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

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.

Vinorelbine cationic liposomes modified with wheat germ agglutinin for inhibiting tumor metastasis in treatment of brain glioma

“…There is an increasing evidence that the inability to obtain a precise boundary definition of glioma has compromised on the complete resection and radiation therapy [3]. Although chemotherapy has been considered as a significant strategy for glioma therapy, the therapeutic effect is still unsatisfactory due to the existence of blood-brain barrier (BBB), the properties of tumor metastasis and the obvious side effects of antitumor drugs [4]. Therefore, there is an urgent need for developing a new chemotherapy strategy to overcome those limitations.…”

Photodynamic Therapy for the Treatment of Glioblastoma

“…Upconverting nanoparticles, nanoparticles that convert multiple incident photons (generally in the infrared range) into an emitted photon (in the visible light range) of higher energy for PDT is an area of active research (77,78). Another shortcoming of clinically available photosensitizers is the peak excitation wavelength necessary for activation requires wavelengths of light that poorly penetrate brain tissue.…”

“…Another shortcoming of clinically available photosensitizers is the peak excitation wavelength necessary for activation requires wavelengths of light that poorly penetrate brain tissue. To address this limitation, nanoparticles are in development that are activated by deeperpenetrating near infrared light which causes the nanoparticles to release photons at the photosensitizer excitation wavelengths (78). The goal is to achieve a higher degree of tumor cell specificity (even in regions with intact BBB) while being able to apply PDT at greater distances from the light source and, therefore, over a larger tissue volume than can be achieved using current PDT techniques.…”

Near-Infrared Light-Triggered Photodynamic Therapy and Apoptosis Using Upconversion Nanoparticles With Dual Photosensitizers

“…Therefore, to increase the light penetration depth, it is necessary to develop efficient PDT agents that are excited by long wavelengths, such as near-infrared (NIR) light (Kobayashi and Choyke, 2019). Recently, lanthanide-doped upconversion nanoparticles (UCNPs) were developed to achieve NIR-triggered PDT (Guo et al, 2010;Tsai et al, 2018). As an anti-Stokes shifting material, UCNPs are the most efficient materials for converting NIR light to UV and visible light (Chen et al, 2014;Dong et al, 2015).…”