Manganese dioxide nanosheets-based redox/pH-responsive drug delivery system for cancer theranostic application

Abstract

The aim of this study was to construct redox- and pH-responsive degradable manganese dioxide (MnO₂) nanosheets for cancer theranostic application. The small MnO₂ nanosheets were synthesized, and then functionalized by hyaluronic acid (HA), demonstrating excellent stability and tumor-targeting ability. Cisplatin (cis-diamminedichloroplatinum [CDDP]) was absorbed by the nanosheets through a physical action, which was designed as MnO₂/HA/CDDP. The prepared MnO₂/HA/CDDP formulation was able to efficiently deliver CDDP to tumor cells in vitro and in vivo, resulting in improved therapeutic efficiency. Subsequently, they were triggered by lower pH and higher level of reduced glutathione to generate Mn²⁺, enabling magnetic resonance imaging. The smart multifunctional system combining efficient magnetic resonance imaging and chemotherapy has the potential to be used as a tumor-targeting theranostic nanomedicine.

Keywords:

• manganese dioxide nanosheets
• hyaluronic acid
• magnetic resonance imaging
• theranostic application

Supplementary materials

Figure S1 XRD spectrum of MnO₂ nanosheets.

Abbreviations: MnO₂, manganese dioxide; XRD, X-ray diffraction.

Figure S2 The interaction between CDDP and HA.

Notes: (A) The interaction of CDDP with carboxyl groups in HA from adjacent nanosheets. (B) The weakening of the metal–carboxylate bond via protonation of the carboxylic groups of the HA units.

Abbreviations: CDDP, cis-diamminedichloroplatinum; HA, hyaluronic acid.

Figure S3 The color change of different formulations under various conditions.

Notes: The images of MnO₂/HA/CDDP in pH 5.0 (A), reductive pH 7.4 PBS containing 2 mM GSH (B) and pH 5.0 containing 2 mM GSH (C). (D) The appearance of the dialysis tubing after 12-hour dialysis for the in vitro release experiment.

Abbreviations: CDDP, cis-diamminedichloroplatinum; GSH, reduced glutathione; HA, hyaluronic acid; MnO₂, manganese dioxide; PBS, phosphate-buffered saline.

Figure S4 H&E staining of major organs from different groups (200×).

Abbreviations: CDDP, cis-diamminedichloroplatinum; HA, hyaluronic acid; H&E, hematoxylin and eosin; MnO₂, manganese dioxide.

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (nos 81572991, 81272527, and 81302717), the China Postdoctoral Science Foundation (nos 2014M562002 and 2015T80783), and the Youth Teacher Development Foundation of Zhengzhou University (no 1421331073).

Disclosure

The authors report no conflicts of interest in this work.