3 O 4 and the different stabilities of these two manganese oxide phases under physiological conditions. It is envisaged that the MnO nanoparticle trapped in the thin shell of an urchin-shaped stable Mn 3 O 4 phase can be unloaded in the form of Mn II ions to the low-pH sites (< pH 7) in the tumor. While the low pH of tumor cells has been exploited for the fabrication of numerous activatable drug-delivery systems, [7] a nanoparticle-based pH-activatible MRI agent is unprecedented to our knowledge. The combination of the T 1 contrast effect from the empty Mn 3 O 4 urchin shell with a high surface area and the released Mn II ions should make the MnO@Mn 3 O 4 nanourchin a powerful MRI T 1 contrast agent. Herein we report the synthesis of the MnO@Mn 3 O 4 nanourchin through facet-selective etching as well as its successful application as a pH-responsive activatable T 1 contrast agent,

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Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T₁ Contrast Agents for Magnetic Resonance Imaging

et al. 2011

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“…MRI has been used to image nanoparticle distribution in a variety of contexts, such as neuroinflammation in root compression (28), soft tissue infection (29), atherosclerosis (30, 31), and angiogenesis in tumor models (32, 33), as well as to confirm SPIO delivery to rabbit liver tumors (8, 34). Recent work in a different rodent model of HCC showed that MRI can quantify both intratumoral uptake of SPIOs after intravenous delivery (17) and labeled NK cells after intra-arterial delivery (35).…”

Section: Discussionmentioning

confidence: 99%

MR Imaging Enables Measurement of Therapeutic Nanoparticle Uptake in Rat N1-S1 Liver Tumors after Nanoablation

McDevitt

Mouli

Tyler

et al. 2014

Journal of Vascular and Interventional Radiology

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Purpose Superparamagnetic iron oxide nanoparticles (SPIOs) functionalized with doxorubicin (DOX) can serve dual diagnostic and therapeutic purposes. Nanoablation is an approach to increase intratumoral nanoparticle uptake that combines IV nanoparticle delivery with reversible electroporation. However, a method to quantify drug delivery during this therapy is needed. This study tested the hypothesis that MRI can quantify intratumoral SPIO uptake after nanoablation. Methods DOX-SPIOs were synthesized. N1-S1 hepatomas were successfully induced in 17 Sprague-Dawley rats distributed into three dosage groups. Baseline tumor R2* values (the reciprocal of T2*) were determined using 7T MRI. Following IV injection of SPIOs, reversible electroporation (1300 V/cm, 8 pulses, 100 µs pulse duration) was applied. Animals were imaged to determine post-procedural tumor R2* and change in R2* (ΔR2*) was calculated. Inductively-coupled plasma mass spectrometry was used to determine post-procedure intratumoral iron concentration, which served as a proxy for SPIO uptake. Mean tumor iron concentration and ΔR2* for each subject were assessed for correlation with linear regression, and mean iron concentration for each dosage group was compared with analysis of variance. Results ΔR2* significantly correlated with tumor SPIO uptake after nanoablation (r=0.50, p=0.039). On average, each 0.1 ms−1 increase in R2* corresponded to a 0.1394 mM increase in iron concentration. There was no significant difference in mean SPIO uptake among dosage groups (p=0.57). Conclusion Intratumoral SPIO uptake after nanoablation can be successfully quantified non-invasively with 7T MRI. Imaging can thus be used as a method to estimate localized drug delivery after nanoablation.

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“…Recent studies have identified key angiogenic factors, such as basic fibroblast growth factor, interleukin-8, hypoxia-inducible factors, and vascular endothelial growth factor A (VEGFA). Among these, VEGFA and one of its receptors (vascular endothelial growth factor receptor 2, VEGFR2) have been established as the primary proangiogenic factors [11,12]. …”

Section: Introductionmentioning

confidence: 99%

Aptamer-modified magnetic nanoprobe for molecular MR imaging of VEGFR2 on angiogenic vasculature

et al. 2013

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Nucleic acid-based aptamers have been developed for the specific delivery of diagnostic nanoprobes. Here, we introduce a new class of smart imaging nanoprobe, which is based on hybridization of a magnetic nanocrystal with a specific aptamer for specific detection of the angiogenic vasculature of glioblastoma via magnetic resonance (MR) imaging. The magnetic nanocrystal imaging core was synthesized using the thermal decomposition method and enveloped by carboxyl polysorbate 80 for water solubilization and conjugation of the targeting moiety. Subsequently, the surface of the carboxylated magnetic nanocrystal was modified with amine-functionalized aptamers that specifically bind to the vascular growth factor receptor 2 (VEGFR2) that is overexpressed on angiogenic vessels. To assess the targeted imaging potential of the aptamer-conjugated magnetic nanocrystal for VEGFR2 markers, the magnetic properties and MR imaging sensitivity were investigated using the orthotopic glioblastoma mouse model. In in vivo tests, the aptamer-conjugated magnetic nanocrystal effectively targeted VEGFR2 and demonstrated excellent MR imaging sensitivity with no cytotoxicity.

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Sensitive Angiogenesis Imaging of Orthotopic Bladder Tumors in Mice Using a Selective Magnetic Resonance Imaging Contrast Agent Containing VEGF121/rGel

Abstract: Synthesized VEGF121/rGel-MNPs as targeted MR imaging contrast agents can be specifically delivered to tumors and bind to KDR-expressing angiogenic tumor vessels.

Cited by 35 publications

References 17 publications

Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T₁ Contrast Agents for Magnetic Resonance Imaging

Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T₁ Contrast Agents for Magnetic Resonance Imaging

MR Imaging Enables Measurement of Therapeutic Nanoparticle Uptake in Rat N1-S1 Liver Tumors after Nanoablation

Aptamer-modified magnetic nanoprobe for molecular MR imaging of VEGFR2 on angiogenic vasculature

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Sensitive Angiogenesis Imaging of Orthotopic Bladder Tumors in Mice Using a Selective Magnetic Resonance Imaging Contrast Agent Containing VEGF121/rGel

Abstract: Synthesized VEGF121/rGel-MNPs as targeted MR imaging contrast agents can be specifically delivered to tumors and bind to KDR-expressing angiogenic tumor vessels.

Cited by 35 publications

References 17 publications

Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T1 Contrast Agents for Magnetic Resonance Imaging

Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T1 Contrast Agents for Magnetic Resonance Imaging

MR Imaging Enables Measurement of Therapeutic Nanoparticle Uptake in Rat N1-S1 Liver Tumors after Nanoablation

Aptamer-modified magnetic nanoprobe for molecular MR imaging of VEGFR2 on angiogenic vasculature

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Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T₁ Contrast Agents for Magnetic Resonance Imaging

Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T₁ Contrast Agents for Magnetic Resonance Imaging