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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

Comparison of the therapeutic efficacy of EPC:Chol:PEG-DSPE NSSL-TMN and DMPC:DPPC:Chol:PEG-DSPE NSSL-TMN in acute EAE mice model.SJL/J mice (n = 10) were treated by IV injections every other day starting on day 8 with: EPC:Chol:PEG-DSPE NSSL-TMN 8.5 mg/kg BW (■), DMPC:DPPC:Chol:PEG-DSPE NSSL-TMN 8.5mg/kg BW (▲), and dextrose 5% (control) (●).
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pone.0130442.g004: Comparison of the therapeutic efficacy of EPC:Chol:PEG-DSPE NSSL-TMN and DMPC:DPPC:Chol:PEG-DSPE NSSL-TMN in acute EAE mice model.SJL/J mice (n = 10) were treated by IV injections every other day starting on day 8 with: EPC:Chol:PEG-DSPE NSSL-TMN 8.5 mg/kg BW (■), DMPC:DPPC:Chol:PEG-DSPE NSSL-TMN 8.5mg/kg BW (▲), and dextrose 5% (control) (●).

Mentions: The DMPC:DPPC-based NSSL-TMN nano-drug demonstrated an improved storage stability at 2–8°C compared to the EPC-based NSSL-TMN nano-drug. However, the high resistance to release may reduce the therapeutic efficacy due to a slower release rate at 37°C (Fig 2C). When comparing the therapeutic efficacy of DMPC:DPPC-based NSSL-TMN and EPC-based NSSL-TMN in acute EAE mice, we demonstrated that not only was the less "fluid", optimized DMPC:DPPC formulation therapeutically active, it actually showed a better and prolonged therapeutic effect compared to the EPC-based NSSl-TMN. DMPC:DPPC-based NSSL-TMN demonstrated superior therapeutic efficacy compared to the control group and EPC-based NSSL-TMN- treated group (mean burden of disease of 0.26±0.05 compared to 0.77±0.08 and 0.5±0.07, respectively, Fig 4, Table 4). The lower leakage rate of TMN from DMPC:DPPC-based NSSL than from EPC-based NSSL (Fig 2) might explain the in vivo benefits of DMPC:DPPC-based NSSL-TMN. This formulation showed reduced amounts of TMN release in vitro at 37°C, and therefore probably lower “leakage” into the blood circulation, leading to a high TMN level at the disease site and better therapeutic efficacy compared to EPC-based NSSL. EPC-based liposomes (having low Tm of -5°C and low SO-to-LD transition ∆H) are characterized by a lipid bilayer having high compressibility [49], namely, the LO phase membrane has a much larger number of free volume defects [49–52]. This free volume is what determines the kinetic order and rate of drug release. In short, in NSSL based on high-Tm PCs, the small number of free volume defects becomes saturated already at low drug concentration, and consequently the system operates under conditions of Vmax, which results in a slow, zero-order release. In terms of medical application, if a liposome bilayer in the LO phase is composed of a phospholipid with a Tm much below 37°C, like EPC, when these liposomes are used in vivo at 37°C the membrane will have high compressibility due to the high level of membrane free volume. This will allow encapsulated agents (in our case TMN) to be released faster than from liposomes with membranes based on liposome-forming lipid with Tm above 37C, where even at the LO phase the free volume is small.


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)

Comparison of the therapeutic efficacy of EPC:Chol:PEG-DSPE NSSL-TMN and DMPC:DPPC:Chol:PEG-DSPE NSSL-TMN in acute EAE mice model.SJL/J mice (n = 10) were treated by IV injections every other day starting on day 8 with: EPC:Chol:PEG-DSPE NSSL-TMN 8.5 mg/kg BW (■), DMPC:DPPC:Chol:PEG-DSPE NSSL-TMN 8.5mg/kg BW (▲), and dextrose 5% (control) (●).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130442.g004: Comparison of the therapeutic efficacy of EPC:Chol:PEG-DSPE NSSL-TMN and DMPC:DPPC:Chol:PEG-DSPE NSSL-TMN in acute EAE mice model.SJL/J mice (n = 10) were treated by IV injections every other day starting on day 8 with: EPC:Chol:PEG-DSPE NSSL-TMN 8.5 mg/kg BW (■), DMPC:DPPC:Chol:PEG-DSPE NSSL-TMN 8.5mg/kg BW (▲), and dextrose 5% (control) (●).
Mentions: The DMPC:DPPC-based NSSL-TMN nano-drug demonstrated an improved storage stability at 2–8°C compared to the EPC-based NSSL-TMN nano-drug. However, the high resistance to release may reduce the therapeutic efficacy due to a slower release rate at 37°C (Fig 2C). When comparing the therapeutic efficacy of DMPC:DPPC-based NSSL-TMN and EPC-based NSSL-TMN in acute EAE mice, we demonstrated that not only was the less "fluid", optimized DMPC:DPPC formulation therapeutically active, it actually showed a better and prolonged therapeutic effect compared to the EPC-based NSSl-TMN. DMPC:DPPC-based NSSL-TMN demonstrated superior therapeutic efficacy compared to the control group and EPC-based NSSL-TMN- treated group (mean burden of disease of 0.26±0.05 compared to 0.77±0.08 and 0.5±0.07, respectively, Fig 4, Table 4). The lower leakage rate of TMN from DMPC:DPPC-based NSSL than from EPC-based NSSL (Fig 2) might explain the in vivo benefits of DMPC:DPPC-based NSSL-TMN. This formulation showed reduced amounts of TMN release in vitro at 37°C, and therefore probably lower “leakage” into the blood circulation, leading to a high TMN level at the disease site and better therapeutic efficacy compared to EPC-based NSSL. EPC-based liposomes (having low Tm of -5°C and low SO-to-LD transition ∆H) are characterized by a lipid bilayer having high compressibility [49], namely, the LO phase membrane has a much larger number of free volume defects [49–52]. This free volume is what determines the kinetic order and rate of drug release. In short, in NSSL based on high-Tm PCs, the small number of free volume defects becomes saturated already at low drug concentration, and consequently the system operates under conditions of Vmax, which results in a slow, zero-order release. In terms of medical application, if a liposome bilayer in the LO phase is composed of a phospholipid with a Tm much below 37°C, like EPC, when these liposomes are used in vivo at 37°C the membrane will have high compressibility due to the high level of membrane free volume. This will allow encapsulated agents (in our case TMN) to be released faster than from liposomes with membranes based on liposome-forming lipid with Tm above 37C, where even at the LO phase the free volume is small.

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