Nanomedicines Jakarta

7/27/2019 Nanomedicines Jakarta

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Biomedical technology and innovation

A Shmulewitz and R Langer, Nature Biotechology 24:277-280 (2006)

Nano Tech

Bio Tech Info Tech


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Nanoscale medicinesState of the art of nanoparticles as drug delivery systems

Hans P. MerkleDepartment of Chemistry and Applied BioSciences, D-CHAB

ETH Zurich, CH-8093 Zurich, Switzerland

www.galenik.ethz.ch - [email protected]

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Welcome to Zurich

Welcome to ETH Zurich

ETH Campus Hnggerberg


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Biochemistry

Biophysics

Chemical and Bio-Engineering

Inorganic ChemistryMaterials Science

Microbiology

Organic Chemistry

Pharmaceutical Sciences

Physical Chemistry


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Colloidal silicon dioxide is a widely

established excipient in drug formulation

Particle size ca. 15 nm

Specific surface

50380 m2g-1 (BET)

Tablet disintegrant

Powder flow regulation

agent

Anticaking agent Adsorbent

Suspending agent

Viscosity-increasing agent

1 m

Aerosil A-200

Degussa

Aerosil (Degussa, DE)

Cab-O-Sil (Cabot Corp., USA)

Wacker HDK (Wacker-Chemie, DE)


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TiO2and ZnO nanoparticles in sunscreens

ZnO

TiO2

500 nm

200 nm

AO Gamer et al. Toxicology

in Vitro 20:301

307 (2006)

(Safety) ... would only be of concern inpeople using sunscreens if the ZnO and

TiO2penetrated into viable skin cells.

The weight of current evidence is that

they remain on the surface of the skinand in the outer dead layer

(stratum corneum) of the skin.

http://www.tga.gov.au/npmeds/

sunscreen-zotd.htm


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Superparamagnetic

iron oxide (SPIO)

Fe2O

3or Fe

3O

4

nanoparticles as

contrast agents

for MRI diagnostic

imaging

T1

Gd, T1

SPIO, T2

SPIO + Gd, T2SPIO, true FISP

SPIO, T2 grad

i.v. SPIO nanoparticles

greatly improve visibility

of hepatic metastases from

colon cancer

A Jackson and DA Nicholson

DOI 10.1007/3-540-26420-5_14

http://www.springerlink.com/

content/h1072l0h60326p48/

Springer (2006)
http://www.springerlink.com/content/h1072l0h60326p48/http://www.springerlink.com/content/h1072l0h60326p48/http://www.springerlink.com/content/h1072l0h60326p48/http://www.springerlink.com/content/h1072l0h60326p48/http://www.springerlink.com/content/h1072l0h60326p48/


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What makes nanoparticles so attractive

as platform for drug delivery?

Delivery by nanoparticles helps to decouple

the three major functions of drugs ...

- Therapeutic activity

- Biodistribution

- Unwanted side effects

Drug

Nanoparticle


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Agenda

Historical aspects

Nanomedicinesa forward look

Examples and technologies for nanoparticles Biodistribution of nanoparticles

The challengelong circulating

nanoparticles Ligand-mediated delivery

Conclusions


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Birth of nanoparticles as drug delivery

systems at ETH Zurich in 1976

G Birrenbach & PP Speiser, J Pharm Sci 65:1763 (1976)

... the partition of drugs

in such nanoparts

seems to be promisingas a new drug delivery

system for long term

therapy ...


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Nanoparticles for therapeuticsFrequency of scientific publications per year

0

100

200

300

400

500

600

700

800

900

1990 1992 1994 1996 1998 2000 2002 2004 2006

East

up to June 2007

Numberofpublicatio

nsperyear

19902007

(nanoparticle* OR nanocapsul*) AND drug


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Nanomedicine

Scope Analytical tools

Nanoimaging

Nanomaterials and nanodevices

Novel therapeutics andnanodevices

Clinical, regulatory and

toxicological issues

Regulatory issues Guidelines to ensure safe and

reliable transfer of advances in

nanomedicine from laboratory to

bedside

Definitions Size range from 1 nm to

several hundreds ofnanometers

To be included in a micro-

device or a biological

environment

To monitor, control,construct, repair, defend

and improve all human

biological systems

Ultimately to achieve

medical benefit

Concerns To ensure short and long

term safety

http://www.esf.org/
http://www.esf.org/http://www.esf.org/


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NCI Alliance for Nanotechnology

in Cancer, 2005

http://nano.cancer.gov/news_center/nanotech_news.asp

Bibliography

2002 - 2007

Website

http://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asp
http://nano.cancer.gov/news_center/nanotech_news.asphttp://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asphttp://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asphttp://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asphttp://nano.cancer.gov/resource_center/sci_biblio_enabled-therapeutics_abstracts.asphttp://nano.cancer.gov/news_center/nanotech_news.asp


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Clinical potential of nanoparticles

Parenteral and peroral deliveryof drugs of very low aqueous

solubility

Delivery to organs, tissuesand cells of the mononuclear

phagocyte systems, MPS

Extravasation into tumor tissue

Targeted ligand-mediated

delivery

(Mucosal delivery)

- Liver

- Lung

- Lymph nodes

- Macrophages

- APC

Therapeutics

Diagnostics

Vaccines


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Examples and Technologies


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Nanosuspensions of poorly soluble drugs

Unfavorable

energetics leading

to agglomeration

Charge or sterically

stabilized surface

using surfactants

Nanosuspension SolutionCrystal

BE Rabinow, Nat Rev Drug Disc 3:785 (2004)


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Abraxane -

the first nanoparticle

therapeutic on the market:

http://www.abraxane.com/HCP/index.htm

FDA approval of

Abraxane on

January 7, 2005

Taxol

Paclitaxel

Human serum albuminnanoparticles of ca. 150 nm

made by desolvation and

glutardialdehyde crosslinkage.

Vitali Vogel et al. Progr Colloid

Polymer Sci 119:31 (2002)
http://www.abraxane.com/HCP/index.htmhttp://www.abraxane.com/HCP/index.htm


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Solid lipid nanoparticles, SLN

Excipients Mono-, di- and triglycerides

Fatty acids

Cationic lipids

Surfactants

Manufacturing

High shear homogenisation

Ultrasound Extrusion

Solvent evaporation

DB Chen et al. Chem Pharm Bull

49:1444 (2001)

Long-circulating SLNcontaining paclitaxelt1/2= 10 h (SLP) vs. 1.3 h (PTX)

200 nm

W Mehnert & K Mader, Adv Drug Deliv

Rev 47:165 (2001)


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Nucleic Acid Solutionin Buffer

Free Nucleic AcidRemoval

LB Jeffs et al. Pharm

Res 22:362 (2005)

with DNA

no DNA

200 nm

Liposomes forencapsulation

of nucleic

acids

Scalable, extrusion-

free technology for

stabilized nucleic

acid lipid particles

(SNALP)


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Cellular delivery with micellar core-shell

self-assemblies of amphiphilic polymers

JA Hubbell, Science

300:595 (2003)

Packaging

nucleic acid

Packaging

hydrophobic

drugs

1

2


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Biodistribution of nanoparticles


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Efficient phagocytosis of

human serum albumin

nanoparticles bymacrophages in vitro

0.01 mg/ml HSA

0.025 mg/ml HSA

0.1 mg/ml HSA

1.0 mg/ml HSA

Flow cytometry

C

ounts

FITC intensity

No HSA nanoparticles

Macrophages with

HSA nanoparticles

100 nm

K Langer et al. Int J Pharm

257:169 (2003)


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The Mononuclear

Phagocyte System

MPS

Liver, Kupffer cells

Lungs, macrophages

Spleen, macrophages Lymph nodes,

macrophages

Kidney phagocytes

Blood monocytes

Bone marrow

precursor cells

Brain, microglia

Kupffer cells loaded with

ink particles in liver sinusoids

SV = central vein

Kupffer cells K with

ink nanoparticles in

liver sinusoids. SV:

centrilobular vein

Macrophages M

and erythrocytes E

in spleen tissue

K

M

M

M

E

E


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The liver as a component of the MPS

Liver lobule with portal tract

T and centrilobular vein CV

Centrilobularvein

Lobule

Herpatic vein

Bileduct

Heparticportal vein HPV

Hepaticartery HA

Bile duct HA HPV

T

T

T

CV

From PR Wheather et al.Functional Histology, Churchill

Livingstone, Edinburgh 1987

T

T


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Splenic

accumulation

of NP in the rat

... caused by

filtration at the

interendothelial cell

slits IES or by direct

splenic macrophage

recognition?

SM Moghimi et al.

J Leukoc Biol 54:513 (1993)2 m

Accumulation in lysosomes of rat

splenic red pulp macrophages.

220 nm poly(styrene) nanoparticles.


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Biodistribution of Rhodamin 123 loaded

PGA-PLA nanoparticles in mice

HF Liang et al.

Biomaterials

27:2051 (2006)

100 nm nanoparticles


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Extravasation into tumor tissueEnhanced permeability and retention (EPR) effect

TM Allen & PR Cullis Science 303:1818 (2004)

Y Matsumura et al. Gan To Kagaku Ryoho 14:821 (1987)T Inai et al. Am J Pathol

165:32 (2004))

Endothelial

fenestrations

to tumor tissue


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Passage of nanoparticles across the BBB

is mediated by binding of ApoE

Blood

vessel

Neuron

Endothelium

AstrocyteBasement

membrane

PericyteTight junction

ApoE

receptor

Release

of drug

Endotheli

um

ApoE

ApoEcoated NP

Polysorbate 80

coated NP


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Long-circulating "stealth"

nanoparticles

... how to avoid clearance by the MPS?


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Toward protein resistant "stealth" surfaces

Adsorption of hydrophilic block-co-polymers onhydrophobic surfaces

Poloxamines a 20; b 120

Poloxamers a 60; b 100120

Covalent conjugation of PEGa a 40 - 100 SMMoghimi

etal.Pharmaco

lRev53:283(20

01)

PEGb PPGa PPGa PEGb

PEGb PPGa PPGa PEGb

NCH2CH2N

PEGb PPGa PEGb


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The surface makes the difference

Polystyrene nanospheres of 200 nm.

Due to surface hydrophobicityuncoated particles tend to aggregate.

Upon iv injection uncoated particles

are cleared within minutes by the

hepatic Kupffer cells.

SM Moghimi et al. FASEB J 19:311 (2005)

Polystyrene nanospheres of 200 nm

with poloxamine 908 coating of 8 nm.Coating prevents aggregation, and

results in ordered stacking. Upon iv

injection, coated particles circulate for

extended periods of time. Eventual

clearance by spleen is due to filtration.

Uncoated nanoparticles Poloxamine 908 coated


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Paclitaxel loaded core-shell

assemblies extend circulation

and antitumor activityin tumor-bearing mice

JA Hubbell, Science

300:595 (2003)

Negative

control

T Hamaguchi et al.

Brit J Cancer 92:1240 (2005)

25, 50 and 100 mg kg-1

Paclitaxel alone

Paclitaxel micelles

Paclitaxel

Control


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Breakthrough in

siRNA delivery

K Whalley, Nature Rev Drug Discov 4:1 (2006)


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4040

LiposomesStabilized nucleic acid

lipid particles (SNALP)for DNA and RNA delivery

Lipid excipients

H

+

PEG-lipid


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SNALP for systemic

siRNA mediated

ApoB gene silencingto lower LDL

TS Zimmermann et al.

Nature 441:111 (2006)

siRNA delivery throughSNALP can lower both

ApoB and LDL levels in

cynomolgus monkeys

RelativeAp

oBlevel

RelativeLDLlevel

ApoB

LDL

LDL particle ApoB


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Ligand mediated deliveryof nanoparticles


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Gal-PLA-PGA nanoparticles

HF Liang et al.

Bioconj Chem

17:291-299 (2006)

Poly(L-lactic acid)

PLA

Activated PLA

Carbodiimid

Poly(-glutamic acid)

Amphiphilic

block copolymer

NanoparticleGalactosylated nanoparticle

Galactosamine

Galactosamine

Targeted nanoparticles

for paclitaxel delivery

Hydrophilic,

anionic shell


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Tumor

Liver

Spleen

Gal-Rhod-NPRhod-NP

Liver and tumor targeted localization of

galactosamin modified nanoparticles

HF Liang et al.

Biomaterials

27:2051 (2006)

Partial reduction of

spleenic acculation

in mice

Increased liver uptake

Increased tumor uptake


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Targeted organdistribution ofgalactosamin

modifiedpaclitaxel NPs

HF Liang et al.

Biomaterials

27:2051 (2006)

Galactosamin

negative control

Galactosamin

modified NPs

Intensity

counts/mg

Inten

sity

counts/mg

Rhodamin 123loaded Gal-NPs in

hepatoma-tumor-

bearing nude mice


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Superior tumor volume response of

galactosamin modified paclitaxel NPs

HFLianget

al.Biomaterials

27:2051(2006)


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Conclusions

The future of nanomedicines has alreadybegun.

Nanomedicines raise novel prospects for

diagnosis and drug delivery.

Nanomedicines can decouple the delivery of

drugs from their normal biodistribution.

Scientific challenges are long circulation

("stealth") and ligand-mediated delivery

Laboratory-to-clinic is demanding, but niches

are about to come up.


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Thank you for your attention

[email protected]

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