Insulin Nanogels: a New Strategy for the Treatment of Alzheimer’s Disease

Risultato della ricerca: Paper

Abstract

A growing body of evidence shows that Insulin, Insulin Receptor (IR) and IR signaling are involved in brain cognitive functions and their dysfunction is implicated in Alzheimer’s disease (AD) degeneration. Thus, administration of insulin could be a strategy for AD treatment. For this aim we have designed, synthesized and characterized a nanogel system (NG) to deliver insulin to the brain, as a tool for the development of a new therapy for AD. A carboxyl-functionalized poly(N-vinyl pyrrolidone) nanogel system produced by ionizing radiation was chosen as substrate for the covalent attachment of insulin or fluorescent molecules relevant for its characterization. Biocompatibility of the naked carrier was demonstrated by absence of cytotoxicity, oxidative stress and mitochondrial dysfunction. Hemocompatibility was demonstrated by hemolysis, coagulation time, leukocyte proliferation and inflammatory response tests. By immonufluorescence measurements we demonstrated that insulin conjugated to the NG (NG-In) is preotected by protease degradation and is able to bind and activate insulin receptor bringing to trigger the insulin signalling via AKT activation. Moreover, to provide consistent evidence on the functionality of the conjugated insulin on the glucose levels, the effect of NG-In was tested in mice demonstrating that plasma glucose levels was reduced. Neuroprotection of NG-In against dysfunction induced by amyloid β, a peptide mainly involved in AD, was verified. Finally, the potential of NG-In to be efficiently transported across the Blood Brain Barrier was demonstrated by using an in vitro system. All together these results indicated that the synthesized NG-In was a suitable vehicle system for insulin delivery in biomedicine and a very promising tool to develop new therapies for neurodegenerative diseases. The research eas supported by MIUR, FLAGSHIP PROJECT NanoMAX.
Lingua originaleEnglish
Stato di pubblicazionePublished - 2016

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Alzheimer Disease
Insulin
Insulin Receptor
Glucose
NanoGel
Amyloid beta-Peptides
Brain
Hemolysis
Ionizing Radiation
Blood-Brain Barrier
Neurodegenerative Diseases
Cognition
Oxidative Stress
Leukocytes
Peptide Hydrolases
Therapeutics
Research

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title = "Insulin Nanogels: a New Strategy for the Treatment of Alzheimer’s Disease",
abstract = "A growing body of evidence shows that Insulin, Insulin Receptor (IR) and IR signaling are involved in brain cognitive functions and their dysfunction is implicated in Alzheimer’s disease (AD) degeneration. Thus, administration of insulin could be a strategy for AD treatment. For this aim we have designed, synthesized and characterized a nanogel system (NG) to deliver insulin to the brain, as a tool for the development of a new therapy for AD. A carboxyl-functionalized poly(N-vinyl pyrrolidone) nanogel system produced by ionizing radiation was chosen as substrate for the covalent attachment of insulin or fluorescent molecules relevant for its characterization. Biocompatibility of the naked carrier was demonstrated by absence of cytotoxicity, oxidative stress and mitochondrial dysfunction. Hemocompatibility was demonstrated by hemolysis, coagulation time, leukocyte proliferation and inflammatory response tests. By immonufluorescence measurements we demonstrated that insulin conjugated to the NG (NG-In) is preotected by protease degradation and is able to bind and activate insulin receptor bringing to trigger the insulin signalling via AKT activation. Moreover, to provide consistent evidence on the functionality of the conjugated insulin on the glucose levels, the effect of NG-In was tested in mice demonstrating that plasma glucose levels was reduced. Neuroprotection of NG-In against dysfunction induced by amyloid β, a peptide mainly involved in AD, was verified. Finally, the potential of NG-In to be efficiently transported across the Blood Brain Barrier was demonstrated by using an in vitro system. All together these results indicated that the synthesized NG-In was a suitable vehicle system for insulin delivery in biomedicine and a very promising tool to develop new therapies for neurodegenerative diseases. The research eas supported by MIUR, FLAGSHIP PROJECT NanoMAX.",
author = "Flavia Mule' and Valeria Militello and Antonella Amato and Clelia Dispenza and Sabatino, {Maria Antonietta} and Ditta, {Lorena Anna}",
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T1 - Insulin Nanogels: a New Strategy for the Treatment of Alzheimer’s Disease

AU - Mule', Flavia

AU - Militello, Valeria

AU - Amato, Antonella

AU - Dispenza, Clelia

AU - Sabatino, Maria Antonietta

AU - Ditta, Lorena Anna

PY - 2016

Y1 - 2016

N2 - A growing body of evidence shows that Insulin, Insulin Receptor (IR) and IR signaling are involved in brain cognitive functions and their dysfunction is implicated in Alzheimer’s disease (AD) degeneration. Thus, administration of insulin could be a strategy for AD treatment. For this aim we have designed, synthesized and characterized a nanogel system (NG) to deliver insulin to the brain, as a tool for the development of a new therapy for AD. A carboxyl-functionalized poly(N-vinyl pyrrolidone) nanogel system produced by ionizing radiation was chosen as substrate for the covalent attachment of insulin or fluorescent molecules relevant for its characterization. Biocompatibility of the naked carrier was demonstrated by absence of cytotoxicity, oxidative stress and mitochondrial dysfunction. Hemocompatibility was demonstrated by hemolysis, coagulation time, leukocyte proliferation and inflammatory response tests. By immonufluorescence measurements we demonstrated that insulin conjugated to the NG (NG-In) is preotected by protease degradation and is able to bind and activate insulin receptor bringing to trigger the insulin signalling via AKT activation. Moreover, to provide consistent evidence on the functionality of the conjugated insulin on the glucose levels, the effect of NG-In was tested in mice demonstrating that plasma glucose levels was reduced. Neuroprotection of NG-In against dysfunction induced by amyloid β, a peptide mainly involved in AD, was verified. Finally, the potential of NG-In to be efficiently transported across the Blood Brain Barrier was demonstrated by using an in vitro system. All together these results indicated that the synthesized NG-In was a suitable vehicle system for insulin delivery in biomedicine and a very promising tool to develop new therapies for neurodegenerative diseases. The research eas supported by MIUR, FLAGSHIP PROJECT NanoMAX.

AB - A growing body of evidence shows that Insulin, Insulin Receptor (IR) and IR signaling are involved in brain cognitive functions and their dysfunction is implicated in Alzheimer’s disease (AD) degeneration. Thus, administration of insulin could be a strategy for AD treatment. For this aim we have designed, synthesized and characterized a nanogel system (NG) to deliver insulin to the brain, as a tool for the development of a new therapy for AD. A carboxyl-functionalized poly(N-vinyl pyrrolidone) nanogel system produced by ionizing radiation was chosen as substrate for the covalent attachment of insulin or fluorescent molecules relevant for its characterization. Biocompatibility of the naked carrier was demonstrated by absence of cytotoxicity, oxidative stress and mitochondrial dysfunction. Hemocompatibility was demonstrated by hemolysis, coagulation time, leukocyte proliferation and inflammatory response tests. By immonufluorescence measurements we demonstrated that insulin conjugated to the NG (NG-In) is preotected by protease degradation and is able to bind and activate insulin receptor bringing to trigger the insulin signalling via AKT activation. Moreover, to provide consistent evidence on the functionality of the conjugated insulin on the glucose levels, the effect of NG-In was tested in mice demonstrating that plasma glucose levels was reduced. Neuroprotection of NG-In against dysfunction induced by amyloid β, a peptide mainly involved in AD, was verified. Finally, the potential of NG-In to be efficiently transported across the Blood Brain Barrier was demonstrated by using an in vitro system. All together these results indicated that the synthesized NG-In was a suitable vehicle system for insulin delivery in biomedicine and a very promising tool to develop new therapies for neurodegenerative diseases. The research eas supported by MIUR, FLAGSHIP PROJECT NanoMAX.

UR - http://hdl.handle.net/10447/211635

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