Original Article
Selenium-doped calcium phosphate biomineral reverses multidrug resistance to enhance bone tumor chemotherapy

https://doi.org/10.1016/j.nano.2020.102322Get rights and content

Abstract

The construction of a functional drug delivery system to reverse the multidrug resistance (MDR) of bone tumors in cases of failed chemotherapy remains a challenge. Herein, we demonstrate a selenium-doped calcium phosphate (Se-CaP) biomineral with high biocompatibility, biodegradability and pH-sensitive drug release properties. Se-CaP may not only serve as an effective drug-carrier to enhance the uptake of doxorubicin (DOX), but may also synchronously induce caspases-mediated apoptosis of osteosarcoma by generating intracellular reactive oxygen species (ROS). Furthermore, in vitro and in vivo studies obviously demonstrate that Se-CaP can reverse the MDR of osteosarcoma by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (ABCB1 and ABCC1). Finally, DOX-loaded Se-CaP can significantly inhibit DOX-resistant MG63 (MG63/DXR) tumor growth in nude mice. Considering its biomimetic chemical properties, the Se-CaP biomineral, with the multiple functions mentioned above, could be a promising candidate for treating bone tumors with MDR characteristics.

Graphical Abstract

Selenium-doped calcium phosphate (Se-CaP) biominerals with high biocompatibility, biodegradability and pH-sensitive drug release properties have been prepared, which not only serve as effective drug-carrier to enhance the uptake of Doxorubicin, but also synchronously induce the apoptosis of osteosarcoma in vitro and in vivo. With the similar chemical properties to the inorganic component of hard tissue, Se-CaP biomineral may be a promising candidate in treating bone tumor with MDR characteristic.

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Section snippets

Materials and methods

Se-CaPs with Se/(Se + P) molar ratios of 0, 0.005, 0.01, 0.03, 0.09 and 0.15 were synthesized through a microwave-assisted hydrothermal method using adenosine 5′-triphosphate disodium salt hydrate (C10H14N5O13P3Na2·xH2O, Na2ATP) (Sigma-Aldrich Co., US) as the organic phosphorus source. The obtained products were labeled as control, Se0.005-CaP, Se0.01-CaP, Se0.03-CaP, Se0.09-CaP and Se0.15-CaP. The as-prepared different Se-CaPs samples were characterized with X-ray powder diffraction (XRD),

Synthesis and characterization

A series of CaP and Se-CaP microspheres were synthesized using Na2ATP as a phosphorus source, under a microwave-assisted hydrothermal reaction at 110 °C for 10 min (Figure 1, A). Scanning electron microscopy (SEM, Figure 1, B, C) and transmission electron microscopy (TEM, Figure 1, E, F) were used to characterize the morphologies of CaP and Se-CaP products, which displayed a microsphere structure with diameters of approximately 200 nm and 150 nm, respectively. After the addition of SeO32− in

Discussion

To overcome MDR, numerous innovative therapeutic strategies have been designed, and among them, NDDS has achieved great success and drawn much attention.30 One of the most inspiring results is the pegylated liposomal doxorubicin, which has been applied in clinical treatments for cancer therapy.31 Pegylated liposomal doxorubicin has also been reported to be effective for advanced sarcomas after the failure of conventional agents with modest toxicity.32,33

Most NDDSs are designed to facilitate

Declaration of competing interest

There are no conflicts to declare.

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    • Cited by (6)

    The financial support from the National Natural Science Foundation of China (81572630, 81872174, 31771081), the Science and Technology Commission of Shanghai Municipality (18ZR1445100, 19XD1402900, 19JC1414300) and S&T Innovation 2025 Major Special Programme of Ningbo (2018B10040) is gratefully acknowledged.

    1

    These authors contributed equally to this work and should be considered co-first authors.

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