le potenziali applicazioni della nanomedicina alle ... f_27.03.2018.pdf · malattie...
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Le potenziali applicazionidella NANOMEDICINA alle
malattie neurodegenerative
Dr. Francesca Re
School of Medicine and Surgery - Nanomedicine Center Biochemistry Unit
University of Milano-Bicocca, Monza (IT)
30 Marzo 2018
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Uno sguardo al futuro…
Siamo nel 2083. Anna ha 110 anni, è ancora ingamba, ma inciampa in un tappeto e caderompendosi il femore; resta distesa adaspettare e nel giro di una decina di minutipotrà rialzarsi in piedi poiché il femore siè auto-riparato. Come è potuto accadere?Dall’anno 2070 gli ultracentenari assumononano-particelle autoadesive che vanno arimpiazzare una parte dei costituenti delleossa.
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Non stiamo parlando di fantascienza, ma dell’ultima frontiera della medicina, che fa già oggi uso di minuscoli dispositivi di qualche miliardesimo di metro programmabili, intelligenti, e capaci di svolgere diversi compiti contemporaneamente per curare o diagnosticare malattie.
Qual è il presente della piccola scienza di domani?
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Un semplice esempio per capire le potenzialità delle nanotecnologie:
la natura sfrutta da moltissimo tempo la nanostrutturazione della materia vivente per ottenere proprietà assolutamente “nuove” fino a poco tempo fa ritenute irraggiungibili
copiando la natura (“materiali bioispirati”) anche l’uomo sta avvicinandosi a queste “nuove” proprietà
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Il geco cammina sul soffitto grazie alla nanostrutturazione dei suoi polpastrelli
La sommatoria di un elevatissimo numero di piccolissime forze di attrazione supera la forza gravità
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L’uomo è riuscito a riprodurre questa nanostrutturazione:
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La Nanomedicina è definita come la applicazione delle nanotecnologie
alla salute umana. Sfruttando le migliorate e spesso nuove proprietà
fisiche, chimiche e biologiche dei nanomateriali.
[US-National Institute of Health Roadmap for Medical Research in Nanomedicine]
Definition of NANOMEDICINE
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All-in-one nanodevice: NANOPARTICLESSmart nanostructures for diagnosis and therapy
with a size of 1-100 nanometers
[US-National Institute of Health Roadmap for Medical Research in Nanomedicine]
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Applications of Nanomedicine
o Diagnosis
o Therapy
o Regenerative medicine
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Advantages:
o Drug targeting
o Lesser drug is necessary
o Lesser side effects
o Protection of drugs from degradation
longer half-life
o Multi-functionalization
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Multi-functionalizationTHERANOSTIC
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Nanoparticles features make them ideal for therapy and diagnosis of different diseases,
including disorders of the central nervous system
BLOOD
BRAIN Blood-Brain Barrier (BBB)
Physical and biochemical barrier
that regulates the flow of molecules
between blood and brain
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Alzheimer’s Disease (AD)
o Neurodegenerative disease that culminates in total
loss of cognition and executive functions
o Worldwide, nearly 30 million people have AD
o Only 1-in-4 people with AD have been diagnosed
o Sporadic (majority). Only 5 % cases are familial forms
http://www.alz.org/
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No cure for AlzheimerCurrently available drugs may help
to prevent some symptoms
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Hallmarks of Alzheimer’s Disease
o Plaques (Aβ peptide)
o Tangles (hyperphosphorylated Tau)
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Nanoparticles for therapy and diagnosis of Alzheimer’s disease
Design and development of advanced nanomedicines to overcome biological barriers and to treat severe
mApoE-Functionalized Lipidic -and Polymeric- Nanocomposite for Human Glioblastoma Imaging and Treatment
Smart Nanoparticles For Boosted Drug Brain Targeting
Our approach to Alzheimer’s Disease
Development of a Novel Multicellular In Vitro Model of Alzheimer’s disease-like Blood-Brain Barrier
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Sphingomyelin/cholesterol (1:1 M/M)5 mol% phosphatidic acid2.5 mol% DSPE-PEG-maleimide
PEG
mApoE
Liposomes (mApoE-PA-LIP) able to (in vitro)
bind Ab with high affinity
disaggregate Ab assemblies
slow down Ab aggregation
overcome a Blood brain barrier model
be biocompatible
Diameter 100-150 nm
ARE THESE NP SUITABLE FOR TREATING
ALZHEIMER DISEASE IN VIVO ?
[Bana L. et al., Nanomedicine 2014]
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mApoE-LIP reach intact mouse brain after systemic administration
Confocal microscopy (hippocampal regions)
BODIPYFL-sphingomyelin
Rhodamine B
[Balducci C. et al., J. Neurosci. 2014][Bana L. et al., Nanomed. 2014]
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APP/PS1
DOUBLE TRANSGENIC
Animal model
10-12 MONTHS OF AGE:
Evident amyloid plaques Evident cognitive deficits
[Garcia-Alloza M et al., Neurobiol Dis 2006]
APPswe PSEN1dE9
5 MONTHS OF AGE:
Initial Aβ deposition Absence of cognitive deficits
Model of PRE-SYMPTOMATIC AD
Model of SEVERE AD
Proof-of-concept in vivo
• Therapeutic treatment on SEVERE AD Tg mice
APP/PS1 of 10 months of age
Intraperitoneal injection
100mL of [40mM] mApoE-PA-LIP
(total lipids = 2.5 mg/injection)
3 injection/week for 3 weeks
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Translational issues:• Irreversible brain damages present at severe AD stage
in humans• Failure of clinical trials focused on mild to moderate
stages of AD
Aβ accumulation in the brain begins ~10–20 years prior to the onset of clinically detectable symptoms
This early stage is considered the most promising time frame to start with disease-modifying therapies
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APP/PS1
DOUBLE TRANSGENIC
Animal model
10-12 MONTHS OF AGE:
Evident amyloid plaques Evident cognitive deficits
[Garcia-Alloza M et al., Neurobiol Dis 2006]
APPswe PSEN1dE9
5 MONTHS OF AGE:
Initial Aβ deposition Absence of cognitive deficits
Model of PRE-SYMPTOMATIC AD
Model of SEVERE AD
Proof-of-concept in vivo
• Preventive treatment on PRE-SYMPTOMATIC AD Tg mice
APP/PS1 of 5 months of ageIntraperitoneal injection100mL of [40mM] mApoE-PA-LIP (total lipids = 2.5 mg/injection) 1 injection/week for 7 months
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At the end of each treatment mice were analyzed for:
o Memory impairment by novel object recognition test (NORT)
o Brain Ab content by immunohistochemical, biochemical and
imaging assays
o Amount of Ab in liver and spleen by ELISA assay
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AFTER ACUTE TREATMENT WITH mApoE-PA-LIP
o Treated mice significantly recovered their long-term
recognition memory
[Balducci C. et al., J. Neurosci. 2014]
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AFTER ACUTE TREATMENT WITH mApoE-PA-LIP
o Strong reduction (-35%) of amyloid plaques and Ab burden in
the brain of treated mice
[Balducci C. et al., J. Neurosci. 2014]
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PREVENTIVE TREATMENT WITH mApoE-PA-LIP
o Prevents the onset of memory impairment and the occurrence
of AD-like cerebral abnormalities
[Mancini S. et al. J Cont Rel 2017]
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PREVENTIVE TREATMENT WITH mApoE-PA-LIP
o Strongly reduces (-30%) the amyloid plaques deposition in the
brain
[Mancini S. et al. J Cont Rel 2017]
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AFTER TREATMENTS WITH mApoE-PA-LIP
o Increase of Ab in the liver and spleen
[Mancini S. et al. J Cont Rel 2017]
[Balducci C. et al., J. Neurosci. 2014]
LIVER SPLEEN
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PEG
mApoE
PA
Plaques
BBB crossing
Soluble Ab
assemblies
BLOOD
BRAIN
Liverspleen
MoA of mApoE-PA-LIP
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We developed a nanomedicine able to
o target and reduce brain Ab
o hinder the memory impairment
mApoE-PA-lip (Amyposomes®) are promising
nanodevices for prevention and treatment of AD
The aim of the NewCo is to bring Amyposomes® to the P-o-C clinical phases in humans
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School of Medicine Prof. Massimo MasseriniPoC in animal models Human samplesS. Mancini C. FerrareseG. Sancini C. ZoiaV. Zambelli E. ContiPoC in vitroI.RivoltaFunctionalizationM.GregoriS.SesanaBiocompatibilityE. CazzanigaA. CoxCharacterizationF.MantegazzaD.Salerno
Dept. Biotechnologyand BioscienceChemical synthesisF.NicotraB. La FerlaC. Airoldi
Claudia BalducciGianluigi ForloniMario SalmonaMarco GobbiPaolo Bigini
Turku PET Centre
Juha RinneMerjia HapaarantaAnniina Sleman
F. WandosellA. Ordonez-Gutierrez
Thanks to …
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available to collaborations
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…Ritornando
al futuro…
NANOROBOTS: FACT OR FICTION?
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Thanks for your attention
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mApoE-PA-LIP effects were maintained 3 monthsafter treatment discontinuation
LRP-1 RAGE