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Theranostics 2020; 10(6):2791-2802. doi:10.7150/thno.42906 This issue Cite

Research Paper

LDH-stabilized ultrasmall iron oxide nanoparticles as a platform for hyaluronidase-promoted MR imaging and chemotherapy of tumors

Ni Zhang^1*, Yue Wang^2*, Changchang Zhang¹, Yu Fan¹, Du Li¹, Xueyan Cao¹, Jindong Xia², Xiangyang Shi¹, Rui Guo^1✉

1. State Key Laboratory for Modification of Chemical Fiber and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-dimension Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201600, People's Republic of China
2. Department of Radiology, Shanghai Songjiang District Central Hospital, Shanghai 201600, People's Republic of China
*These authors contributed equally to this work.

✉ Corresponding author: Tel: +86 21 67792750; Fax: +86 21 67792306 804. E-mail addresses: ruiguoedu.cn (R. Guo).

Abstract

Development of unique theranostic nanoplatforms for tumor imaging and therapy remains an active topic in current nanomedicine. Here, we designed a novel targeted theranostic nanoplatform for enhanced T₁-weighted magnetic resonance (MR) imaging-guided chemotherapy by constructing layered double hydroxide (LDH)-stabilized ultrasmall iron oxide (Fe₃O₄) nanoparticles with hyaluronic acid (HA) modified as targeting agents, and anticancer drug doxorubicin (DOX) loaded with a high loading efficiency.

Methods: The structure and release property of LDH-Fe₃O₄-HA/DOX nanoplatforms were characterized systematically. B16 melanoma cells with CD44 receptors overexpressed were used as model cells to determine the biocompatibility, targeting capability, and therapeutic efficiency of nanoplatforms. For in vivo experiment, hyaluronidase (HAase) pretreatment was combined with nanoplatform administration to investigate the MR imaging and chemotherapeutic effect.

Results: The LDH-Fe₃O₄-HA nanohybrids possess good colloidal stability and cytocompatibility, display an r₁ relaxivity 10-fold higher than the pristine ultrasmall Fe₃O₄ (4.38 mM^-1 s^-1 vs 0.42 mM^-1 s^-1), and could release drug in a pH-responsive manner. In vitro experiments demonstrate that LDH-Fe₃O₄-HA/DOX nanohybrids are able to specifically target B16 cells overexpressing CD44 receptors and effectively release DOX to nucleus. In vivo results show that with the pretreatment of tumor tissue by HAase to degrade the overexpressed HA in extra-cellular matrix, the designed nanoplatforms have a better tumor penetration for significantly enhanced MR imaging of tumors and tumor chemotherapy with low side effects.

Conclusion: The designed LDH-Fe₃O₄-HA/DOX nanohybrids may be developed as a novel targeted theranostic nanoplatform for enhanced T₁-weighted MR imaging-guided chemotherapy of CD44 receptor-overexpressing tumors.

Keywords: layered double hydroxide, ultra-small iron oxide, hyaluronic acid, hyaluronidase, theranostic nanoplatform

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