In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide

Abstract

Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ~ 120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. 64 Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of 64 Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript when compared with that of non-targeted GO conjugates ( 64 Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics. Graphical Abstract KeywordsNano-graphene oxide (GO); Angiogenesis; Follicle-stimulating hormone receptor (FSHR); Breast cancer metastasis; Positron emission tomography (PET); Image-guided drug delivery

Molybdenum disulfide/graphene oxide nanocomposites show favorable lung targeting and enhanced drug loading/tumor-killing efficacy with improved biocompatibility

“…In parallel to these phenotypes, GO accumulation could be visualized in the lung, as characterized by dark spots representative of GO-cell complexes (indicated by arrows) (Figure 6a and c), analogous to previous studies. 67 In stark contrast, no significant damages were observed in lung sections from mice administrated with bulk MoS 2 , Lys-MoS 2 , FA-MoS 2 and MoS 2 /GO (Figure 6a and b). Plus, no observable pathological alterations were recognized in hearts, spleens and kidneys in all treated mice by these materials (Supplementary Figures S10 − S12).…”

Oxidized graphene nanoparticles as a delivery system for the pro‐apoptotic sphingolipid C6 ceramide

“…Such modified forms of graphene can include materials such as iron oxide nanoparticles, polypyrrole, and silver nanoparticles, and the combination of these materials with graphene oxide can be induced to release more drug loaded onto them through the external application of stimuli such as magnetic fields, electricity, and near‐infrared light, respectively . Graphene can also be functionalized with a wide variety of materials that would allow for the specific targeting of cancer cells, including folic acid, antibodies, and RGD peptides . Such modifications can not only enable higher effective doses of drug delivered to cancer cells, but can also reduce the toxicity to surrounding healthy tissue caused by nonspecific delivery.…”

Recent advancements in two‐dimensional nanomaterials for drug delivery

“…After the oxidation from graphene, abundant functional groups, such as epoxide, hydroxyl, and carboxylic acid, show up on the surface of GO (D. Yang et al, ). Such oxidation largely enhances the biocompatibility of GO and facilitates its combination with biomolecules (including proteins and anticancer drugs), thus making it a much better candidate for biomedical applications (Sharafeldin et al, ; C. Zhu, Du, & Lin, ; J. Zhu, Xu, et al, ).…”