Brain-Targeted Delivery of Pre-miR-29b Using Lactoferrin-Stearic Acid-Modified-Chitosan/Polyethyleneimine Polyplexes

Pereira, Patrícia; Roque-Barreira, Maria Cristina; Cruz, Carla; Tomás, Joana; Luís, Ângelo; Pedro, Ana; Queiroz, João A.; Sousa, Fani

doi:10.3390/ph13100314

Cited by 20 publications

(13 citation statements)

References 65 publications

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“…Finally, the peptide-SA conjugate was redispersed in dH2O and lyophilized. The molecular weight of the lyophilized conjugate was determined by LC-ESI-MS (31,32).…”

Section: Conjugation Of the Peptide With Stearic Acidmentioning

confidence: 99%

Angiotensin(1-7)-Stearic Acid Conjugate: Synthesis and Characterization

Acar¹,

Uçar

2022

Journal of the Turkish Chemical Society Section A: Chemistry

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The novel coronavirus, SARS-CoV-2, broken out as the COVID-19 epidemic, is transported into the cytoplasm by angiotensin-converting enzyme-2 (ACE2), a key protein of the renin-angiotensin-system (RAS). ACE2 is a protective protein that reduces angiotensin (Ang) II, the bioactive component of RAS, by converting it to its potent antagonist, Ang-(1-7) peptide, in order to provide a pathophysiological response to stimuli. Although ACE-2 is upregulated especially in pulmonary endothelial cells and alveolar epithelial cells, downregulation of ACE-2 in the lung owing to loss of key regulatory factors explains the enzymedependent lethality of SARS-CoV-2. The N-terminal domain (NTD) of S1, one of the protein subunits of coronaviruses, is known to recognize acetylated sialic acids on glycosylated cell surface receptors. In this study, the stearic acid-peptide conjugate mimicking the sialic acid structure was synthesized, which will be able to balance uncontrolled inflammatory response and excessive cytokine production, and depending on these to suppress pneumonia and acute respiratory distress syndrome (ARDS), against SARS-CoV-2. It was expected that fatty acid acylation would greatly enhance cellular internalization and cytosolic distribution of the peptide through the cell membrane. Thus, we synthesized fatty acyl derivative of the N-Ac-Gly4-Ang (1-7) peptide. The peptide was synthesized using Fmoc/tBu solid-phase peptide chemistry and characterized by FT-IR, Zetasizer, and LC-ESI-MS. This study provided more detailed insights into understanding and meeting the basic structural requirements for optimal cellular delivery and formulation of the stearyl Ang (1-7)-peptide conjugate.

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“…Finally, the peptide-SA conjugate was redispersed in dH2O and lyophilized. The molecular weight of the lyophilized conjugate was determined by LC-ESI-MS (31,32).…”

Section: Conjugation Of the Peptide With Stearic Acidmentioning

confidence: 99%

Angiotensin(1-7)-Stearic Acid Conjugate: Synthesis and Characterization

Acar¹,

Uçar

2022

Journal of the Turkish Chemical Society Section A: Chemistry

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“…A widely used method is the packaging in polyplexes, consisting of polymers and complexed nucleic acids, which has been exploited in various studies [ 273 , 274 , 275 , 276 ]. Here, the toxicity needs to be balanced with the miR binding capacity.…”

Section: Delivery Of Mir Therapeuticsmentioning

confidence: 99%

Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment

Raue

Frank

Syed

et al. 2021

IJMS

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The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside.

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“…Amino acid-based molecules were also studied to in relation to BBB transport and to delivery of anticancer agents [45,46]. Furthermore, poly-amine materials such as polyamidoamine (PAMAM) dendrimers were also reported as a platform for brain drug delivery [47][48][49]. Fana et al reported that PAMAM nanocarriers can be used to deliver bioactive molecules for the treatment of glioblastoma [48].…”

Section: Discussionmentioning

confidence: 99%

“…Fana et al reported that PAMAM nanocarriers can be used to deliver bioactive molecules for the treatment of glioblastoma [48]. Pereira et al reported that recombinant-precursor microRNA (pre-miR-29b) was delivered to the brain with the aid of nanocarriers based on chitosan/polyethyleneimine (PEI) [49]. They argued that chitosan-based nanocarriers can deliver pre-miR-29b across the BBB more efficiently than PEI-based carriers.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of N-Methyl-d-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application

Kim

Jeong

2021

IJMS

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The aim of this study is to fabricate reactive oxygen species (ROS)-sensitive nanoparticles composed of succinyl β-cyclodextrin (bCDsu), memantine and thioketal linkages for application in Alzheimer’s disease, and to investigate the suppression of N-methyl-d-aspartate (NMDA) receptor 1 (NMDAR1) in cells. Thioketal diamine was attached to the carboxyl group of bCDsu to produce thioketal-decorated bCDsu conjugates (bCDsu-thioketal conjugates) and memantine was conjugated with thioketal dicarboxylic acid (memantine-thioketal carboxylic acid conjugates). Memantine-thioketal carboxylic acid conjugates were attached to bCDsu-thioketal conjugates to produce bCDsu-thioketal-memantine (bCDsuMema) conjugates. SH-SY5Y neuroblastoma cells and U87MG cells were used for NMDAR1 protein expression and cellular oxidative stress. Nanoparticles of bCDsuMema conjugates were prepared by means of a dialysis procedure. Nanoparticles of bCDsuMema conjugates had small particle sizes less than 100 nm and their morphology was found to be spherical in transmission electron microscopy observations (TEM). Nanoparticles of bCDsuMema conjugates responded to H2O2 and disintegrated or swelled in aqueous solution. Then, the nanoparticles rapidly released memantine according to the concentration of H2O2. In an in vivo animal imaging study, thioketal-decorated nanoparticles labelled with fluorescent dye such as chlorin e6 (Ce6) showed that the fluorescence intensity was stronger in the brain than in other organs, indicating that bCDsuMema nanoparticles can efficiently target the brain. When cells were exposed to H2O2, the viability of cells was time-dependently decreased. Memantine or bCDsuMema nanoparticles did not practically affect the viability of the cells. Furthermore, a western blot assay showed that the oxidative stress produced in cells using H2O2 increased the expression of NMDAR1 protein in both SH-SY5Y and U87MG cells. Memantine or bCDsuMema nanoparticles efficiently suppressed the NMDAR1 protein, which is deeply associated with Alzheimer’s disease. Fluorescence microscopy also showed that H2O2 treatment induced green fluorescence intensity, which represents intracellular ROS levels. Furthermore, H2O2 treatment increased the red fluorescence intensity, which represents the NMDAR1 protein, i.e., oxidative stress increases the expression of NMDAR1 protein level in both SH-SY5Y and U87MG cells. When memantine or bCDsuMema nanoparticles were treated in cells, the oxidative stress-mediated expression of NMDAR1 protein in cells was significantly decreased, indicating that bCDsuMema nanoparticles have the capacity to suppress NMDAR1 expression in brain cells, which has relevance in terms of applications in Alzheimer’s disease.

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Brain-Targeted Delivery of Pre-miR-29b Using Lactoferrin-Stearic Acid-Modified-Chitosan/Polyethyleneimine Polyplexes

Cited by 20 publications

References 65 publications

Angiotensin(1-7)-Stearic Acid Conjugate: Synthesis and Characterization

Angiotensin(1-7)-Stearic Acid Conjugate: Synthesis and Characterization

Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment

The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of N-Methyl-d-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application

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