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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 50 and 10mg/kg NSSL-MPS in the acute EAE mice model.SJL mice were treated by IV injections on days 10, 12, 14 post-immunization with saline (control) (◆), 10mg/kg NSSL-MPS (▲) or 50mg/kg NSSL-MPS (■).
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pone.0130442.g005: Comparison of the therapeutic efficacy of 50 and 10mg/kg NSSL-MPS in the acute EAE mice model.SJL mice were treated by IV injections on days 10, 12, 14 post-immunization with saline (control) (◆), 10mg/kg NSSL-MPS (▲) or 50mg/kg NSSL-MPS (■).

Mentions: We have shown that treatment with 50mg/kg NSSL-MPS administered IV in the acute EAE mice model had superior therapeutic efficacy than free MPS and currently used drugs (Betaferon and Copaxone)[9]. In Fig 5 we compared the therapeutic efficacy of 50 and 10mg/kg NSSL-MPS in the acute EAE mice model. Treatment with NSSL-MPS showed significant therapeutic efficacy even at 5-fold lower dosage (10mg/kg compared to 50mg/kg) and the mean burden of disease was significantly lower for both treatment groups compared to control group (Fig 5, Table 5). Our results are in agreement with previously published dose titration experiments underscoring a dose-dependent efficacy of liposomal GC (using prednisolone phosphate as the active drug instead of MPS prodrug) with a sustained efficacy especially of the higher dosage (10mg/kg, but not at 4mg/kg) in MOG-EAE DA rats [19]. While the optimal dosage for GC pulse in treatment of MS is still under debate, many studies point to a dose-dependent efficacy of free GC. At a lower concentration, GC effects are mainly mediated by the classical nuclear GC receptor, but at a higher concentration, additional, non-genomic mechanisms may be operative, such as through membrane receptors (for example, G-protein-coupled receptors [53]) and activation of a second messenger system [54, 55]. These pathways are thought to be one possible explanation for the observed superiority of high and ultra-high doses in the treatment of some autoimmune disorders [56]. Although tissue targeting by NSSL formulations already results in higher local tissue concentrations, dose-dependency is apparently of similar importance for the action of liposomal GC as for free GC.


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 50 and 10mg/kg NSSL-MPS in the acute EAE mice model.SJL mice were treated by IV injections on days 10, 12, 14 post-immunization with saline (control) (◆), 10mg/kg NSSL-MPS (▲) or 50mg/kg NSSL-MPS (■).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130442.g005: Comparison of the therapeutic efficacy of 50 and 10mg/kg NSSL-MPS in the acute EAE mice model.SJL mice were treated by IV injections on days 10, 12, 14 post-immunization with saline (control) (◆), 10mg/kg NSSL-MPS (▲) or 50mg/kg NSSL-MPS (■).
Mentions: We have shown that treatment with 50mg/kg NSSL-MPS administered IV in the acute EAE mice model had superior therapeutic efficacy than free MPS and currently used drugs (Betaferon and Copaxone)[9]. In Fig 5 we compared the therapeutic efficacy of 50 and 10mg/kg NSSL-MPS in the acute EAE mice model. Treatment with NSSL-MPS showed significant therapeutic efficacy even at 5-fold lower dosage (10mg/kg compared to 50mg/kg) and the mean burden of disease was significantly lower for both treatment groups compared to control group (Fig 5, Table 5). Our results are in agreement with previously published dose titration experiments underscoring a dose-dependent efficacy of liposomal GC (using prednisolone phosphate as the active drug instead of MPS prodrug) with a sustained efficacy especially of the higher dosage (10mg/kg, but not at 4mg/kg) in MOG-EAE DA rats [19]. While the optimal dosage for GC pulse in treatment of MS is still under debate, many studies point to a dose-dependent efficacy of free GC. At a lower concentration, GC effects are mainly mediated by the classical nuclear GC receptor, but at a higher concentration, additional, non-genomic mechanisms may be operative, such as through membrane receptors (for example, G-protein-coupled receptors [53]) and activation of a second messenger system [54, 55]. These pathways are thought to be one possible explanation for the observed superiority of high and ultra-high doses in the treatment of some autoimmune disorders [56]. Although tissue targeting by NSSL formulations already results in higher local tissue concentrations, dose-dependency is apparently of similar importance for the action of liposomal GC as for free GC.

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