DY-675-g7-Poly(lactic-co-glycolic acid) nanoparticles

DY-g7-PLGA NPs

Leung K.

Publication Details

Image

Table

In vitro Rodents

Background

[PubMed]

Optical fluorescence imaging is increasingly being used to monitor biological functions of specific targets (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (~700–1,000 nm) detection avoids the natural background fluorescence interference of biomolecules, providing a high contrast between target and background tissues in small animals. NIR fluorophores have a wider dynamic range and minimal background fluorescence as a result of reduced scattering compared with visible fluorescence detection. NIR fluorophores also have high sensitivity, attributable to low background fluorescence, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is a non-invasive complement to radionuclide imaging in small animals.

Opioids such as morphine are analgesics that are commonly used in clinical practice. Three opioid receptors (mu, µ; delta, δ; and kappa, κ) that mediate opioid effects have been identified by molecular cloning: δ (enkephalin-preferring), κ (dynorphin-preferring), and µ (morphine- and ß-endorphin–preferring) (4). Each type of opioid receptor consists of subtypes of receptors as suggested by pharmacological studies (5, 6). These receptors exhibit apparent specificity to both the central and peripheral nervous systems, and their presence is ubiquitous in these systems. The opioid receptors (G-protein–coupled, resulting in decreased adenylyl cyclase activity) play an important role in the regulation of analgesia, shock, appetite, thermoregulation, and cardiovascular, mental, and endocrine function (5-8). Although µ opioid receptors are the major receptors to mediate the analgesic effects of opioids, δ and κ receptors are also important in antinociception. Opioids have been found to protect cells from ischemic injury in the heart and brain via the δ receptors. On the other hand, κ antagonists prevent neurodegeneration.

The µ opioid receptors are localized predominately in the hypothalamus and thalamus, and the δ opioid receptors are localized predominately in the striatum, limbic system, and cerebral cortex (9, 10). The κ opioid receptors (κ1 and κ2) are the most abundant brain opioid receptors and are widely distributed in deeper layers of the neocortex (particularly temporal, parietal, and frontal cortices), striatum, amygdala, and thalamus, with lower levels in the hippocampus, occipital cortex, and cerebellum (11-13). The κ opioid receptors have been implicated in several clinical brain disorders, including drug abuse (14), epilepsy (15), Tourette’s syndrome (16), and Alzheimer’s disease (17). Tyr-d-Thr-Gly-Phe-Leu-Ser-(O-β-d-Glucose)CONH2 (g7) is a glycosylated derivative of the Leu-enkephalin analog Tyr-d-Thr-Gly-Phe-Leu-Ser-CONH2 (18). The g7 peptide exhibits an agonistic activity to rat and human µ/δ opioid receptors and an ability to penetrate the blood–brain barrier (BBB). Tosi et al. (19) conjugated g7 and the NIR dye DY-675 to poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to form DY-g7-PLGA NPs for in vivo NIR imaging of the BBB.

Synthesis

[PubMed]

DY-g7-PLGA NPs were prepared by mixing a solution of g7-PLGA, DY-PLGA, and PLGA (1:1.5:1.5, w:w:w) in acetone with 25 ml water containing Pluronic F68 (100 mg) (19). DY-g7-PLGA NPs were isolated with column chromatography. Laser particle-size analysis showed that the mean diameter of the NPs in water solution was ~200 nm. The surface charge was negative in all NPs. DY-g7-PLGA NPs exhibited an excitation maximum at 633 nm and an emission maximum at 700 nm. The chemical purity and final ratios of components specifically the number of DY fluorescent molecules and g7 opioids per NP were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Elmagbari et al. (18) reported that g7 exhibited 50% inhibition concentrations of 8.16 nM and 3.35 nM for µ and δ opioid receptors, respectively.

Animal Studies

Rodents

[PubMed]

Tosi et al. (19) used a whole-body fluorescence detection system to perform in vivo time-domain optical imaging at 0, 0.1, 1, and 2 h after intravenous injection of DY-g7-PLGA NPs (8 mg/mouse) in normal mice. Fluorescence signal was first observed in the blood circulation with subsequent localization to the brain, lungs, and liver within a few minutes after injection. The fluorescence intensity in the brain stayed constant over time, whereas the fluorescence intensity in the lung and liver migrated to the abdominal region within 1 h. The fluorescence intensity in the brain was weaker than that in the lungs and liver. Fluorescent and confocal microscopy studies of the brain sections showed that DY-g7-PLGA NPs localized very close to nuclear structures of the brain cells at 3 h after injection, suggesting that DY-g7-PLGA NPs were able to cross the BBB. DY-PLGA NPs were not tested as a control. No blocking studies to demonstrate specificity were performed.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

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