Doxorubicin and indocyanine green loaded superparamagnetic iron oxide nanoparticles with PEGylated phospholipid coating for magnetic resonance with fluorescence imaging and chemotherapy of glioma

Chen Shen1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]

Xiaoxiong Wang1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]

Zhixing Zheng1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]

Chuang Gao3 Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China, [email protected]

Xin Chen1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]

Shiguang Zhao1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]Correspondence[email protected]

Zhifei Dai3 Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China, [email protected]Correspondence[email protected]

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Abstract

Background

Glioma represents the most common malignant brain tumor. Outcomes of surgical resection are often unsatisfactory due to low sensitivity or resolution of imaging methods. Moreover, the use of traditional chemotherapeutics, such as doxorubicin (DOX), is limited due to their low blood–brain barrier (BBB) permeability. Recently, the development of nanotechnology could overcome these obstacles.

Materials and methods

Hydrophobic superparamagnetic iron oxide nanoparticles (SPIO NPs) were prepared with the use of thermal decomposition method. They were coated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG 2000) and DOX using a thin-film hydration method followed by loading of indocyanine green (ICG) into the phospholipid layers. Details regarding the characteristics of NPs were determined. The in vitro biocompatibility and antitumor efficacy were established with the use of MTT assay. In vivo fluorescence and magnetic resonance (MR) imaging were used to evaluate BBB penetration and accumulation of NPs at the tumor site. Antitumor efficacy was evaluated using measures of tumor size, median survival times, body weights, and H&E staining.

Results

The multifunctional NPs generated had an average diameter of 22.9 nm, a zeta potential of −38.19 mV, and were capable of providing a sustained release of DOX. In vitro experiments demonstrated that the SPIO@DSPE-PEG/DOX/ICG NPs effectively enhanced cellular uptake of DOX as compared with that of free DOX. In vivo fluorescence and MR imaging revealed that the NPs not only effectively crossed the BBB but selectively accumulated at the tumor site. Meanwhile, among all groups studied, C6 glioma-bearing rats treated with the NPs exhibited the maximal degree of therapeutic efficacy, including smallest tumor volume, lowest body weight loss, and longest survival times, with no obvious side effects.

Conclusion

These results suggest that the SPIO@DSPE-PEG/DOX/ICG NPs can not only function as a nanoprobe for MR and fluorescence bimodal imaging, but also as a vehicle to deliver chemotherapeutic drugs to the tumor site, to achieve the theranostic treatment of glioma.

Keywords:

Supplementary materials

Figure S1 Body weights of glioma-bearing Wistar rats treated with saline, SPIO@DSPE-PEG NPs, free DOX, and SPIO@DSPE-PEG/DOX/ICG NPs. Data are shown as mean ± SD, n=6.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure S2 TUNEL analysis of frozen tumor sections after different treatments.

Note: Green: TUNEL-stained apoptosis cells; blue: DAPI-labeled cell nuclei; G: glioma tissues; B: brain tissues.

Figure S3 Histological sections of the heart, liver, spleen, lung, kidney, and muscle stained with H&E.

Acknowledgments

This work was financially supported by the National Key Research and Development Program of China (No. 2016YFA0201400) and National Natural Science Foundation of China (No. 81472368). The authors are grateful to Yanyan Li, Yongbo Yang, Yushen Jin, and Prof Jie Tian for providing support to the current work.

Disclosure

The authors report no conflicts of interest in this work.