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Bombesin-functionalized Superparamagnetic Iron Oxide Nanoparticles for Dual-Modality MR/NIRFI in Mouse Models of Breast Cancer

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Bombesin-functionalized Superparamagnetic Iron Oxide Nanoparticles for Dual-Modality MR/NIRFI in Mouse Models of Breast Cancer

Li Li et al. Int J Nanomedicine.

Abstract

Background: The early and accurate detection afforded by imaging techniques significantly reduces mortality in cancer patients. However, it is still a great challenge to achieve satisfactory performance in tumor diagnosis using any single-modality imaging method. Magnetic resonance imaging (MRI) has excellent soft tissue contrast and high spatial resolution, but it suffers from low sensitivity. Fluorescence imaging has high sensitivity, but it is limited by penetration depth. Thus, the combination of the two modes could result in synergistic benefits. Here, we design and characterize a novel dual-modality MR/near-infrared fluorescence imaging (MR/NIRFI) nanomicelle and test its imaging properties in mouse models of breast cancer.

Methods: The nanomicelles were prepared by incorporating superparamagnetic iron oxide (SPIO) nanoparticles into 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] micelles to which an NIRF dye and a tumor-targeted peptide (N3-Lys-bombesin, Bom) were conjugated. The nanomicelles were characterized for particle size, zeta potential and morphology. The transverse relaxivity, targeting specificity and imaging ability of the nanomicelles for MR/NIRFI were also examined.

Results: The fabricated nanomicelles displayed a well-defined spherical morphology with a mean diameter of 145±56 nm and a high transverse relaxivity (493.9 mM-1·s-1, 3.0T). In MRI, the T2 signal reduction of tumors in the Bom-targeted group was 24.1±5.7% at 4 hrs postinjection, whereas only a 0.1±3.4% (P=0.003) decrease was observed in the nontargeted group. In NIRFI, the contrast increased gradually in the targeted group, and the tumor/muscle ratio increased from 3.7±0.3 at 1 hr to 4.7±0.1 at 2 hrs and to 6.4±0.2 at 4 hrs. No significant changes were observed in the nontargeted group at any time points.

Conclusion: Considering all our results, we conclude that these novel MR/NIRFI dual-modality nanomicelles could be promising contrast agents for cancer diagnosis.

Keywords: SPIO nanoparticles; magnetic resonance imaging; near-infrared fluorescence imaging; tumor diagnosis.

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic diagram for the synthesis of SPIO/DSPE-PEG5k-(Bom&Cy5). Abbreviations: SPIO, superparamagnetic iron oxide; NHS, N-hydroxysuccinimide.
Figure 2
Figure 2
Nanomicelle characterization. Notes: (A) A TEM image of Bom-targeted nanomicelles (scale bar =100 nm). (B) Size distribution of Bom-targeted (blue) and nontargeted (red) nanomicelles in aqueous solution measured by DLS. Abbreviations: TEM, transmission electron microscopy; DLS, dynamic light scattering.
Figure 3
Figure 3
Relaxivity and magnetization measurement. Notes: (A) T2-weighted images of SPIO/DSPE-PEG5k-(Bom&Cy5) nanomicelle samples at different iron concentrations (3.0 T, spin-echo sequence: TR =5000 ms, TE =12 ms). (B) Chart of the change in 1/T2 values with Fe concentration. (C) Hysteresis loops of the SPIO nanoparticles (black) and SPIO/DSPE-PEG5k-(Bom&Cy5) nanomicelles (red) measured at 300 K. Abbreviation: SPIO, superparamagnetic iron oxide.
Figure 4
Figure 4
Cytotoxicity and in vivo toxicology. Notes: (A) In vitro cell viability of HUVEC, L02 and HEK-293 cells after incubation with various concentrations of SPIO/DSPE-PEG5k-(Bom&Cy5) nanomicelles for 24 hrs. (B) Serum biochemistry data on ALT, AST, BUN and CREA. (C) Micrographs of H&E-stained organ slices (heart, lung, liver, spleen and kidney) from mice 3 days, 7 days and 21 days after intravenous injection of SPIO/DSPE-PEG5k-(Bom&Cy5) nanomicelles (H&E staining, 40×). Scale bar =50 µm. Abbreviations: SPIO, superparamagnetic iron oxide; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CREA, creatinine.
Figure 5
Figure 5
Targeting performance in cells. Notes: Fluorescence microscopy of MDA-MB-231 cells incubated with Bom-targeted nanomicelles (1st line), nontargeted nanomicelles (2nd line) and Bom-targeted nanomicelles with free Bom (3rd line). From left to right are DAPI-labeled nuclei, Cy5-labeled nanomicelles and their overlay (scale bar =50 µm).
Figure 6
Figure 6
In vivo dual-modality imaging performance. Notes: (A) MR images (3.0 T, T2-weighted fast spin echo sequence: TR =4000 ms, TE =66 ms, FOV =50 mm × 50 mm, slice thickness =1 mm) and (B) NSI of an MDA-MB-231 mouse xenograft tumor at different times after the intravenous injection of Bom-targeted nanomicelles and nontargeted nanomicelles. NSI=SItumor/SIwater phantom. (C) NIRF images and (D) average radiant efficiencies (p/s/cm2/sr)/(μW/cm2) at different times after the injection of Bom-targeted or nontargeted nanomicelles. The red arrows indicate tumors. Abbreviations: NSI, normalized signal intensity; NIRF, near-infrared fluorescence.
Figure 7
Figure 7
Prussian blue staining of tumor sections. Notes: Prussian blue-stained tumor tissue section from mice treated with SPIO/DSPE-PEG5k-(Bom&Cy5) nanomicelles (A) and SPIO/DSPE-PEG5k-Cy5 nanomicelles (B), respectively. The red arrows indicate SPIO nanoparticles. Scale bar =50 µm. Abbreviation: SPIO, superparamagnetic iron oxide.

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