Original Article
Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: Potential for targeting experimental brain tumors

https://doi.org/10.1016/j.nano.2013.12.006Get rights and content

Abstract

Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50 nm or 120 nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120 nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors.

From the Clinical Editor

This study demonstrates the use of magnetic resonance image-guided transcranial focused ultrasound to open the BBB and enable spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS)-based molecular imaging for experimental tumor tracking.

Graphical Abstract

Surface enhanced Raman scattering (SERS) nanoparticles have gained prominence in their potential diagnostic and therapeutic applications in cancer medicine. Focused ultrasound is a novel technique that can enhance the delivery of nanoparticles across the blood-brain barrier. In this study we demonstrate the feasibility of delivering SERS gold nanoparticles to the invasive front of a malignant brain tumor model. In addition, we demonstrate in-vitro uptake of multifunctional SERS gold nanoparticles by glioblastoma cells and the capacity to use these particles for glioblastoma tumor cell labeling in-vivo.

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Section snippets

Cell culture

The following cell types were cultured as described in Supplementary Methods: rat gliosarcoma cell line 9L; rat C6 glioma; human GBM cells U87, A172, U251, U373; normal fetal human astrocytes; primary oligodendroglioma tumor cells BT2012036; and GBM adherent stem cell line GLINS1.27

Nanoparticle synthesis and characterization

GNPs (50 nm) coated with PEG (MW 2000 Da) were purchased from Nanocs, New York, USA. Silica coated SERS-reporter gold nanoparticles were purchased from Cabot Security Materials, Massachusetts, USA (see Supplementary

Results

Targeted delivery of polyethylene glycol (PEG) (5000 MW) coated 50 nm GNPs to intra-axial brain tumors and their margins was performed using TcMRgFUS. The disruption of the BBB at tumor margins was confirmed by the presence of increased Gadodiamide enhancement at the tumor periphery (Figure 1). Opening of the BBB with fixed acoustic power resulted in extravasation of circulating 50 nm GNPs adjacent to the infiltrating tumor margin observed by silver enhancement histology (Figure 1). No parenchymal

Discussion

Multiple approaches to the delivery of nanoparticles to brain tumors have been described recently including convection enhanced direct tumor delivery,40 focal radiation,3 and focused ultrasound BBB disruption combined with magnetic steering.41 We have shown in this study that TcMRgFUS can be used to target the delivery of GNPs with the capacity for cellular internalization and SERS detection to the invasive margin of a malignant brain tumor model. TcMRgFUS offers a radiation-free and reversible

Acknowledgments

We thank Dr. Christopher Smith for providing advice on multivesicular body labeling in GBM cells. The rat FUS experiments were greatly facilitated by the technical expertise of Shawna Rideout and Alexandra Garces, Sunnybrook Research Institute. We thank James Jonkman of the Advanced Optical Microscopy Facility, University Health Network for facilitating the use of the Raman confocal microscope. Dr. Peter Dirks (The Hospital for Sick Children, Toronto) and Dr. Sunit Das (St. Michael’s Hospital,

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      The contrast is administered either IV simultaneously or after FUS, or as an intraperitoneal bolus injection [46,74]. Several studies set out dynamic contrast enhanced (DCE)-MRI protocols to follow the dynamics of BBB opening [35,57,63]. Nevertheless, the generally used method to confirm BBB opening remains ex vivo histological assessment following IV injection of anionic dyes such as Trypan or Evans blue, alone or coupled with contrast enhanced MRI prior to animal sacrifice.

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    Funding: RJD and PZM are Canada Vanier Graduate Scholars. Project funding from Canadian Institutes of Health Research (CIHR) MOP-74610, Canadian Cancer Society Research Institute, Brain Tumour Foundation of Canada, brainchild – Canada, Canadian Research Chairs program, and National Institutes of Health grant no. EB00326. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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