Theranostics 2018; 8(5):1435-1448. doi:10.7150/thno.22482

Research Paper

Targeted Delivery of Functionalized Upconversion Nanoparticles for Externally Triggered Photothermal/Photodynamic Therapies of Brain Glioblastoma

Yuan-Chung Tsai1, Priya Vijayaraghavan1, Wen-Hsuan Chiang1, Hsin-Hung Chen1,2, Te-I Liu1, Ming-Yin Shen1,3, Ayumu Omoto4, Masao Kamimura4,5, Kohei Soga4,5✉, Hsin-Cheng Chiu1✉

1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
2. Department of Chemical Engineering, National Chung Hsing University, Taichung 40249, Taiwan
3. Department of Surgery, National Taiwan University Hospital-Hsinchu Branch, Hsinchu 30013, Taiwan
4. Department of Materials Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan
5. Imaging Frontier Center (IFC), Research Institute for Science and Technology (RIST), Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan

Abstract

Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work.

Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS). The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis.

Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days).

Conclusion: In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM.

Keywords: Upconversion nanoparticles, glioblastoma multiforme, orthotopic tumor, angiopep-2, photothermal therapy, photodynamic therapy

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How to cite this article:
Tsai YC, Vijayaraghavan P, Chiang WH, Chen HH, Liu TI, Shen MY, Omoto A, Kamimura M, Soga K, Chiu HC. Targeted Delivery of Functionalized Upconversion Nanoparticles for Externally Triggered Photothermal/Photodynamic Therapies of Brain Glioblastoma. Theranostics 2018; 8(5):1435-1448. doi:10.7150/thno.22482. Available from http://www.thno.org/v08p1435.htm