Francesca Re

Nanomedicine Seminar - Synthesis of nano-biomaterials, modelling, and applications
common issues
in the treatment/diagnosis of different diseases

worse for the treatment of diseases affecting the central
...
to develop drug delivery strategies that will allow the
passage of drug molecules from the blood to the brain
in a safe an...
 Biological hurdles
 Modifications of the NP’s surface that occurs after
administration in biological environment

 Phy...
the problem
 Highly selective barrier
 Lack of specific/exclusive molecules on the BBB
 Presence of transport mechanisms on the BBB...
potential solutions
Functionalized nanoparticles

+

Lipoproteins

[Fernandes C. Pharm Res. 2010]
Transwell system for BBB model in vitro

Brain capillary endothelial cells

CELLULAR UPTAKE
MONOLAYER PERMEABILITY (cm/min...
CHARACTERIZATION OF BBB MODEL
BIOELECTRICAL PROPERTIES

FUNCTIONAL PROPERTIES

TRANS-ENDOTHELIAL ELECTRICAL RESISTANCE
140...
Adsorptive pathways:
 Cationic proteins: cationic albumin
 Cell-penetrating peptides: modified TAT-1 from HIV

Receptor-...
NP-Cationic albumin

[Liu X. Biomaterials. 2013]

IN VIVO

NP-TAT-1 peptide

[Gregori M. J Nanomed Nanotech. 2013]

IN VIT...
IN VIVO
NP + modified peptide of the receptor-binding domain of ApoE

IN VITRO

[Re F. Nanomedicine. 2011]
[Bana L. Nanome...
NP

NP + anti-TfR antibody

IN VITRO

[Salvati E. Int J Nanomed. 2013]
[Markoutsa E. Eur J Pharm Biopharm. 2011]
THE NP CHEMICAL DESIGN AFFECTS THE BBB CROSSING:
ligand density on the NP surface
LIGAND DENSITY IN THE NP SURFACE

[Re F....
THE NP CHEMICAL DESIGN AFFECTS THE BBB CROSSING:
method of ligand conjugation on the NP surface

NP-b/s-anti-TfR antibody
...
NANOPARTICLES

[Re F. Nanomedicine. 2011]

DRUG
 Biological hurdles
 Modifications of the NP’s surface that occurs after
administration in biological environment

 Phy...
the problem
Targeting
moieties

adsorption of biomolecules to the NP surface
Y
Adsorption of plasma proteins to the NP sur...
potential solutions
SMART SURFACE ENGINEERED APPROACHES
TO AVOID PROTEIN CORONA
Design a NP surface that exhibits
minimal ...
Striped gold NP
#

3,0E-04

IN VITRO

Permeability (cm/sec)

1,2E-04 2,5E-04

Permeability (cm/sec)

PB

**

1,0E-04 2,0E-...
[unpublished data]
 Biological hurdles
 Modifications of the NP’s surface that occurs after
administration in biological environment

 Phy...
the problem
brain

nanoparticles

1 step: NP dilution into the blood

2 step: NP dilution into CSF

potential solutions
An...
Drugs bound to NP for brain delivery

The development of delivery system to transport drugs into the
brain in a safe and e...
AD MICE MODEL TREATED WITH AMYLOSOMES
(functionalized with mApoE as BBB ligand)
TREATED WITH PBS

TREATED WITH LIP

-40%
*...
The BBB represents the main
mechanism of defense of the CNS

The risk-benefit balance due
to NP accumulation in the
CNS sh...
NP DESIGN FOR BRAIN TARGETING
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NP DESIGN FOR BRAIN TARGETING

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Transcript of "NP DESIGN FOR BRAIN TARGETING"

  1. 1. Francesca Re Nanomedicine Seminar - Synthesis of nano-biomaterials, modelling, and applications
  2. 2. common issues in the treatment/diagnosis of different diseases worse for the treatment of diseases affecting the central nervous system (neurodegeneration and cerebral tumors) There are increasingly high expectations for the delivery of drugs to the brain using NANOPARTICLES
  3. 3. to develop drug delivery strategies that will allow the passage of drug molecules from the blood to the brain in a safe and effective manner Considerable efforts have been made to enhance the delivery of therapeutic molecules to the CNS BUT after two decades of research, nanotechnology approaches to brain drug delivery remain yet underdeveloped
  4. 4.  Biological hurdles  Modifications of the NP’s surface that occurs after administration in biological environment  Physical hurdles SMART DESIGN OF NANOPARTICLES
  5. 5. the problem
  6. 6.  Highly selective barrier  Lack of specific/exclusive molecules on the BBB  Presence of transport mechanisms on the BBB 2-3 nm X
  7. 7. potential solutions Functionalized nanoparticles + Lipoproteins [Fernandes C. Pharm Res. 2010]
  8. 8. Transwell system for BBB model in vitro Brain capillary endothelial cells CELLULAR UPTAKE MONOLAYER PERMEABILITY (cm/min)
  9. 9. CHARACTERIZATION OF BBB MODEL BIOELECTRICAL PROPERTIES FUNCTIONAL PROPERTIES TRANS-ENDOTHELIAL ELECTRICAL RESISTANCE 140 TJ: CLAUDIN RATIO PROPRANOLOL SUCROSE PROPR/SUCR = 1,3 AJ: CADERIN TEER = 114.3Ωxcm2 TEER (Ohms x cm2) 120 100 80 60 40 20 0 10 11 12 13 14 15 16 17 18 Days after seeding (day) [Re F.; Andreozzi P]
  10. 10. Adsorptive pathways:  Cationic proteins: cationic albumin  Cell-penetrating peptides: modified TAT-1 from HIV Receptor-mediated pathways:  A modified receptor-binding domain peptide of ApoE (CWLRKLRKRLLR or its tandem dimer) for LDLR  Anti-TfR antibodies (OX-26, RI-7217)
  11. 11. NP-Cationic albumin [Liu X. Biomaterials. 2013] IN VIVO NP-TAT-1 peptide [Gregori M. J Nanomed Nanotech. 2013] IN VITRO
  12. 12. IN VIVO NP + modified peptide of the receptor-binding domain of ApoE IN VITRO [Re F. Nanomedicine. 2011] [Bana L. Nanomedicine 2013, submitted] [Balducci C. PNAS 2013, submitted]
  13. 13. NP NP + anti-TfR antibody IN VITRO [Salvati E. Int J Nanomed. 2013] [Markoutsa E. Eur J Pharm Biopharm. 2011]
  14. 14. THE NP CHEMICAL DESIGN AFFECTS THE BBB CROSSING: ligand density on the NP surface LIGAND DENSITY IN THE NP SURFACE [Re F. J Biotechnol. 2010]
  15. 15. THE NP CHEMICAL DESIGN AFFECTS THE BBB CROSSING: method of ligand conjugation on the NP surface NP-b/s-anti-TfR antibody NP-cov-anti-TfR antibody [Salvati E. Int J Nanomed. 2013]
  16. 16. NANOPARTICLES [Re F. Nanomedicine. 2011] DRUG
  17. 17.  Biological hurdles  Modifications of the NP’s surface that occurs after administration in biological environment  Physical hurdles SMART DESIGN OF NANOPARTICLES
  18. 18. the problem Targeting moieties adsorption of biomolecules to the NP surface Y Adsorption of plasma proteins to the NP surface  NP NP with new biological identity Protein corona  NP cellular uptake and trafficking  Biodistribution in vivo The formation of protein corona depend of NP:  SIZE  SURFACE CURVATURE  SURFACE CHEMISTRY NP-cell membranes interaction [Krol S. J Control Rel. 2012]
  19. 19. potential solutions SMART SURFACE ENGINEERED APPROACHES TO AVOID PROTEIN CORONA Design a NP surface that exhibits minimal interaction with biological environment TO EXPLOIT PROTEIN CORONA Design a NP surface that exhibits a specific interaction with biological environment  Apolipoproteins (ApoE)  Tween 80  Human serum albumin NP [Mahon E. J Control Rel. 2012]
  20. 20. Striped gold NP # 3,0E-04 IN VITRO Permeability (cm/sec) 1,2E-04 2,5E-04 Permeability (cm/sec) PB ** 1,0E-04 2,0E-04 [unpublished data] # # IN VITRO M # 8,0E-05 1,5E-04 * [Verma A. Nat Mater. 2008] 6,0E-05 1,0E-04 4,0E-05 5,0E-05 2,0E-05 0,0E+00 PBS 2 % FBS 10% FBS [unpublished data] 0,0E+00 ST1 Au NANOPARTICLES (prime preparazioni di striped) ST2 MUS1 Au NANOPARTICLES MUS2 all-MUS [Verma A. Nat Mater. 2008]
  21. 21. [unpublished data]
  22. 22.  Biological hurdles  Modifications of the NP’s surface that occurs after administration in biological environment  Physical hurdles SMART DESIGN OF NANOPARTICLES
  23. 23. the problem brain nanoparticles 1 step: NP dilution into the blood 2 step: NP dilution into CSF potential solutions An increased retention of the nanoparticles in the brain blood capillaries combined with an adsorption to the capillary walls. This could create a higher concentration gradient that would increase the transport across the endothelial cell layer and as a result enhance the delivery to the brain. [Krol S. J Control Rel. 2012]
  24. 24. Drugs bound to NP for brain delivery The development of delivery system to transport drugs into the brain in a safe and effective manner and in a non-homeopathic doses are still under exploration [Kreuter J. Adv Drug Del Rev. 2013]
  25. 25. AD MICE MODEL TREATED WITH AMYLOSOMES (functionalized with mApoE as BBB ligand) TREATED WITH PBS TREATED WITH LIP -40% * Immunohistoch. Cortex + Hippocampus (Ab 6E10) [Balducci C. PNAS 2013, submitted]
  26. 26. The BBB represents the main mechanism of defense of the CNS The risk-benefit balance due to NP accumulation in the CNS should be carefully evaluated Some NP (e.g. gold, TiO2 and silica NP) are able to reach the brain even in the absence of any specific functionalization [Sousa F, 2010 Nanoscale; Wu J, 2011 ACS Nano]
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