Abstract
Tumorous metastasis is a difficult challenge to resolve for researchers and for clinicians. Targeted delivery of antitumor drugs towards tumor cells’ nuclei can be a practical approach to resolving this issue. This work describes an efficient nuclear-targeting delivery system prepared from trans-activating transcriptional activator (TAT) peptide-functionalized graphene nanocarriers. The TAT peptide, originally observed in a human immunodeficiency virus 1 (HIV-1), was incorporated with graphene via an edge-functionalized ball-milling method developed by the author’s research group. High tumor-targeting capability of the resulting nanocarrier was realized by the strong affinity between TAT and the nuclei of cancer cells, along with the enhanced permeability and retention (EPR) effect of two-dimensional graphene nanosheets. Subsequently, a common antitumor drug, mitomycin C (MMC), was covalently linked to the TAT-functionalized graphene (TG) to form a nuclear-targeted nanodrug MMC-TG. The presence of nanomaterials inside the nuclei of ocular choroidal melanoma (OCM-1) cells was shown using transmission electron microscopy (TEM) and confocal laser scanning microscopy. In vitro results from a Transwell co-culture system showed that most of the MMC-TG nanodrugs were delivered in a targeted manner to the tumorous OCM-1 cells, while a very small amount of MMC-TG was delivered in a non-targeted manner to normal human retinal pigment epithelial (ARPE-19) cells. TEM results further confirmed that apoptosis of OCM-1 cells was started from the lysis of nuclear substances, followed by the disappearance of nuclear membrane and cytoplasm. This suggests that the as-synthesized MMC-TG is a promising nuclear-target nanodrugfor resolution of tumorous metastasis issues at the headstream.
Highlights
New drug delivery systems are required thatare highly active in the body and have a high specific targeting capability
The apoptosis of tumor cells was found to start from lysis of the nuclei, and was followed by the dissolution of karyotheca and cytoplasm. These results suggest the usefulness of the as-synthesized TAT-functionalized graphene (TG)-based system as a highly efficient nuclear-targeting antitumor drug-carrier and as a possible treatment to reduce the metastatic properties of malignant tumors
The as-synthesized mitomycin C (MMC)-TG had a strong suppression capability towards tumorous OCM-1 cells and a low toxicity against normal ARPE-19 cells
Summary
New drug delivery systems are required thatare highly active in the body and have a high specific targeting capability. This goal is considered an ultimate outcome for chemotherapy. Novel nanomaterials may penetrate these physiological barriers and may offer opportunities for the preparation of novel ocular drug delivery systems that can effectively target specific sites of importance. To this end, various biocompatible nanomaterials have been developed to serve as nanosized drug carriers for chemotherapy. It is commonly known that cell nuclei are the source of gene inheritance and transcription [7]
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