The blood–brain barrier (BBB) is a main obstacle for drug delivery targeting the central nervous system (CNS) and treating Alzheimer's disease (AD). In order to enhance the efficiency of drug delivery without harming the BBB integrity, nanoparticle-mediated drug delivery has become a popular therapeutic strategy. Carbon dots (CDs) are one of the most promising and novel nanocarriers. In this study, amphiphilic yellow-emissive CDs (Y-CDs) were synthesized with an ultrasonication-mediated methodology using citric acid and o -phenylenediamine with a size of 3 nm that emit an excitation-independent yellow photoluminescence (PL). The content of primary amine and carboxyl groups on CDs was measured as 6.12 × 10 −5 and 8.13 × 10 −3 mmol mg −1 , respectively, indicating the potential for small-molecule drug loading through bioconjugation. Confocal image analyses revealed that Y-CDs crossed the BBB of 5-day old wild-type zebrafish, most probably by passive diffusion due to the amphiphilicity of Y-CDs. And the amphiphilicity and BBB penetration ability didn't change when Y-CDs were coated with different hydrophilic molecules. Furthermore, Y-CDs were observed to enter cells to inhibit the overexpression of human amyloid precursor protein (APP) and β-amyloid (Aβ) which is a major factor responsible for AD pathology. Therefore, data suggest that Y-CDs have a great potential as nontoxic nanocarriers for drug delivery towards the CNS as well as a promising inhibiting agent of Aβ-related pathology of the AD.
more »
« less
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.
more »
« less
- Award ID(s):
- 1809060
- NSF-PAR ID:
- 10287437
- Date Published:
- Journal Name:
- Nanoscale Advances
- Volume:
- 3
- Issue:
- 13
- ISSN:
- 2516-0230
- Page Range / eLocation ID:
- 3942 to 3953
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Altered Biodistribution and Tissue Retention of Nanoparticles Targeted with Pglycoprotein SubstratesLow molecular weight substrates of the efflux transporter, P-glycoprotein, alter the biodistribution and tissue retention of nanoparticles following intravenous administration. Of particular interest is the retention of the targeted nanoparticles in the brain. Drug delivery to the brain is hindered by the restricted transport of drugs through the blood-brain barrier (BBB). Drugs that passively diffuse across the BBB also have large volumes of distribution; therefore, alteration of their biodistribution to increase their concentration in the brain may help to enhance efficacy and reduce off-target side effects. In this work, targeted nanoparticles were used to explore a new approach to target drugs to the brain--the exploitation of the P-glycoprotein efflux pump. The retention of nanoparticles containing a strong P-glycoprotein substrate, rhodamine 6G, tethered to a PLA nanoparticle through a PEG spacer was greater than two-fold relative to untargeted nanoparticles and to nanoparticles tethered to a weaker Pglycoprotein substrate, rhodamine 123. In a P-glycoprotein knockout mouse model (mdr1a (-/-)), there were no significant differences in brain accumulation between rhodamine 6G targeted particles and controls, strongly supporting the role of Pglycoprotein. This proof of concept report shows the potential applicability of low molecular weight P-gp substrates to alter nanoparticle biodistribution.more » « less
-
more » « less
Abstract Oxime antidotes regenerate organophosphate‐inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [18F]‐VXS as a positron emission tomography tracer for active AChE, the
in vivo distribution of [18F]‐VXS was evaluated after an LD50dose (250 μg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [18F]‐VXS tracer alone had significantly higher radioactivity (two‐ to threefold) in the heart and lung than rats given LD50POX at 20 or 60 min prior to [18F]‐VXS. When rats were given LD50POX followed by 2‐PAM (cationic), RS194b (ionizable), or monoisonitrosoacetone (MINA) (neutral), central nervous system (CNS) radioactivity returned to levels at or above untreated naive rats (no POX), whereas CNS radioactivity did not increase in rats given the dication oximes HI‐6 or MMB‐4. MINA showed a significant, pairwise increase in CNS brain radioactivity compared with POX‐treated rats. This newin vivo dynamic platform using [18F]‐VXS tracer measures and quantifies peripheral and CNS relative changes in AChE availability after POX exposure and is suitable for comparing oxime delivery and AChE reactivation in rats. -
Pediatric glioblastomas are known to be one of the most dangerous and life-threatening cancers among many others regardless of the low number of cases reported. The major obstacles in the treatment of these tumors can be identified as the lack of prognosis data and the therapeutic requirement to be able to cross the blood–brain barrier (BBB). Due to this lack of data and techniques, pediatric patients could face drastic side effects over a long-time span even after survival. Therefore, in this study, the capability of non-toxic carbon nitride dots (CNDs) to selectively target pediatric glioblastoma cells was studied in vitro . Furthermore, the nanocarrier capability and efficiency of CNDs were also investigated through conjugation of a chemotherapeutic agent and transferrin (T f ) protein. Gemcitabine (GM) was introduced into the system as a chemotherapeutic agent, which has never been successfully used for the treatment of any central nervous system (CNS) cancer. More than 95% of selective damage of SJGBM2 glioma cells was observed at 1 μM of CN–GM conjugate with almost 100% viability of non-cancerous HEK293 cells, although this ability was diminished at lower concentrations. However, further conjugation of T f to obtain CN–GM–T f allowed the achievement of selective targeting and prominent anti-cancer activity at a 100-fold lower concentration of 10 nM. Furthermore, both conjugates were capable of effectively damaging several other brain tumor cells, which were not well responsive towards the single treatment of GM. The capability of BBB penetration of the conjugates was observed using a zebrafish model, which confirms the CNDs’ competence as an excellent nanocarrier to the CNS.more » « less
-
more » « less
Key points Pregnancy increases sympathetic nerve activity (SNA), although the mechanisms responsible for this remain unknown. We tested whether insulin or leptin, two sympathoexcitatory hormones increased during pregnancy, contribute to this.
Transport of insulin across the blood–brain barrier in some brain regions, and into the cerebrospinal fluid (CSF), was increased, although brain insulin degradation was also increased. As a result, brain and CSF insulin levels were not different between pregnant and non‐pregnant rats.
The sympathoexcitatory responses to insulin and leptin were abolished in pregnant rats.
Blockade of arcuate nucleus insulin receptors did not lower SNA in pregnant or non‐pregnant rats.
Collectively, these data suggest that pregnancy renders the brain resistant to the sympathoexcitatory effects of insulin and leptin, and that these hormones do not mediate pregnancy‐induced sympathoexcitation. Increased muscle SNA stimulates glucose uptake. Therefore, during pregnancy, peripheral insulin resistance coupled with blunted insulin‐ and leptin‐induced sympathoexcitation ensures adequate delivery of glucose to the fetus.
Abstract Pregnancy increases basal sympathetic nerve activity (SNA), although the mechanism responsible for this remains unknown. Insulin and leptin are two sympathoexcitatory hormones that increase during pregnancy, yet, pregnancy impairs central insulin‐ and leptin‐induced signalling. Therefore, to test whether insulin or leptin contribute to basal sympathoexcitation or, instead, whether pregnancy induces resistance to the sympathoexcitatory effects of insulin and leptin, we investigated α‐chloralose anaesthetized late pregnant rats, which exhibited increases in lumbar SNA (LSNA), splanchnic SNA and heart rate (HR) compared to non‐pregnant animals. In pregnant rats, transport of insulin into cerebrospinal fluid and across the blood–brain barrier in some brain regions increased, although brain insulin degradation was also increased; brain and cerebrospinal fluid insulin levels were not different between pregnant and non‐pregnant rats. Although
i.c.v. insulin increased LSNA and HR and baroreflex control of LSNA and HR in non‐pregnant rats, these effects were abolished in pregnant rats. In parallel, pregnancy completely prevented the actions of leptin with respect to increasing lumbar, splanchnic and renal SNA, as well as baroreflex control of SNA. Blockade of insulin receptors (with S961) in the arcuate nucleus, the site of action of insulin, did not decrease LSNA in pregnant rats, despite blocking the effects of exogenous insulin. Thus, pregnancy is associated with central resistance to insulin and leptin, and these hormones are not responsible for the increased basal SNA of pregnancy. Because increases in LSNA to skeletal muscle stimulates glucose uptake, blunted insulin‐ and leptin‐induced sympathoexcitation reinforces systemic insulin resistance, thereby increasing the delivery of glucose to the fetus.
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D1NA00145K
