Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases
The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental auto...
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| Veröffentlicht in: | PloS one 2015-07, Vol.10 (7), p.e0130442 |
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| creator | Turjeman, Keren Bavli, Yaelle Kizelsztein, Pablo Schilt, Yaelle Allon, Nahum Katzir, Tamar Blumenfeld Sasson, Efrat Raviv, Uri Ovadia, Haim Barenholz, Yechezkel |
| description | The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component. |
| doi_str_mv | 10.1371/journal.pone.0130442 |
| format | Article |
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We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0130442</identifier><identifier>PMID: 26147975</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adoptive transfer ; Alzheimer's disease ; Amyloid beta-Peptides - metabolism ; Animal models ; Animals ; Anti-Inflammatory Agents - chemistry ; Anti-Inflammatory Agents - pharmacokinetics ; Anti-Inflammatory Agents - pharmacology ; Antioxidants ; Apolipoprotein E ; Apolipoproteins ; Apolipoproteins E - metabolism ; Biochemistry ; Blood-brain barrier ; Brain research ; Chemical compounds ; Corticosteroids ; Cyclic N-Oxides - chemistry ; Cyclic N-Oxides - pharmacokinetics ; Cyclic N-Oxides - pharmacology ; Disease ; Disease Models, Animal ; Drug delivery systems ; Drug Delivery Systems - methods ; Drug development ; Drug dosages ; Drugs ; Effectiveness ; Encephalomyelitis, Autoimmune, Experimental - drug therapy ; Encephalomyelitis, Autoimmune, Experimental - metabolism ; Experimental allergic encephalomyelitis ; Free radicals ; Health aspects ; Inflammation - drug therapy ; Inflammation - metabolism ; Laboratories ; Liposomes ; Liposomes - chemistry ; Medical research ; Medical schools ; Medical treatment ; Methylprednisolone ; Methylprednisolone Hemisuccinate - chemistry ; Methylprednisolone Hemisuccinate - pharmacokinetics ; Methylprednisolone Hemisuccinate - pharmacology ; Mice ; Molecular biology ; Multiple sclerosis ; Multiple Sclerosis - drug therapy ; Multiple Sclerosis - metabolism ; Nanoparticles - chemistry ; Neurodegenerative diseases ; Neurodegenerative Diseases - drug therapy ; Neurodegenerative Diseases - metabolism ; Neurological diseases ; Neurology ; Neuropathology ; Neurosurgery ; Nitroxide ; NMR ; Nuclear magnetic resonance ; Peptides ; Permeability ; Pharmacokinetics ; Pharmacology ; Prodrugs - chemistry ; Prodrugs - pharmacokinetics ; Prodrugs - pharmacology ; Spinal cord ; Tissue Distribution ; Toxicity ; β-Amyloid</subject><ispartof>PloS one, 2015-07, Vol.10 (7), p.e0130442</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Turjeman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Turjeman et al 2015 Turjeman et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-9c9eb28a4eb64f0da85773e51df83263e180b4c1ee171e1dd0a19f06f49975f93</citedby><cites>FETCH-LOGICAL-c758t-9c9eb28a4eb64f0da85773e51df83263e180b4c1ee171e1dd0a19f06f49975f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492950/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492950/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23853,27911,27912,53778,53780,79357,79358</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26147975$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Infante-Duarte, Carmen</contributor><creatorcontrib>Turjeman, Keren</creatorcontrib><creatorcontrib>Bavli, Yaelle</creatorcontrib><creatorcontrib>Kizelsztein, Pablo</creatorcontrib><creatorcontrib>Schilt, Yaelle</creatorcontrib><creatorcontrib>Allon, Nahum</creatorcontrib><creatorcontrib>Katzir, Tamar Blumenfeld</creatorcontrib><creatorcontrib>Sasson, Efrat</creatorcontrib><creatorcontrib>Raviv, Uri</creatorcontrib><creatorcontrib>Ovadia, Haim</creatorcontrib><creatorcontrib>Barenholz, Yechezkel</creatorcontrib><title>Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.</description><subject>Adoptive transfer</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animal models</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - chemistry</subject><subject>Anti-Inflammatory Agents - pharmacokinetics</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Antioxidants</subject><subject>Apolipoprotein E</subject><subject>Apolipoproteins</subject><subject>Apolipoproteins E - metabolism</subject><subject>Biochemistry</subject><subject>Blood-brain barrier</subject><subject>Brain research</subject><subject>Chemical compounds</subject><subject>Corticosteroids</subject><subject>Cyclic N-Oxides - chemistry</subject><subject>Cyclic N-Oxides - pharmacokinetics</subject><subject>Cyclic N-Oxides - pharmacology</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Drug delivery systems</subject><subject>Drug Delivery Systems - methods</subject><subject>Drug development</subject><subject>Drug dosages</subject><subject>Drugs</subject><subject>Effectiveness</subject><subject>Encephalomyelitis, Autoimmune, Experimental - drug therapy</subject><subject>Encephalomyelitis, Autoimmune, Experimental - metabolism</subject><subject>Experimental allergic encephalomyelitis</subject><subject>Free radicals</subject><subject>Health aspects</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - metabolism</subject><subject>Laboratories</subject><subject>Liposomes</subject><subject>Liposomes - chemistry</subject><subject>Medical research</subject><subject>Medical schools</subject><subject>Medical treatment</subject><subject>Methylprednisolone</subject><subject>Methylprednisolone Hemisuccinate - chemistry</subject><subject>Methylprednisolone Hemisuccinate - pharmacokinetics</subject><subject>Methylprednisolone Hemisuccinate - pharmacology</subject><subject>Mice</subject><subject>Molecular biology</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis - drug therapy</subject><subject>Multiple Sclerosis - metabolism</subject><subject>Nanoparticles - chemistry</subject><subject>Neurodegenerative diseases</subject><subject>Neurodegenerative Diseases - drug therapy</subject><subject>Neurodegenerative Diseases - metabolism</subject><subject>Neurological diseases</subject><subject>Neurology</subject><subject>Neuropathology</subject><subject>Neurosurgery</subject><subject>Nitroxide</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Peptides</subject><subject>Permeability</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - 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metabolism</topic><topic>Experimental allergic encephalomyelitis</topic><topic>Free radicals</topic><topic>Health aspects</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - metabolism</topic><topic>Laboratories</topic><topic>Liposomes</topic><topic>Liposomes - chemistry</topic><topic>Medical research</topic><topic>Medical schools</topic><topic>Medical treatment</topic><topic>Methylprednisolone</topic><topic>Methylprednisolone Hemisuccinate - chemistry</topic><topic>Methylprednisolone Hemisuccinate - pharmacokinetics</topic><topic>Methylprednisolone Hemisuccinate - pharmacology</topic><topic>Mice</topic><topic>Molecular biology</topic><topic>Multiple sclerosis</topic><topic>Multiple Sclerosis - drug therapy</topic><topic>Multiple Sclerosis - metabolism</topic><topic>Nanoparticles - chemistry</topic><topic>Neurodegenerative diseases</topic><topic>Neurodegenerative Diseases - drug therapy</topic><topic>Neurodegenerative Diseases - metabolism</topic><topic>Neurological diseases</topic><topic>Neurology</topic><topic>Neuropathology</topic><topic>Neurosurgery</topic><topic>Nitroxide</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Peptides</topic><topic>Permeability</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Prodrugs - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Turjeman, Keren</au><au>Bavli, Yaelle</au><au>Kizelsztein, Pablo</au><au>Schilt, Yaelle</au><au>Allon, Nahum</au><au>Katzir, Tamar Blumenfeld</au><au>Sasson, Efrat</au><au>Raviv, Uri</au><au>Ovadia, Haim</au><au>Barenholz, Yechezkel</au><au>Infante-Duarte, Carmen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-07-06</date><risdate>2015</risdate><volume>10</volume><issue>7</issue><spage>e0130442</spage><pages>e0130442-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26147975</pmid><doi>10.1371/journal.pone.0130442</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-07, Vol.10 (7), p.e0130442 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1694520290 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adoptive transfer Alzheimer's disease Amyloid beta-Peptides - metabolism Animal models Animals Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacokinetics Anti-Inflammatory Agents - pharmacology Antioxidants Apolipoprotein E Apolipoproteins Apolipoproteins E - metabolism Biochemistry Blood-brain barrier Brain research Chemical compounds Corticosteroids Cyclic N-Oxides - chemistry Cyclic N-Oxides - pharmacokinetics Cyclic N-Oxides - pharmacology Disease Disease Models, Animal Drug delivery systems Drug Delivery Systems - methods Drug development Drug dosages Drugs Effectiveness Encephalomyelitis, Autoimmune, Experimental - drug therapy Encephalomyelitis, Autoimmune, Experimental - metabolism Experimental allergic encephalomyelitis Free radicals Health aspects Inflammation - drug therapy Inflammation - metabolism Laboratories Liposomes Liposomes - chemistry Medical research Medical schools Medical treatment Methylprednisolone Methylprednisolone Hemisuccinate - chemistry Methylprednisolone Hemisuccinate - pharmacokinetics Methylprednisolone Hemisuccinate - pharmacology Mice Molecular biology Multiple sclerosis Multiple Sclerosis - drug therapy Multiple Sclerosis - metabolism Nanoparticles - chemistry Neurodegenerative diseases Neurodegenerative Diseases - drug therapy Neurodegenerative Diseases - metabolism Neurological diseases Neurology Neuropathology Neurosurgery Nitroxide NMR Nuclear magnetic resonance Peptides Permeability Pharmacokinetics Pharmacology Prodrugs - chemistry Prodrugs - pharmacokinetics Prodrugs - pharmacology Spinal cord Tissue Distribution Toxicity β-Amyloid |
| title | Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases |
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