Abstract
.Significance: The blood–brain barrier (BBB) is a major obstacle to detecting and treating brain tumors. Overcoming this challenge will facilitate the early and accurate detection of brain lesions and guide surgical resection of tumors.Aim: We generated an orthotopic brain tumor model that simulates the pathophysiology of gliomas at early stages; determine the BBB integrity and breakdown over the time course of tumor progression using generic and cancer-targeted near-infrared (NIR) fluorescent molecular probes.Approach: We developed an intracranial tumor xenograft model that rapidly reestablished BBB integrity and monitored tumor progression by bioluminescence imaging. Sham control mice were injected with phosphate-buffered saline only. Fluorescence molecular tomography (FMT) was used to quantify the uptake of tumor-targeted and passive NIR fluorescent imaging agents in orthotopic glioma (U87-GL-GFP PDE7B H217Q cells) tumor model. Cancer-induced and transient (with focused ultrasound, FUS) disruption of BBB integrity was monitored with NIR fluorescent dyes.Results: Stereotactic injection of 50,000 cells into mouse brain allowed rapid reestablishment of BBB integrity within a week, as determined by the inability of both tumor-targeted and generic NIR imaging agents to extravasate into the brain. Tumor-induced BBB disruption was observed 7 weeks after tumor implantation. FUS achieved a similar effect at any time point after reestablishing BBB integrity. While tumor uptake and retention of the passive NIR dye, indocyanine green, was negligible, both actively tumor-targeting agents exhibited selective accumulation in the tumor region. The tumor-targeting molecular probe that clears rapidly from nontumor brain tissue exhibits higher contrast than the analogous vascular-targeting agent and helps delineate tumors from sham control.Conclusions: We highlight the utility of FMT imaging for longitudinal assessment of brain tumors and the interplay between the stages of BBB disruption and molecular probe retention in tumors, with potential application to other neurological diseases.
Highlights
Glioblastoma (GBM) remains one of the most aggressive and deadly types of cancer with an estimated 5-year survival rate of 5.5%.1 It is the most common type of primary malignant brain tumor with 12,760 cases projected in the United States in 2018.1 Management of GBM presents many unique obstacles owing to the relative importance of CNS tissue, necessitating the sparing of tissue during surgical resection
This technique is advantageous over other optical imaging techniques that have been previously utilized for molecular imaging of brain tumors, such as fluorescence reflectance imaging and bioluminescence imaging (BLI) because of the acquisition of paired excitation and fluorescence images that account for tissue inhomogeneity and the ability to localize fluorescence in 3-D with absolute quantification.[7,8,9]
Implanted brain cancer cells expressing a bioluminescent reporter (U87-GLGFP PDE7B H217Q cells) allowed for facile longitudinal localization and monitoring of tumor burden using a commercialBLI system,[25,26] and fluorescence molecular tomography (FMT) was used to quantify the delivery of indocyanine green (ICG) and LS301 to tumors (Fig. 1)
Summary
Glioblastoma (GBM) remains one of the most aggressive and deadly types of cancer with an estimated 5-year survival rate of 5.5%.1 It is the most common type of primary malignant brain tumor with 12,760 cases projected in the United States in 2018.1 Management of GBM presents many unique obstacles owing to the relative importance of CNS tissue, necessitating the sparing of tissue during surgical resection. In addition to offering a wide variety of commercially available molecular probes, high detection sensitivity, and minimal exposure to ionizing radiation, optical methods are generally low cost, portable, and scalable from the microscopic to macroscopic scale compared with traditional imaging systems.[6] Near-infrared (NIR) FMT is akin to x-ray computed tomography in that it produces three-dimensional (3-D) reconstructions of fluorescence distribution by acquiring multiple fluorescence projection images This technique is advantageous over other optical imaging techniques that have been previously utilized for molecular imaging of brain tumors, such as fluorescence reflectance imaging and bioluminescence imaging (BLI) because of the acquisition of paired excitation and fluorescence images that account for tissue inhomogeneity and the ability to localize fluorescence in 3-D with absolute quantification.[7,8,9]
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