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Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.

Turjeman K, Bavli Y, Kizelsztein P, Schilt Y, Allon N, Katzir TB, Sasson E, Raviv U, Ovadia H, Barenholz Y - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

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.

No MeSH data available.


Related in: MedlinePlus

Effect of membrane lipid composition (EPC:Chol:PEG-DSPE or DMPC:DPPC:Chol:PEG-DSPE) on TMN retention in NSSL.% Free TMN was determined by ESR for both lipid compositions, EPC:Chol:PEG-DSPE (■) and DMPC:DPPC:Chol:PEG-DSPE () in vitro at 5°C (A), 25°C (B), and 37°C (C) during 4.5 months.
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pone.0130442.g002: Effect of membrane lipid composition (EPC:Chol:PEG-DSPE or DMPC:DPPC:Chol:PEG-DSPE) on TMN retention in NSSL.% Free TMN was determined by ESR for both lipid compositions, EPC:Chol:PEG-DSPE (■) and DMPC:DPPC:Chol:PEG-DSPE () in vitro at 5°C (A), 25°C (B), and 37°C (C) during 4.5 months.

Mentions: We determined TMN release in vitro at 5°C, 25°C, and 37°C during 4.5 months by ESR for both lipid compositions, EPC:Chol:PEG-DSPE (54:41:5 mole ratio) and DMPC:DPPC:Chol:PEG-DSPE (24:30:41:5 mole ratio) (Fig 2A–2C). Indeed, we found that this PC composition has clear benefits in vitro. EPC-based liposomes (having low Tm = -5°C and low SO-to-LD transition ∆H) support a fast release rate at 2–8°C storage (which is above EPC Tm) with the majority of the drug (66%) released as free TMN. The DMPC:DPPC-based liposomes showed very similar release profiles at 25°C and 5°C as these are still below the Tm and the level of free volume is low, while at 37°C, release rate was higher than the release at 5 and 25°C. However, EPC-based liposomes released the majority of the drug (60–77%) at 25°C during the first month and reached a steady state. These results are in correlation to the Tm and ∆H of the liposomes made of DMPC:DPPC mixture 24:30 mole ratio (described above). The release from EPC-based NSSL at 37°C was similar to the release at 25°C; more than 50% of the drug was released after the first month. Temperature is only one parameter affecting the release rate in vivo in the inflamed brain. There are probably additional local inflammation factors (e.g., cytokines, MMPs, etc.) that may support a more selective drug release in the diseased brain. The increased release rate of TMN at 37°C is an acceptable but not absolute indication of a better therapeutic effect.


Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.

Turjeman K, Bavli Y, Kizelsztein P, Schilt Y, Allon N, Katzir TB, Sasson E, Raviv U, Ovadia H, Barenholz Y - PLoS ONE (2015)

Effect of membrane lipid composition (EPC:Chol:PEG-DSPE or DMPC:DPPC:Chol:PEG-DSPE) on TMN retention in NSSL.% Free TMN was determined by ESR for both lipid compositions, EPC:Chol:PEG-DSPE (■) and DMPC:DPPC:Chol:PEG-DSPE () in vitro at 5°C (A), 25°C (B), and 37°C (C) during 4.5 months.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492950&req=5

pone.0130442.g002: Effect of membrane lipid composition (EPC:Chol:PEG-DSPE or DMPC:DPPC:Chol:PEG-DSPE) on TMN retention in NSSL.% Free TMN was determined by ESR for both lipid compositions, EPC:Chol:PEG-DSPE (■) and DMPC:DPPC:Chol:PEG-DSPE () in vitro at 5°C (A), 25°C (B), and 37°C (C) during 4.5 months.
Mentions: We determined TMN release in vitro at 5°C, 25°C, and 37°C during 4.5 months by ESR for both lipid compositions, EPC:Chol:PEG-DSPE (54:41:5 mole ratio) and DMPC:DPPC:Chol:PEG-DSPE (24:30:41:5 mole ratio) (Fig 2A–2C). Indeed, we found that this PC composition has clear benefits in vitro. EPC-based liposomes (having low Tm = -5°C and low SO-to-LD transition ∆H) support a fast release rate at 2–8°C storage (which is above EPC Tm) with the majority of the drug (66%) released as free TMN. The DMPC:DPPC-based liposomes showed very similar release profiles at 25°C and 5°C as these are still below the Tm and the level of free volume is low, while at 37°C, release rate was higher than the release at 5 and 25°C. However, EPC-based liposomes released the majority of the drug (60–77%) at 25°C during the first month and reached a steady state. These results are in correlation to the Tm and ∆H of the liposomes made of DMPC:DPPC mixture 24:30 mole ratio (described above). The release from EPC-based NSSL at 37°C was similar to the release at 25°C; more than 50% of the drug was released after the first month. Temperature is only one parameter affecting the release rate in vivo in the inflamed brain. There are probably additional local inflammation factors (e.g., cytokines, MMPs, etc.) that may support a more selective drug release in the diseased brain. The increased release rate of TMN at 37°C is an acceptable but not absolute indication of a better therapeutic effect.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Membrane and Liposome Research, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

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.

No MeSH data available.


Related in: MedlinePlus