The improved blood–brain barrier permeability of endomorphin-1 using the cell-penetrating peptide synB3 with three different linkages

Liu, Hui; Zhang, Wei; Ma, Linnan; Fan, Lei; Gao, Fei-Yun; Ni, Jingman; Wang, Rui

doi:10.1016/j.ijpharm.2014.08.045

Cited by 33 publications

(26 citation statements)

References 37 publications

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“…Disulfide bonds have been extensively used as reductionresponsive linkers in brain targeted drug delivery because of their susceptibility to a reductive environment and the rapid cleavage by reducing agents such as glutathione (GSH). [22][23][24] In our previous study, we also confirmed that, as compared to amide and maleimide, the disulfide bond was the most efficient linkage to promote endomorphin-1 translocation across the BBB due to its reductive effect. 25) Importantly, disulfide bonds play a significant role in the folding and aggregation of peptides and proteins, 26) which potentially can promote self-assembling.…”

Section: Introductionsupporting

confidence: 76%

Amphiphilic Endomorphin-1 Derivative Functions as Self-assembling Nanomedicine for Effective Brain Delivery

Liu

Zhao

Shan

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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Endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 , EM-1), an endogenous μ-opioid receptor ligand with strong antinociceptive activity, is not in clinical use because of its limited metabolic stability and membrane permeability. In this study, we develop a short-peptide self-delivery system for brain targets with the capability to deliver EM-1 without vehicle. Two amphiphilic EM-1 derivatives, C 18-SS-EM1 and C 18-CONH-EM1, were synthesized by attaching a stearyl moiety to EM-1 via a disulfide and amide bond, respectively. The amphiphilicity of EM-1 derivatives enabled self-assembling into nanoparticles for brain delivery. The study assessed morphology, circular dichroism, and metabolic stability of the formulations, as well as their pharmacodynamics and in vivo distribution, directly monitored by near-IR fluorescence imaging in mouse brains. In aqueous solution, the C 18-SS-EM1 derivative self-assembled into spherical nanostructures with a diameter of 10-20 nm. Near-IR fluorescence analysis visualized the accumulation of the peptides in the brain. Importantly, the analgesic effect of C 18-SS-EM1 nanoparticles was significantly stronger as compared to that of unmodified EM-1 or C 18-CONH-EM1 nanoparticles. An in vitro release study demonstrated that self-assembled C 18-SS-EM1 nanoparticles possessed reduction-responsive behavior. In summary, self-assembling C 18-SS-EM1 nanoparticles, which integrate the advantages of lipidization, nanoscale characteristics and, labile disulfide bonds, represent a promising strategy for brain delivery of short peptides.

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Section: Introductionsupporting

confidence: 76%

Amphiphilic Endomorphin-1 Derivative Functions as Self-assembling Nanomedicine for Effective Brain Delivery

Liu

Zhao

Shan

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Two hours after intranasal administration of Rho-MOTS-c or Rho-MP alone into nasal cavity, mice were sacrificed and perfused with 20 ml PBS to remove residual blood followed by 60 ml 4% paraformaldehyde. The frozen brain tissue was cut into 30 µm-thick sections using a cryotome and observed with an Olympus FluoView FV1000 confocal laser scanning microscope[29].2.12. Flow cytometryTo obtain a direct insight into the cellular uptake of FITC-labeled peptides in cells, BV-2 and U87 cells (1 × 10 6 cells/well) were plated into 6 well microplates and cultured overnight.…”

mentioning

confidence: 99%

“…The brain was removed and placed into an imaging system. Images were captured by a CCD camera embedded in the imaging system and analyzed by the Lumina II Living Imaging 4 software[29].2.15. Statistical analysisAll data are presented as the mean ± SEM for repeats twice of each experiment.…”

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confidence: 99%

Peripheral administration of a cell-penetrating MOTS-c analogue enhances memory and attenuates Aβ1-42 or LPS induced memory impairment through inhibiting neuroinflammation

Jiang

Chang

Nie

et al. 2019

Preprint

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Background: MOTS-c is a 16-amino acid mitochondrial derivative peptide reported to be involved in regulating insulin resistance and obesity, osteoporosis and inflammatory responses. Accumulating evidences suggest that inhibiting neuroinflammation is a potential target in therapeutic or preventive strategies for Alzheimer’s disease (AD). Due to the widespread distribution of MOTS in the CNS and its role in metabolism and immune system, previous reports also pointed out that MOTS-c may be effective as a therapeutic option toward the prevention of the aging processes. Therefore, it is important to understand the roles of MOTS-c in neuroinflammation. Methods: The mouse memory function was evaluated using novel object recognition (NOR) and object location recognition (OLR) tasks. Brain hippocampus tissue samples were analyzed by quantitative PCR, western blotting, ELISA and immunostaining. Near-infrared fluorescent and confocal microscopy experiments were used to detect the brain uptake and distribution of intranasal or intravenous MOTS-c or MP (MOTS-c conjugated with cell penetrating peptides). Peptides drugs were synthesized by a standard Fmoc-based solid-phase synthetic method. Results: Central MOTS-c enhances object and location recognition memory formation and consolidation, and ameliorates the memory deficit induced by Aβ1-42 or LPS in NOR and OLR tasks, whereas dorsomorphin (AMPK inhibitor, i.p.) significantly blocked the memory-ameliorating effects of MOTS-c. Western blotting experiments showed that MOTS-c provided neuroprotection against LPS or Aβ1-42-induced neuroinflammation, which was related with phosphorylation of AMPK, but not MAPK including ERK, JNK and p38. The underlying mechanism of MOTS-c neuroprotection may be involved of inhibiting the activation of astrocytes and microglia and production of proinflammatory cytokines including TNF-α, IL-6, IL-1β, COX-2 and iNOS. In order to improve the brain intake of MOTS-c, we screen out (PRR)5, a cell penetrating peptides, as a carrier for MOTS-c into the brain. Then in NOR task, intranasal or intravenous MP, but not MOTS-c, showed good memory performance on memory formation, memory consolidation and memory impairment. Finally, compared with control and Rho-MOTS-c groups, significant fluorescence signals of Rho-MP were detected in the brain by NIR fluorescence imaging. Conclusion: MOTS-c might be a new potential target for treatment of cognitive decline in AD and this way of administration MP will be the potential strategy for non-invasive therapeutic intervention.

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“…The use of ex vivo whole-organ imaging using live-imaging devices has increased over time due to their ease of use and ability to quickly create an accurate comparison of the relative concentrations of labeled compounds without requiring the further processing of tissues 4 . However, while ex vivo whole-organ imaging can allow for easy analysis and comparison, it does not generate a quantitative measure of absolute compound concentrations within a tissue.…”

Section: Introductionmentioning

confidence: 99%

The Use of <em>Ex Vivo</em> Whole-organ Imaging and Quantitative Tissue Histology to Determine the Bio-distribution of Fluorescently Labeled Molecules

McGowan

Bidwell

2016

JoVE

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Fluorescent labeling is a well-established process for examining the fate of labeled molecules under a variety of experimental conditions both in vitro and in vivo. Fluorescent probes are particularly useful in determining the bio-distribution of administered large molecules, where the addition of a small-molecule fluorescent label is unlikely to affect the kinetics or bio-distribution of the compound. A variety of methods exist to examine bio-distribution that vary significantly in the amount of effort required and whether the resulting measurements are fully quantitative, but using multiple methods in conjunction can provide a rapid and effective system for analyzing bio-distributions. Ex vivo whole-organ imaging is a method that can be used to quickly compare the relative concentrations of fluorescent molecules within tissues and between multiple types of tissues or treatment groups. Using an imaging platform designed for live-animal or whole-organ imaging, fluorescence within intact tissues can be determined without further processing, saving time and labor while providing an accurate picture of the overall bio-distribution. This process is ideal in experiments attempting to determine the tissue specificity of a compound or for the comparison of multiple different compounds. Quantitative tissue histology on the other hand requires extensive further processing of tissues in order to create a quantitative measure of the labeled compounds. To accurately assess bio-distribution, all tissues of interest must be sliced, scanned, and analyzed relative to standard curves in order to make comparisons between tissues or groups. Quantitative tissue histology is the gold standard for determining absolute compound concentrations within tissues. Here, we describe how both methods can be used together effectively to assess the ability of different administration methods and compound modifications to target and deliver fluorescently-labeled molecules to the central nervous system1.

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The improved blood–brain barrier permeability of endomorphin-1 using the cell-penetrating peptide synB3 with three different linkages

Cited by 33 publications

References 37 publications

Amphiphilic Endomorphin-1 Derivative Functions as Self-assembling Nanomedicine for Effective Brain Delivery

Amphiphilic Endomorphin-1 Derivative Functions as Self-assembling Nanomedicine for Effective Brain Delivery

Peripheral administration of a cell-penetrating MOTS-c analogue enhances memory and attenuates Aβ1-42 or LPS induced memory impairment through inhibiting neuroinflammation

The Use of <em>Ex Vivo</em> Whole-organ Imaging and Quantitative Tissue Histology to Determine the Bio-distribution of Fluorescently Labeled Molecules

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