Hydrothermal vs microwave nanoarchitechtonics of carbon dots significantly affects the structure, physicochemical properties, and anti-cancer activity against a specific neuroblastoma cell line.

Carbon dots (CDs) from glucose were synthesized using two of the most common bottom-up methods, namely, microwave assisted (MW) and hydrothermal carbonization (HT). Synthetic parameters such as reaction time, temperature, and precursor concentration were changed to study the effects of each parameter on CD size, structure, surface functionalities, charge, photoluminescence behavior, quantum yield, cytotoxicity, blood-brain barrier (BBB) crossing ability and bioimaging. A detailed analysis is performed to compare the structure and properties of the CDs synthesized in ten different conditions. We show that the synthesis route drastically changes the structure, properties, and related functions of glucose-derived CDs yielding two different subtypes of CDs. Surprisingly, CDs that was synthesized via HT method showed specific anticancer activity against a neuroblastoma cell line while being non-toxic towards healthy cell lines, indicating significant potential for therapeutic applications. CDs synthesized via MW crosses the BBB in zebrafish and rat models, and accumulates in neurons. CDs synthesized via MW method showed high biocompatibility and a great potential to be used for bioimaging applications in vitro and in vivo targeting neurons. Finally, a formation mechanism of CDs is proposed for both HT and MW synthesis routes.

Carbon Dots: A Future Blood-Brain Barrier Penetrating Nanomedicine and Drug Nanocarrier.

Drug delivery across the blood-brain barrier (BBB) is one of the biggest challenges in modern medicine due to the BBB's highly semipermeable property that limits most therapeutic agents of brain diseases to enter the central nervous system (CNS). In recent years, nanoparticles, especially carbon dots (CDs), exhibit many unprecedented applications for drug delivery. Several types of CDs and CD-ligand conjugates have been reported successfully penetrating the BBB, which shows a promising progress in the application of CD-based drug delivery system (DDS) for the treatment of CNS diseases. In this review, our discussion of CDs includes their classification, preparations, structures, properties, and applications for the treatment of neurodegenerative diseases, especially Alzheimer's disease (AD) and brain tumor. Moreover, abundant functional groups on the surface, especially amine and carboxyl groups, allow CDs to conjugate with diverse drugs as versatile drug nanocarriers. In addition, structure of the BBB is briefly described, and mechanisms for transporting various molecules across the BBB and other biological barriers are elucidated. Most importantly, recent developments in drug delivery with CDs as BBB-penetrating nanodrugs and drug nanocarriers to target CNS diseases especially Alzheimer's disease and brain tumor are summarized. Eventually, future prospects of the CD-based DDS are discussed in combination with the development of artificial intelligence and nanorobots.

Crossing the blood-brain barrier with carbon dots: uptake mechanism and in vivo cargo delivery.

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.

pH and redox triggered doxorubicin release from covalently linked carbon dots conjugates.

Tumor microenvironment responsive drug delivery systems are potential approaches to reduce the acute toxicity caused by high-dose cancer chemotherapy. Notwithstanding the conventional nano-drug delivery systems, the redox and pH stimuli drug delivery systems are currently gaining attention. Therefore, the current study was designed to compare three different covalent carbon dots (C-dots) systems based on doxorubicin (dox) release profiles and cancer cell viability efficacy under acidic and physiological conditions. The C-dots nanosystems that were examined in this study are directly conjugated (C-dots-dox), pH triggered (C-dots-HBA-dox), and the redox stimuli (C-dots-S-S-dox) conjugates. The drug loading content (DLC%) of the C-dots-S-S-dox, C-dots-HBA-dox, and C-dots-dox was 34.2 ± 0.4, 60.0 ± 0.3, and 70.0 ± 0.2%, respectively, that examined by UV-vis spectral analysis. The dox release paradigms were emphasized that all three conjugates were promisingly released the dox from C-dots faster in acidic pH than in physiological pH. The displayed highest dox released percentage in the acidic medium was 74.6 ± 0.8% obtained by the pH stimuli, C-dots-HBA-dox conjugate. When introducing the redox inducer, dithiothreitol (DTT), preferentially, the redox stimuli C-dot-S-S-dox conjugate demonstrated a faster dox release at acidic pH than in the pH 7.4. The SJGBM2 cell viability experiments revealed that the pH stimuli, C-dots-HBA-dox conjugate, displayed a significant cell viability drop in the artificially acidified pH 6.4 medium. However, in the physiological pH, the redox stimuli, C-dots-S-S-dox conjugate, was promising over the pH stimuli C-dots-HBA-dox, exhibiting cell viability of 60%, though its' efficacy dropped slightly in the artificially acidified pH 6.4 medium. Moreover, the current study illustrates the stimuli conjugates' remarkable efficacy on sustain drug release than direct amide linkage.

Metformin derived carbon dots: Highly biocompatible fluorescent nanomaterials as mitochondrial targeting and blood-brain barrier penetrating biomarkers.

Carbon dots (CDs) have been intensively studied since their discovery in 2004 because of their unique properties such as low toxicity, excellent biocompatibility, high photoluminescence (PL) and good water dispersibility. In this study metformin derived carbon dots (Met-CDs) were synthesized using a microwave assisted method. Met-CDs were meticulously characterized using ultra-violet spectroscopy (UV-vis), photoluminescence (PL), Fourier Transform Infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), atomic force (AFM) and transmission electron (TEM) microscopies. According to results of cytotoxicity studies, Met-CDs possess low-toxicity and excellent biocompatibility towards both non-tumor and tumor cell lines indicating that Met-CDs are outstanding candidates for living cell bioimaging studies. Furthermore, bioimaging studies have displayed that Met-CDs can penetrate the cell membrane and disperse throughout the cell structure including the nucleus and mitochondria. More specifically, Met-CDs tend to start localizing selectively inside the mitochondria of cancer cells, but not of non-tumor cells after 1 h of incubation. Finally, a zebrafish study confirmed that Met-CDs cross the blood-brain barrier (BBB) without the need of any other ligands. In summary, this study presents synthesis of Met-CDs which feature abilities such as mitochondrial and nucleus localizations along with BBB penetration.

Direct conjugation of distinct carbon dots as Lego-like building blocks for the assembly of versatile drug nanocarriers.

As a promising drug nanocarrier, carbon dots (CDs) have exhibited many excellent properties. However, some properties such as bone targeting and crossing the blood-brain barrier (BBB) only apply to a certain CD preparation with limited drug loading capacity. Therefore, it is significant to conjugate distinct CDs to centralize many unique properties on the novel drug nanocarrier. Considering that CDs have abundant and tunable surface functionalities, in this study, a direct conjugation was initiated between two distinct CD models, black CDs (B-CDs) and gel-like CDs (G-CDs) via an amidation reaction. As a result of conjugation at a mass ratio of 5:3 (B-CDs to G-CDs) and a two-step purification process, the conjugate, black-gel CDs (B-G CDs) (5:3) inherited functionalities from both CDs and obtained an enhanced thermostability, aqueous stability, red-shifted photoluminescence (PL) emission, and a figure-eight shape with a width and length of 3 and 6 nm, respectively. In addition, the necessity of high surface primary amine (NH2) content in the CD conjugation was highlighted by replacing G-CDs with other CDs with lower surface NH2 content. Meanwhile, the carboxyl groups (COOH) on G-CDs were not enough to trigger self-conjugation between G-CDs. Moreover, the drug loading capacity was enhanced by 54.5% from B-CDs to B-G CDs (5:3). Furthermore, when the mass ratio of B-CDs to G-CDs was decreased from 5:30, 5:100 to 5:300, the obtained nanostructures revealed a great potential of CDs as Lego-like building blocks. Also, bioimaging of zebrafish demonstrated that various B-G CDs exhibited properties of both bone targeting and crossing the BBB, which are specific properties of B-CDs and G-CDs, respectively.

Recent Advances on Utilization of Bioprinting for Tumor Modeling.

Despite the recent rigorous studies towards a possible cure, cancer still remains as one of the most daunting problems faced by the humanity. Currently utilized two-dimensional cancer models are known to have various insuperable limitations such as insufficient biomimicry of the heterogeneous conditions of tumors and their three-dimensional structures. Discrepancies between the laboratory models and the actual tumor environment significantly impair a thorough comprehension of the carcinogenesis process and development of successful remedies against cancer. Modeling tumor microenvironments through bioprinting poses strong potential to minimize the effects of the aforementioned issues thanks to its freeform nature, adaptability, customizability, scalability and diversity. Numerous research studies involving three-dimensional modeling of various cancer types using bioprinting technologies have been reported, recently. In this review, we provide a broad summary of these studies to help better represent their potential and analyze their contribution to cancer research.

Close-Packed Langmuir Monolayers of Saccharide-Based Carbon Dots at the Air-Subphase Interface.

Carbon dots (CDs) are zero-dimensional carbon-based spherical nanoparticles with diameters less than 10 nm. Here, we report for the first time CDs forming stable Langmuir monolayers at the air-subphase interface. Langmuir monolayers are of great interest both fundamentally to study the interactions at the interfaces and for many applications such as the development of sensors. However, CDs usually do not form Langmuir monolayers because of their highly hydrophilic nature. In this study, amphiphilic CDs were prepared through hydrothermal carbonization using saccharides as the precursors. The surface chemistry behavior and optical properties of CDs at the air-subphase interface were studied. CDs derived from saccharides consistently formed stable Langmuir monolayers which show all essential phases, namely, gas, liquid-expanded, liquid-condensed, and solid phases. The compression-decompression cycle method showed minimum hysteresis (4.3%), confirming the retaining capacity of the CDs as a monolayer. Limiting CD areas from surface pressure-area isotherm at the air-subphase interface were used to calculate the average diameter of the CDs at the air-subphase interface. UV/vis absorption spectra of CDs dispersed in water and in Langmuir monolayers had the same bands in the UV region. The intensity of the UV/vis absorption increases with increasing surface pressure at the air-subphase interface. Interestingly, photoluminescence (PL) of the Langmuir monolayer of CDs was excitation-independent, whereas the same CDs had excitation-dependent PL when dispersed in water.

Nanoparticle-mediated targeted drug delivery for breast cancer treatment.

Breast cancer (BC) is the most common malignancy in women worldwide, and one of the deadliest after lung cancer. Currently, standard methods for cancer therapy including BC are surgery followed by chemotherapy or radiotherapy. However, both chemotherapy and radiotherapy often fail to treat BC due to the side effects that these therapies incur in normal tissues and organs. In recent years, various nanoparticles (NPs) have been discovered and synthesized to be able to selectively target tumor cells without causing any harm to the healthy cells or organs. Therefore, NPs-mediated targeted drug delivery systems (DDS) have become a promising technique to treat BC. In addition to their selectivity to target tumor cells and reduce side effects, NPs have other unique properties which make them desirable for cancer treatment such as low toxicity, good compatibility, ease of preparation, high photoluminescence (PL) for bioimaging in vivo, and high loadability of drugs due to their tunable surface functionalities. In this study, we summarize with a critical analysis of the most recent therapeutic studies involving various NPs-mediated DDS as alternatives for the traditional treatment approaches for BC. It will shed light on the significance of NPs-mediated DDS and serve as a guide to seeking for the ideal methodology for future targeted drug delivery for an efficient BC treatment.

The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications.

Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10 µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity. These hit compounds were then rescreened against the target in 8-point dose-response curves and 11 compounds were found to inhibit enzymatic activity with IC50 values of less than 10 µM. Finally, compounds (1-5) were docked against RpMetAP with AutoDock to determine potential binding mechanisms and the results were compared with crystal structures deposited within the PDB.

Surface Chemistry and Spectroscopic Study of a Cholera Toxin B Langmuir Monolayer.

In this article, we explored the surface chemistry properties of a cholera toxin B (CTB) monolayer at the air-subphase interface and investigated the change in interfacial properties through in situ spectroscopy. The study showed that the impact of the blue shift was negligible, suggesting that the CTB molecules were minimally affected by the subphase molecules. The stability of the CTB monolayer was studied by maintaining the constant surface pressure for a long time and also by using the compression-decompression cycle experiments. The high stability of the Langmuir monolayer of CTB clearly showed that the driving force of CTB going to the amphiphilic membrane was its amphiphilic nature. In addition, no major change was detected in the various in situ spectroscopy results (such as UV-vis, fluorescence, and IR ER) of the CTB Langmuir monolayer with the increase in surface pressure. This indicates that no aggregation occurs in the Langmuir monolayer of CTB.

Embedding Carbon Dots in Superabsorbent Polymers for Additive Manufacturing.

A type of orange carbon dots (O-CDs) synthesized via an ultrasonication route with citric acid and 1,2-phenylenediamine as precursors was embedded into sodium polyacrylate (SPA) as the ink for 3D printing. Characterizations of these spherical O-CDs revealed an ultra-small size (~2 nm) and excitation-independent, but solvent dependent, emission. The O-CDs were evenly distributed with low degree of aggregation in sodium polyacrylate (SPA), which was achieved due to the property that SPA can absorb water together with O-CDs. The 3D printed photoluminescent objective with the ink revealed a great potential for high yield application of these materials for additive manufacturing. This also represents the first time, bare CDs have been reported as a photoluminescent material in 3D printing, as well as the first time SPA has been reported as a material for 3D printing.

Crossing the blood-brain barrier with nanoparticles.

The blood-brain barrier (BBB) is one of the most essential protection mechanisms in the central nervous system (CNS). It selectively allows individual molecules such as small lipid-soluble molecules to pass through the capillary endothelial membrane while limiting the passage of pathogens or toxins. However, this protection mechanism is also a major obstacle during disease state since it dramatically hinders the drug delivery. In recent years, various tactics have been applied to assist drugs to cross the BBB including osmotic disruption of the BBB and chemical modification of prodrugs. Additionally, nanoparticles (NPs)-mediated drug delivery is emerging as an effective and non-invasive system to treat cerebral diseases. In this review, we will summarize and analyze the advances in the drug delivery across the BBB using various NPs in the last decade. The NPs will cover both traditional and novel nanocarriers. The traditional nanocarriers consist of poly(butylcyanoacrylate), poly(lactic-co-glycolic acid), poly(lactic acid) NPs, liposomes and inorganic systems. In the meanwhile, novel nanocarriers such as carbon quantum dots with their recent applications in drug delivery will also be introduced. In terms of significance, this review clearly depicts the BBB structure and comprehensively describes various NPs-mediated drug delivery systems according to different NPs species. Also, the BBB penetration mechanisms are concluded in general, emphasized and investigated in each drug delivery system.