19 research outputs found
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Crossing Blood‐Brain Barrier with Carbon Quantum Dots
The blood‐brain barrier (BBB) is a semi‐permeable structure, which is essential for the protection of the central nervous system (CNS). BBB selectively allows the passage of the necessary small molecules/nutrients from the blood to the brain while blocking pathogens or toxins. However, BBB becomes a major obstacle during disease since it significantly hinders the drug delivery to the CNS. Therefore, developing a drug delivery system to cross BBB is highly desired. Recently, nanoparticles (NPs) have become emergent tools to assist drugs to cross BBB. Since most NPs cannot cross BBB by themselves, the nanoparticle‐mediated drug delivery heavily depends on conjugating the NPs to the ligands such as transferrin to pass through the BBB via receptor‐mediated endocytosis.
Here, we designed Carbon quantum dots (CDs) that can cross BBB without the need of a ligand. We hypothesized that the saccharide‐based CDs will have an amphiphilic structure with surface groups that resemble the saccharide precursor. Therefore, these CDs will be able to cross BBB either with the aid of glucose transporter proteins or by passive diffusion.
CDs were prepared via a bottom‐up approach using hydrothermal carbonization of saccharides and characterized using various spectroscopic, microscopic and surface chemistry methods such as UV/vis, fluorescence, FTIR/ATR, TEM, AFM and Langmuir monolayers. To test our hypothesis, CDs were injected into the heart of wild‐type zebrafish, Danio rerio. The confocal images showed the accumulation of CDs in the CNS of zebrafish confirming the ability to cross BBB. CDs were also shown to pass through rat BBB 45 min after intravenous tail injection (2.5 mg/kg). Following transcardial perfusion, rat spinal cord is post‐fixed in paraformaldehyde overnight and cryoprotected in sucrose. Presence of CDs in the CNS was confirmed in 40 μm tissue sections via epifluorescence microscopy. These proof‐of‐principle studies suggest that saccharide‐based CDs can cross BBB in different vertebrate species. Further studies should address if the amount of BBB penetration is sufficient to cause a biologically meaningful effect in the CNS.
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal
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
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
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Carbon Dots: A Future Blood–Brain Barrier Penetrating Nanomedicine and Drug Nanocarrier
Wei Zhang,1,* Ganesh Sigdel,1,* Keenan J Mintz,1 Elif S Seven,1 Yiqun Zhou,1 Chunyu Wang,2,3 Roger M Leblanc1 1Department of Chemistry, University of Miami, Coral Gables, FL, 33146, USA; 2Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA; 3Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA*These authors contributed equally to this workCorrespondence: Roger M Leblanc Email [email protected]: Drug delivery across the bloodâ\u80\u93brain barrier (BBB) is one of the biggest challenges in modern medicine due to the BBBâ\u80\u99s 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 Alzheimerâ\u80\u99s 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 Alzheimerâ\u80\u99s 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.Keywords: carbon dots, bloodâ\u80\u93brain barrier, drug delivery, brain tumor, central nervous system disease
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
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Nanoparticle-mediated approaches for Alzheimer’s disease pathogenesis, diagnosis, and therapeutics
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Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder manifested by memory loss and cognitive impairment. Deposition of the amyloid β plaques has been identified as the most common AD pathology; however, the excessive accumulation of phosphorylated or total tau proteins, reactive oxygen species, and higher acetylcholinesterase activity are also strongly associated with Alzheimer’s dementia. Several therapeutic approaches targeting these pathogenic mechanisms have failed in clinical or preclinical trials, partly due to the limited bioavailability, poor cell, and blood-brain barrier penetration, and low drug half-life of current regimens. The nanoparticles (NPs)-mediated drug delivery systems improve drug solubility and bioavailability, thus renders as superior alternatives. Moreover, NPs-mediated approaches facilitate multiple drug loading and targeted drug delivery, thereby increasing drug efficacy. However, certain NPs can cause acute toxicity damaging cellular and tissue architecture, therefore, NP material should be carefully selected. In this review, we summarize the recent NPs-mediated studies that exploit various pathologic mechanisms of AD by labeling, identifying, and treating the affected brain pathologies. The disadvantages of the select NP-based deliveries and the future aspects will also be discussed
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Graphene Defects in Saccharide Carbon Dots Govern Electrochemical Sensitivity
Galactose (Gal), lactose (Lac), and glucose (Glu) derived carbon dots (CDs) were evaluated for their utility as electrochemical sensing composites using acetaminophen (APAP) as a probe molecule. The goal of this work is to ascertain the role of graphene defects on electrochemical activity. Higher sp2‐to‐sp3 hybridized carbon ratios (in parentheses) in the CDs correlated with higher sensitivity in the order according to measured Raman IG/ID intensities: GluCDs (6.53)<LacCDs (9.30)<GalCDs (10.18). A dynamic measurement in the 0–2.0 mmol dm−3 APAP range at pH=7.0 was achieved, suitable for practical APAP toxicity monitoring. Defect density within the GalCDs provided the highest sensitivity
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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.[Display omitted
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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
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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