Cy5.5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas

doi:10.1016/j.jcis.2015.06.046

Journal of Colloid and Interface Science

Volume 457, 1 November 2015, Pages 27-34

https://doi.org/10.1016/j.jcis.2015.06.046 Get rights and content

Highlights

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MnO NPs were prepared by a thermal decomposition method.
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Water dispersible MnO NPs were obtained by carboxyl silane modification.
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PEG-Cy5.5 conjugated MnO NPs were fabricated as a dual-modal nanoprobe.
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MnO-PEG-Cy5.5 nanoprobe enables a better detection of brain gliomas.

Abstract

The fusion of molecular and anatomical modalities facilitates more reliable and accurate detection of tumors. Herein, we prepared the PEG-Cy5.5 conjugated MnO nanoparticles (MnO-PEG-Cy5.5 NPs) with magnetic resonance (MR) and near-infrared fluorescence (NIRF) imaging modalities. The applicability of MnO-PEG-Cy5.5 NPs as a dual-modal (MR/NIRF) imaging nanoprobe for the detection of brain gliomas was investigated. In vivo MR contrast enhancement of the MnO-PEG-Cy5.5 nanoprobe in the tumor region was demonstrated. Meanwhile, whole-body NIRF imaging of glioma bearing nude mouse exhibited distinct tumor localization upon injection of MnO-PEG-Cy5.5 NPs. Moreover, ex vivo CLSM imaging of the brain slice hosting glioma indicated the preferential accumulation of MnO-PEG-Cy5.5 NPs in the glioma region. Our results therefore demonstrated the potential of MnO-PEG-Cy5.5 NPs as a dual-modal (MR/NIRF) imaging nanoprobe in improving the diagnostic efficacy by simultaneously providing anatomical information from deep inside the body and more sensitive information at the cellular level.

Graphical abstract

Introduction

Magnetic resonance (MR) imaging produces high-resolution images of soft tissues down to 1 mm at clinical field strengths and therefore provides abundant information about anatomical structure and physiological conditions [1]. This together with the lack of ionizing radiation makes it the most used non-invasive diagnostic modality. The introduction of MRI contrast agents could accelerate the relaxivity of water and consequently further boost the contrast [2]. Currently, gadolinium(Gd)-based complexes are dominant contrast agents in clinics, which induce the local relaxation change of the nearby water protons and reduce longitudinal (T₁) relaxation time, resulting in a positive contrast (bright signal) on the T₁-weighted MR image [3]. However, the association of Gd ions with nephrogenic systemic fibrosis (NSF) in patients with severe renal or kidney disease demands alternative T₁ contrast agents [4], [5].

Manganese (Mn) ions have favored properties as T₁ contrast agents including high spin number, labile water exchange and long electronic relaxation time, natural prevalence, and known human biochemistry [6], [7], [8], [9]. As a matter of fact, Mn ions was one of the earliest reported examples of paramagnetic contrast material for MR imaging. For example, MnCl₂ is used in gastrointestinal imaging [10]. However, the use of Mn²⁺-based T₁ contrast agents has been limited due to cardiovascular toxicity [11]. Recently, Mn-based nanoparticles (NPs), e.g. manganese oxide (MnO) NPs with different sizes and morphologies, have been emerging as promising T₁ contrast agents to overcome the drawbacks of Mn²⁺-based T₁ contrast agents, such as toxicity, short circulation time, and low efficiency of cellular accumulation [11], [12], [13], [14]. In vivo MR imaging studies proved that MnO NPs could lead to an increased contrast of entire organs [15], [16], [17]. For instance, clear T₁-weighted images of brain structures, depicting fine anatomic features, were obtained upon injection of MnO NPs [16]. These findings suggest that MnO NPs can be utilized not only for the basic neuroscience research but also for the diagnosis of clinical neurological diseases.

Despite the aid of contrast agents, the sensitivity of MR imaging is relatively low in comparison to other biomedical imaging techniques. In some cases, the contrast difference between tissues (e.g., normal vs. cancer) might be too subtle to provide precise imaging information [18]. Moreover, molecular and/or biological information on the region of interest is hardly provided by MR imaging. Therefore, the integration of other imaging modalities with high sensitivity, such as optical imaging, is highly desirable to offer specific insight into cellular events and real-time intraoperative monitoring of tumor tissue [19], [20]. To this end, near-infrared fluorescence (NIRF) imaging is the most relevant imaging modality in line with MR imaging, not only because of the higher sensitivity but also due to the weaker fluorescence absorption of biological tissues in the 750–1000 nm region, which ensures a deeper optical penetration with attenuated cytotoxicity and high feature fidelity [21], [22].

One of the advantages of nanoparticles-based probes is their flexibility when conjugated with a variety of functional moieties [23]. On this occasion, MnO NPs offer excellent matrix to accommodate optical imaging modality by conjugation NIR dyes. As such, we prepared the MnO-based nanoprobe with MR and NIRF imaging modalities. Specifically, high crystalline MnO NPs were prepared by the thermal decomposition of manganese oleate. Water dispersible and colloidal stable MnO NPs were then obtained by exchanging oleate with carboxyl silane. The carboxyl functional groups allow the conjugation with PEG-Cy5.5 to MnO-NPs to yield the MnO-PEG-Cy5.5 NPs. The potential of these MnO-PEG-Cy5.5 NPs as an MR/NIRF dual-modal imaging nanoprobe was explored in a glioma-bearing nude mouse model.

Section snippets

Materials

Manganese chloride tetrahydrate, sodium oleate, 1-octadecene, and Cy5.5 were purchased from Sigma. N-(Trimethoxysilylpropyl) ethylene diamine triacetic acid, trisodium salt (TETT silane) was supplied by Gelest. NH₂-PEG₅₀₀-NH₂ was received from JenKem Technology Co. Ltd (Beijing, China). N-Hydroxysuccinimide (NHS) and Ethyl(dimethylaminopropyl)-carbodiimide (EDC) were obtained from Acros Oganics (Geel, Belgium). All other chemicals are of analytical grade and used as received.

Preparation of Mn-oleate complex

To a solvent

Results and discussion

To ensure high crystallinity, MnO NPs was prepared by the thermal decomposition method [26]. As the oleate coating prevents aggregation and flocculation, the produced oleate capped MnO NPs could be readily dispersed in nonpolar solvents (e.g., hexanes, toluene, and chloroform) and form a black dispersion. TEM image (Fig. 1A) verified that the MnO-OA NPs were well-separated with a cubic-like shape and the mean size of MnO-OA NPs was 18.59 ± 1.44 nm (Fig. 1B) by statistical analysis of 100 MnO-OA

Conclusions

In summary, we prepared and characterized water-dispersible PEG-Cy5.5 labelled MnO NPs. These MnO-PEG-Cy5.5 NPs possessed a high r₁ relaxivity and showed a good biocompatibility. In vivo MR imaging suggested that the MnO-PEG-Cy5.5 NPs enhanced the tumor contrast. Whole-body NIRF imaging demonstrated that the brain tumor could be visually detected by MnO-PEG-Cy5.5 NPs due to their preferential accumulation in the glioma region, which was revealed by ex vivo CLSM imaging at the cellular level.

Acknowledgements

The authors gratefully acknowledge the financial supports from National Natural Science Foundation of China (81271639, 81372694), Beijing Sanbo Brain Hospital Advance research program of innovation (2012SJ005), and the Basic-clinical Key Research Grant (13JL02, 15JL07) from Capital Medical University, China.

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¹: These authors contributed equally to this work.

View full text

Cy5.5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Preparation of Mn-oleate complex

Results and discussion

Conclusions

Acknowledgements

Radiol. Clin. North Am.

Trends Mol. Med.

Curr. Opin. Chem. Biol.

J. Colloid Interface Sci.

Molecular imaging

Radiology

Pushing the sensitivity envelope of lanthanide-based magnetic resonance imaging (MRI) contrast agents for molecular imaging applications

Acc. Chem. Res.

Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications

Chem. Rev.

Gadolinium-based contrast agents and NSF: evidence from animal experience

J. Magn. Reson. Imaging

Manganese-enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations

NMR Biomed.

Development of manganese-based nanoparticles as contrast probes for magnetic resonance imaging

Theranostics

Paramagnetic inorganic nanoparticles as T1 MRI contrast agents

Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol.

Revisiting an old friend: manganese-based MRI contrast agents

Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol.

Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design

Chem. Rev.

Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dog and rabbit

AJR, Am. J. Roentgenol.

Paramagnetic inorganic nanoparticles as T₁ MRI contrast agents

Cardiovascular toxicity and tissue proton T₁ response to manganese injection in the dog and rabbit