In vivo targeting and positron emission tomography imaging of tumor vasculature with 66Ga-labeled nano-graphene

Abstract

The goal of this study was to employ nano-graphene for tumor targeting in an animal tumor model, and quantitatively evaluate the pharmacokinetics and tumor targeting efficacy through positron emission tomography (PET) imaging using 66Ga as the radiolabel. Nano-graphene oxide (GO) sheets with covalently linked, amino group-terminated six-arm branched polyethylene glycol (PEG; 10 kDa) chains were conjugated to NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid, for 66Ga-labeling) and TRC105 (an antibody that binds to CD105). Flow cytometry analyses, size measurements, and serum stability studies were performed to characterize the GO conjugates before in vivo investigations in 4T1 murine breast tumor-bearing mice, which were further validated by histology. TRC105-conjugated GO was specific for CD105 in cell culture. 66Ga-NOTA-GO-TRC105 and 66Ga-NOTA-GO exhibited excellent stability in complete mouse serum. In 4T1 tumor-bearing mice, these GO conjugates were primarily cleared through the hepatobiliary pathway. 66Ga-NOTA-GO-TRC105 accumulated quickly in the 4T1 tumors and tumor uptake remained stable over time (3.8 ± 0.4, 4.5 ± 0.4, 5.8 ± 0.3, and 4.5 ± 0.4 %ID/g at 0.5, 3, 7, and 24 h post-injection respectively; n = 4). Blocking studies with unconjugated TRC105 confirmed CD105 specificity of 66Ga-NOTA-GO-TRC105, which was corroborated by biodistribution and histology studies. Furthermore, histological examination revealed that targeting of NOTA-GO-TRC105 is tumor vasculature CD105 specific with little extravasation. Successful demonstration of in vivo tumor targeting with GO, along with the versatile chemistry of graphene-based nanomaterials, makes them suitable nanoplatforms for future biomedical research such as cancer theranostics.

Nano-graphene oxide composite for in vivo imaging

“…To address this, regulations specifically governing the current good manufacturing practice of PET radiotracers have been developed in recent years. [10][11][12] To achieve the best contrast for PET imaging, several key issues need to be taken into consideration, such as how to choose the appropriate isotopes as positron emitters and nanoparticles as radiotracers, what chemical reactions can be utilized to improve the labeling efficiency, and how to functionalize the nanoparticles. 13 Nanomaterials have unique properties, and have attracted considerable interest in biomedical applications.…”

Graphene Oxide/Ag Nanoparticles Cooperated with Simvastatin as a High Sensitive X‐Ray Computed Tomography Imaging Agent for Diagnosis of Renal Dysfunctions

“…Moreover, the multifunctional GO and its composites have been synthesized for in vivo imaging of GO through Raman, fluorescence, radioactive, and infrared imaging technology, and so on. [16][17][18][19][20][21] Importantly, in vivo CT imaging of GO to tumor also has been preliminarily studied by labeling of metal nanoparticles. [22][23][24][25] Shi et al [22] synthesized the GO@Ag-DOX nanoparticles for chemo-photothermal therapy and X-ray imaging of the subcutaneous tumor.…”

Radio-graphene in Theranostic Perspectives

“…Radio-graphene has been designed in various synthetic methods [22][23][24][25][26][27]. Functional moiety exposed at the edge of graphene oxide (GO) can be modified for radionuclide labeling.…”

“…Researchers have been working to find strategies for the development of in vivo active tumor targeting of graphene through the incorporation of specific ligands [26][27][28][29]. Using PET imaging, Hong et al evaluated the tumor targeting efficacy and pharmacokinetics of 66 Ga-labeled GO conjugated with TRC105 antibody that targets CD105, an ideal marker for tumor angiogenesis [26].…”

“…Using PET imaging, Hong et al evaluated the tumor targeting efficacy and pharmacokinetics of 66 Ga-labeled GO conjugated with TRC105 antibody that targets CD105, an ideal marker for tumor angiogenesis [26]. The images showed that GO conjugated with TRC105 accumulated very rapidly in the tumor and the uptake remained stable even after 24 h post injection [26].…”