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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

(A) DSC measurements. Samples of SUVs (DMPC:DPPC:Chol:PEG-DSPE, DMPC:DPPC:PEG-DSPE, DMPC:DPPC, DMPC:PEG-DSPE, DPPC:PEG-DSPE, DMPC, DPPC) in saline, and saline in the reference cell, were scanned in the range 10°-80°C, at the heating rate of 1°C/min. (B) Zooming in: Samples of SUVs DMPC:DPPC:Chol:PEG-DSPE, DMPC:DPPC:PEG-DSPE.
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pone.0130442.g001: (A) DSC measurements. Samples of SUVs (DMPC:DPPC:Chol:PEG-DSPE, DMPC:DPPC:PEG-DSPE, DMPC:DPPC, DMPC:PEG-DSPE, DPPC:PEG-DSPE, DMPC, DPPC) in saline, and saline in the reference cell, were scanned in the range 10°-80°C, at the heating rate of 1°C/min. (B) Zooming in: Samples of SUVs DMPC:DPPC:Chol:PEG-DSPE, DMPC:DPPC:PEG-DSPE.

Mentions: DSC measurements were done using SUV formulations of different lipid mixtures of DMPC, DPPC, PEG-DSPE, and cholesterol. As 33 mole% cholesterol is expected to abolish SO-to-LD phase transition of liposomal phospholipids [44], DSC measurements were done using an SUV formulation with the same lipid composition of DMPC:DPPC:PEG-DSPE (42.2: 52.8: 5 mole ratio) but without cholesterol. The thermotropic behavior assessed from the DSC scans presented in Table 2and Fig 1A and 1Bdemonstrates a phase transition range of 24.87 to 43.05°C; the endotherm has a half width of 4.0°C, a Tm of 34.2°C which is slightly below body temperature, and a relatively high phase transition enthalpy (H) of 6.961 kcal/mole. It is well established that for saturated PCs, ∆H increases with increasing PC acyl chain length and that the higher is ∆H, the stronger are the chain-chain associations [45, 46]. For comparison, DMPC-based SUV have a ∆H of 4.35 kcal/mole, while DPPC-based SUV have a ∆H of 8.2kcal/mole. DMPC:DPPC-based SUV demonstrate similar thermotropic behavior with a phase transition range of 24.8–43.5°C; the endotherm has a half width of 3.8°C, a Tm of 34.05°C, and a phase transition enthalpy (∆H) of 5.9 kcal/mole. This means that on storage this DMPC:DPPC-based nano-drug will resemble more the nano-drugs that are based on high-Tm PCs such as HSPC, and therefore will have a very slow drug release rate, which supports good storage conditions. The thermotropic behavior of DMPC:DPPC:PEG-DSPE:Chol assessed from the DSC scans is also presented in Table 2. To our surprise, at high lipid concentration there was a wide phase transition range (11.3–79.7°C) having a low phase transition enthalpy (H of 0.4 kcal/mole) and "width at half height" of 30.5°C. Namely, at 37°C these NSSL will be at the range of the SO-to-LD phase transition temperature, and therefore their LO phase will include enough free volume to enable sufficient release of TMN for therapeutic efficacy. However the 2–8°C storage temperature is below the temperature range of the nano-drug’s PCs phase transition.


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)

(A) DSC measurements. Samples of SUVs (DMPC:DPPC:Chol:PEG-DSPE, DMPC:DPPC:PEG-DSPE, DMPC:DPPC, DMPC:PEG-DSPE, DPPC:PEG-DSPE, DMPC, DPPC) in saline, and saline in the reference cell, were scanned in the range 10°-80°C, at the heating rate of 1°C/min. (B) Zooming in: Samples of SUVs DMPC:DPPC:Chol:PEG-DSPE, DMPC:DPPC:PEG-DSPE.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130442.g001: (A) DSC measurements. Samples of SUVs (DMPC:DPPC:Chol:PEG-DSPE, DMPC:DPPC:PEG-DSPE, DMPC:DPPC, DMPC:PEG-DSPE, DPPC:PEG-DSPE, DMPC, DPPC) in saline, and saline in the reference cell, were scanned in the range 10°-80°C, at the heating rate of 1°C/min. (B) Zooming in: Samples of SUVs DMPC:DPPC:Chol:PEG-DSPE, DMPC:DPPC:PEG-DSPE.
Mentions: DSC measurements were done using SUV formulations of different lipid mixtures of DMPC, DPPC, PEG-DSPE, and cholesterol. As 33 mole% cholesterol is expected to abolish SO-to-LD phase transition of liposomal phospholipids [44], DSC measurements were done using an SUV formulation with the same lipid composition of DMPC:DPPC:PEG-DSPE (42.2: 52.8: 5 mole ratio) but without cholesterol. The thermotropic behavior assessed from the DSC scans presented in Table 2and Fig 1A and 1Bdemonstrates a phase transition range of 24.87 to 43.05°C; the endotherm has a half width of 4.0°C, a Tm of 34.2°C which is slightly below body temperature, and a relatively high phase transition enthalpy (H) of 6.961 kcal/mole. It is well established that for saturated PCs, ∆H increases with increasing PC acyl chain length and that the higher is ∆H, the stronger are the chain-chain associations [45, 46]. For comparison, DMPC-based SUV have a ∆H of 4.35 kcal/mole, while DPPC-based SUV have a ∆H of 8.2kcal/mole. DMPC:DPPC-based SUV demonstrate similar thermotropic behavior with a phase transition range of 24.8–43.5°C; the endotherm has a half width of 3.8°C, a Tm of 34.05°C, and a phase transition enthalpy (∆H) of 5.9 kcal/mole. This means that on storage this DMPC:DPPC-based nano-drug will resemble more the nano-drugs that are based on high-Tm PCs such as HSPC, and therefore will have a very slow drug release rate, which supports good storage conditions. The thermotropic behavior of DMPC:DPPC:PEG-DSPE:Chol assessed from the DSC scans is also presented in Table 2. To our surprise, at high lipid concentration there was a wide phase transition range (11.3–79.7°C) having a low phase transition enthalpy (H of 0.4 kcal/mole) and "width at half height" of 30.5°C. Namely, at 37°C these NSSL will be at the range of the SO-to-LD phase transition temperature, and therefore their LO phase will include enough free volume to enable sufficient release of TMN for therapeutic efficacy. However the 2–8°C storage temperature is below the temperature range of the nano-drug’s PCs phase transition.

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