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BRAIN DELIVERY OF PROTEINS BY THE INTRANASAL ROUTE OF ADMINISTRATION USING CATIONIC LIPOSOMES. Presented by Mattia M. Migliore February 23, 2007 Graduate Materials Links Symposium Northeastern University, Boston MA 02115. Introduction :.

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brain delivery of proteins by the intranasal route of administration using cationic liposomes

BRAIN DELIVERY OF PROTEINS BY THE INTRANASAL ROUTE OF ADMINISTRATION USING CATIONIC LIPOSOMES

Presented by Mattia M. Migliore

February 23, 2007

Graduate Materials Links Symposium

Northeastern University, Boston MA 02115

introduction
Introduction:
  • Neurodegenerative diseases cause the progressive destruction of either peripheral or central nervous system neurons and result in significant cognitive and/or motor dysfunction.
  • Include Alzheimer’s disease, Parkinson’s disease, ALS, brain cancer, Huntington’s disease, and multiple sclerosis.
  • Neurotrophic factors are growth factors that stimulate neuronal regeneration and/or prevent neuronal cell death.
introduction cont
Introduction(cont.):
  • The clinical use of neurotrophic factors and other therapeutic proteins has been limited due to their inability to cross the blood-brain barrier.
  • Currently, administration is limited to invasive intracerebral infusions.
  • The purpose of the present study was to develop a cationic liposomal system for nasal delivery of proteins to the brain.
rationale
Rationale:
  • The intranasal route of administration was selected because it can bypass the blood-brain barrier, avoids systemic absorption, and limits potential peripheral side effects.
  • Two different preparations of cationic liposomes were generated containing a fluorescently tagged model protein, Alexa-488 ovalbumin.
  • Ovalbumin (OVAL) was selected because its molecular weight (45KDa) is similar to the molecular weight of several neurotrophic factors.
specific aims
Specific Aims:
  • Aim # 1: To characterize and optimize a nanoparticle formulation for intranasal delivery of OVAL.
  • Aim # 2: To determine brain delivery, both qualitatively and quantitatively.
  • Aim # 3: To determine brain distribution of OVAL, and protein integrity.
  • Aim # 4: To determine co-localization of OVAL with a dopamine neuronal marker, tyrosine hydroxylase.
specific aim 1
Specific Aim # 1:

Data presented as mean ± SEM

slide7

Specific Aims # 2: Qualitative

Determination of Protein Brain Delivery:

Intranasal Alexa 488-OVAL

(no nanoparticles)

24 hr time point, striatum(20x)

Intranasal Alexa 488-OVAL

(Preparation # 1)

24 hr time point, striatum (20x)

Intranasal Alexa 488-OVAL

(Preparation # 2)

24 hr time point, SN (20x)

specific aim 2 quantitative analysis of protein brain delivery
Specific Aim # 2: Quantitative Analysis of Protein Brain Delivery:

Time course of brain uptake of 111In-OVAL (1 µg/ µl) for liposomal preparations or control (PBS)

slide10

Biodistribution Study:

111In OVAL in Preparation #2 (1 µg/µl)

111In OVAL in Preparation #2 (2 µg/µl)

slide11

Time course of brain uptake of 111In-OVAL (2 µg/µl) for liposomal Preparation # 2 or control (PBS)

slide12

Specific Aim # 3: Protein Brain Distribution

Localization of Alexa 488-OVAL in the corpus striatum after intranasal administration. Alexa 488-OVAL (Preparation # 1),

24 hr time point (20x).

Intracellular uptake of Alexa 488-OVAL in the substantia nigra after

intranasal administration. Alexa 488-OVAL (Preparation # 2), 24 hr time point (40x).

slide13

Posterior

Alexa-488 ovalbumin

brain distribution

Midbrain

Striatum

Olfactory bulb

Frontal

slide14

Specific Aim # 3: ProteinIntegrity

Intranasal OVAL

(Preparation # 2, 2 μg/μl)

24 hr time point, SN (40x).

Intranasal OVAL

(Preparation # 2, 2 μg/μl)

1 hr time point, striatum (20x).

slide15

Specific Aim # 4: Co-localization of Alexa-488 OVAL

with Tyrosine Hydroxylase

Intranasal Alexa 488-OVAL

(Preparation # 2)

24 hr time point, SN (40x)

TH positive dopamine neurons

SN (40x)

Merged image

conclusions
Conclusions:
  • Liposomal preparations of OVAL effectively deliver the protein to brain after intranasal administration to rats.
  • The highest brain levels were detected at the shortest time point, i.e. 1 hr after administration.
  • Liposomal preparations increase brain residence time of the protein at the 24 hr time point when compared to control.
  • Liposomal OVAL delivered intranasally yields discrete protein deposits in both striatum and SN, with apparent cellular uptake in the SN by 24 hrs.
  • Intranasal administration of the 2 µg/µl form of liposomal Preparation #2 provides higher brain

levels and reduced distribution to the GI tract

relative to the more dilute form.

acknowledgements
Work was supported by the NCI-NSF IGERT Nanomedicine S&T award, and a 2005 AFPE (American Foundation for Pharmaceutical Education) fellowship.

Thesis committee:

Dr. Barbara Waszczak

Dr. Mansoor Amiji

Dr. Robert Campbell

Dr. Rebecca carrier

Dr. Ralph Loring

Dr. Robert Schatz

Dr. Tushar Vyas

Dr. Amiji’s lab:

Sandip

Lillian

Mayank

Dr. Campbell’s lab:

Suman and Ashish.

Dr. William Hartner.

Dr. Torchilin’s lab.

Eunice.

Fran.

Acknowledgements: