Targeted Fe-doped silica nanoparticles as a novel ultrasound–magnetic resonance dual-mode imaging contrast agent for HER2-positive breast cancer

Xiaoyu LiUltrasound Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, [email protected]; [email protected]

Shujun XiaUltrasound Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, [email protected]; [email protected]

Wei ZhouUltrasound Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, [email protected]; [email protected]

Ri JiUltrasound Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, [email protected]; [email protected]Correspondence[email protected] [email protected]

Weiwei ZhanUltrasound Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, [email protected]; [email protected]Correspondence[email protected] [email protected]

Abstract

Background

Multimodal contrast agents with low toxicity and targeted modification have opened up new possibilities for specific imaging of breast cancer and shown broad application prospects in biomedicine and great potential for clinical transformation. In this work, a potential multifunctional imaging agent was developed by doping Fe into hollow silica nanoparticles (HS-Fe NPs), followed by modification with specific anti-HER2 antibodies, enabling the NPs to have dual-mode ultrasound (US)–magnetic resonance (MR)-specific imaging capacity with low toxicity.

Methods

Anti-HER2 antibodies were conjugated to silane–polyethylene glycol (PEG)–COOH-modified HS-Fe (HS-Fe-PEG) NPs to produce HER2-targeted HS-Fe-PEG (HS-Fe-PEG-HER2) NPs. The toxicity of HS-Fe-PEG-HER2 NPs on targeted cells in vitro and blood and organ tissue of mice in vivo was investigated. Distribution in vivo was also studied. Confocal laser-scanning microscopy and flow cytometry were used to evaluate the targeting ability of HS-Fe-PEG-HER2 NPs in vitro. US and MR instruments were used for imaging both in vivo and in vitro.

Results

The obtained HS-Fe-PEG-HER2 NPs (average diameter 234.42±48.76 nm) exhibited good physical properties and biosafety. In solution, they showed obvious enhancement of the US signal and negative contrast in T₂-weighted MR imaging. The binding rate of HS-Fe-PEG-HER2 NPs to targeted cells (SKBR3) was 78.97%±4.41% in vitro. US and MR imaging in vivo confirmed that the HS-Fe-PEG-HER2 NPs were delivered passively into the tumor region of SKBR3 and bound specifically to tumor cells. Target enhancement was better than untargeted and targeted competition groups.

Conclusion

HS-Fe-PEG-HER2 NPs have potential as a low-cytotoxicity and dual-mode US–MR-specific imaging agent.

Keywords:

Supplementary materials

Figure S1 T₁-weighted magnetic resonance images of HS-Fe-PEG-HER2 NPs.

Abbreviations: HS, hollow silica; PEG, polyethylene glycol; NPs, nanoparticles.

Figure S1 T1-weighted magnetic resonance images of HS-Fe-PEG-HER2 NPs.Abbreviations: HS, hollow silica; PEG, polyethylene glycol; NPs, nanoparticles.

Figure S2 Major blood-cell analysis after treatment with HS-Fe-PEG-HER2 NPs at different times (0, 1 hour, 4 hours, 8 hours, 24 hours, 7 days, 14 days).

Notes: (A) red blood cells; (B) white blood cells; (C) platelets; (D) monocytes; (E) hemoglobin; (F) lymph cells.

Abbreviations: HS, hollow silica; PEG, polyethylene glycol; NPs, nanoparticles.

Figure S2 Major blood-cell analysis after treatment with HS-Fe-PEG-HER2 NPs at different times (0, 1 hour, 4 hours, 8 hours, 24 hours, 7 days, 14 days).Notes: (A) red blood cells; (B) white blood cells; (C) platelets; (D) monocytes; (E) hemoglobin; (F) lymph cells.Abbreviations: HS, hollow silica; PEG, polyethylene glycol; NPs, nanoparticles.

Figure S3 Confocal microscopy of SKBR3 and MDA-MB-231 incubation with corresponding groups.

Abbreviation: FITC, fluorescein isothiocyanate.

Acknowledgments

This work was partially supported by the National Natural Science Foundation of China (grants 81701710 and 81671688).

Disclosure

The authors report no conflicts of interest in this work.