Emel Kirbas Cilingir

Ultrasmall glucose carbon dots rapidly cross the blood-spinal cord barrier and target neurons at the spinal and supraspinal network. The graphical abstract was created in BioRender.

The carbon nitride dot (CND) is an emerging carbon-based nanomaterial. It possesses rich surface functional moieties and a carbon nitride core. Spectroscopic data have demonstrated the analogy between CNDs and cytosine/uracil. Recently, it was found that CNDs could interrupt the normal embryogenesis of zebrafish. Modifying CNDs with various nucleobases, especially cytosine, further decreased embryo viability and increased deformities. Physicochemical property characterization demonstrated that adenine- and cytosine-incorporated CNDs are similar but different from guanine-, thymine- and uracil-incorporated CNDs in many properties, morphology, and structure. To investigate the embryogenesis interruption at the cellular level, bare and different nucleobase-incorporated CNDs were applied to normal and cancerous cell lines. A dose-dependent decline was observed in the viability of normal and cancerous cells incubated with cytosine-incorporated CNDs, which matched results from the zebrafish embryogenesis experiment. In addition, nucleobase-incorporated CNDs were observed to enter cell nuclei, demonstrating a possibility of CND–DNA interactions. CNDs modified by complementary nucleobases could bind each other via hydrogen bonds, which suggests nucleobase-incorporated CNDs can potentially bind the complementary nucleobases in a DNA double helix. Nonetheless, neither bare nor nucleobase-incorporated CNDs were observed to intervene in the amplification of the zebrafish polymerase-alpha 1 gene in quantitative polymerase chain reactions. Thus, in conclusion, the embryogenesis interruption by bare and nucleobase-incorporated CNDs might not be a consequence of CND–DNA interactions during DNA replication. Instead, CND–Ca²⁺ interactions offer a plausible mechanism that hindered cell proliferation and zebrafish embryogenesis originating from disturbed Ca²⁺ homeostasis by CNDs. Eventually, the hypothesis that raw or nucleobase-incorporated CNDs can be nucleobase analogs proved to be invalid.

Provides a chem/bio basis to understand surface functional group effects on nanocarriers & their cancer cellular uptake, helping to increase the <5% of nanomaterials clinically approved for personalized nanomedicine.

The blood–brain barrier (BBB) is a major obstacle for drug delivery to the central nervous system (CNS) such that most therapeutics lack efficacy against brain tumors or neurological disorders due to their inability to cross the BBB. Therefore, developing new drug delivery platforms to facilitate drug transport to the CNS and understanding their mechanism of transport are crucial for the efficacy of therapeutics. Here, we report (i) carbon dots prepared from glucose and conjugated to fluorescein (GluCD-F) cross the BBB in zebrafish and rats without the need of an additional targeting ligand and (ii) uptake mechanism of GluCDs is glucose transporter-dependent in budding yeast. Glucose transporter-negative strain of yeast showed undetectable GluCD accumulation unlike the glucose transporter-positive yeast, suggesting glucose-transporter-dependent GluCD uptake. We tested GluCDs' ability to cross the BBB using both zebrafish and rat models. Following the injection to the heart, wild-type zebrafish showed GluCD-F accumulation in the central canal consistent with the transport of GluCD-F across the BBB. In rats, following intravenous administration, GluCD-F was observed in the CNS. GluCD-F was localized in the gray matter (e.g. ventral horn, dorsal horn, and middle grey) of the cervical spinal cord consistent with neuronal accumulation. Therefore, neuron targeting GluCDs hold tremendous potential as a drug delivery platform in neurodegenerative disease, traumatic injury, and malignancies of the CNS.

Tumor microenvironment responsive drug delivery systems are potential approaches to reduce the acute toxicity caused by high-dose cancer chemotherapy.