Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles
Using nanoparticle-based RNA interference (RNAi), we have previously shown that silencing the host autophagic protein, Beclin1, in HIV-infected human microglia and astrocytes restricts HIV replication and its viral-associated inflammatory responses. Here, we confirmed the efficacy of Beclin1 small i...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/2/223 |
| _version_ | 1797413875071582208 |
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| author | Myosotys Rodriguez Yemmy Soler Mohan Kumar Muthu Karuppan Yuling Zhao Elena V. Batrakova Nazira El-Hage |
| author_facet | Myosotys Rodriguez Yemmy Soler Mohan Kumar Muthu Karuppan Yuling Zhao Elena V. Batrakova Nazira El-Hage |
| author_sort | Myosotys Rodriguez |
| collection | DOAJ |
| description | Using nanoparticle-based RNA interference (RNAi), we have previously shown that silencing the host autophagic protein, Beclin1, in HIV-infected human microglia and astrocytes restricts HIV replication and its viral-associated inflammatory responses. Here, we confirmed the efficacy of Beclin1 small interfering RNA (siBeclin1) as an adjunctive antiviral and anti-inflammatory therapy in myeloid human microglia and primary human astrocytes infected with HIV, both with and without exposure to combined antiretroviral (cART) drugs. To specifically target human microglia and human astrocytes, we used a nanoparticle (NP) comprised of linear cationic polyethylenimine (PEI) conjugated with mannose (Man) and encapsulated with siBeclin1. The target specificity of the PEI-Man NP was confirmed in vitro using human neuronal and glial cells transfected with the NP encapsulated with fluorescein isothiocyanate (FITC). PEI-Man-siBeclin1 NPs were intranasally delivered to healthy C57BL/6 mice in order to report the biodistribution of siBeclin1 in different areas of the brain, measured using stem-loop RT-PCR. Postmortem brains recovered at 1–48 h post-treatment with the PEI-Man-siRNA NP showed no significant changes in the secretion of the chemokines regulated on activation, normal T cell expressed and secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) and showed significant decreases in the secretion of the cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) when compared to phosphate-buffered saline (PBS)-treated brains. Nissl staining showed minimal differences between the neuronal structures when compared to PBS-treated brains, which correlated with no adverse behavioral affects. To confirm the brain and peripheral organ distribution of PEI-siBeclin1 in living mice, we used the In vivo Imaging System (IVIS) and demonstrated a significant brain accumulation of siBeclin1 through intranasal administration. |
| first_indexed | 2024-03-09T05:25:18Z |
| format | Article |
| id | doaj.art-6b8329896c9a45e79b6ff74aac83f438 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T05:25:18Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-6b8329896c9a45e79b6ff74aac83f4382023-12-03T12:37:32ZengMDPI AGPharmaceutics1999-49232021-02-0113222310.3390/pharmaceutics13020223Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine NanoparticlesMyosotys Rodriguez0Yemmy Soler1Mohan Kumar Muthu Karuppan2Yuling Zhao3Elena V. Batrakova4Nazira El-Hage5Department of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, USADepartment of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, USADepartment of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, USAUNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAUNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, USAUsing nanoparticle-based RNA interference (RNAi), we have previously shown that silencing the host autophagic protein, Beclin1, in HIV-infected human microglia and astrocytes restricts HIV replication and its viral-associated inflammatory responses. Here, we confirmed the efficacy of Beclin1 small interfering RNA (siBeclin1) as an adjunctive antiviral and anti-inflammatory therapy in myeloid human microglia and primary human astrocytes infected with HIV, both with and without exposure to combined antiretroviral (cART) drugs. To specifically target human microglia and human astrocytes, we used a nanoparticle (NP) comprised of linear cationic polyethylenimine (PEI) conjugated with mannose (Man) and encapsulated with siBeclin1. The target specificity of the PEI-Man NP was confirmed in vitro using human neuronal and glial cells transfected with the NP encapsulated with fluorescein isothiocyanate (FITC). PEI-Man-siBeclin1 NPs were intranasally delivered to healthy C57BL/6 mice in order to report the biodistribution of siBeclin1 in different areas of the brain, measured using stem-loop RT-PCR. Postmortem brains recovered at 1–48 h post-treatment with the PEI-Man-siRNA NP showed no significant changes in the secretion of the chemokines regulated on activation, normal T cell expressed and secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) and showed significant decreases in the secretion of the cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) when compared to phosphate-buffered saline (PBS)-treated brains. Nissl staining showed minimal differences between the neuronal structures when compared to PBS-treated brains, which correlated with no adverse behavioral affects. To confirm the brain and peripheral organ distribution of PEI-siBeclin1 in living mice, we used the In vivo Imaging System (IVIS) and demonstrated a significant brain accumulation of siBeclin1 through intranasal administration.https://www.mdpi.com/1999-4923/13/2/223Beclin1intranasal deliveryin vivo imaging systempolyethylenimine nanoparticleHIV |
| spellingShingle | Myosotys Rodriguez Yemmy Soler Mohan Kumar Muthu Karuppan Yuling Zhao Elena V. Batrakova Nazira El-Hage Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles Pharmaceutics Beclin1 intranasal delivery in vivo imaging system polyethylenimine nanoparticle HIV |
| title | Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles |
| title_full | Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles |
| title_fullStr | Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles |
| title_full_unstemmed | Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles |
| title_short | Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles |
| title_sort | targeting beclin1 as an adjunctive therapy against hiv using mannosylated polyethylenimine nanoparticles |
| topic | Beclin1 intranasal delivery in vivo imaging system polyethylenimine nanoparticle HIV |
| url | https://www.mdpi.com/1999-4923/13/2/223 |
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