Intensive Training for earlier Exposure to Research : From chemistry to clinical trial

NANOCARRIERS :
ACTIVE VERSUS PASSIVE TARGETING

Catherine PASSIRANI Inserm U646 Ingnierie de la Vectorisation Particulaire Universit dANGERS

06/07/2010

Ingnierie de la Vectorisation Particulaire

Cancers In vitro / in vivo interactions Pharmaceutical technology Neurobiology

Physico-chemistry of collodal systems Interface study

Clinical and industrial applications

2

Imagery, radiotherapy and diagnostic

CANCER THERAPY Cancer : 10 millions new cases every year ! | Decrease since 2005
|

Tumor biology y Better diagnostic devices y Improved treatments :

y

SURGERY RADIATION CHEMOTHERAPY BUT Healthy cells not avoided by drugs

3

TOXICITY

NANOCARRIER AS AN EMERGING PLATFORM :

ADVANTAGES OVER FREE DRUG Prevention from premature interaction with the biological environment | Protection of the drug from degradation | Control of the pharmacokinetic and drug tissue distribution profile
|

Toxicity site

Immune System Action site

Toxicity site

Immune System
4

ACTION SITE

NANOCARRIER
Gold NP Nanoparticles

Polymer conjugates

Lipid nanocapsules

Micelles 10 100

Liposomes SUV

Liposomes MLV 1000

Log Scale (nm)

NUMEROUS BARRIERS AFTER SYSTEMIC

INJECTION
MPS cells

Plasma proteins (opsonins)

A : non specific uptake by MPS cells

LONG-CIRCULATING OR STEALTH NANOCARRIER

Small hydrophilic neutral nanocarrier
|

Opsonization and phagocytosis mainly affected by y Size (ideal range 70-200 nm)
Surface charge (not too negative and not too positive) y Hydrophilicity / hydrophobicity
y

Chemical modification of nanocarrier surface

Polymers
7

POLY(ETHYLENE GLYCOL) OR PEG

| | |

Inert in biological environment Highly hydrophile Highly flexible steric stabilization effects stealth properties
PEG

Water cloud
(hydrogen bonds) Hydrophobic surface

targeting properties

NUMEROUS BARRIERS AFTER SYSTEMIC

INJECTION
MPS cells

Plasma proteins (C3, opsonins, nucleases)

B: extravasation

EXTRAVASATION THROUGH BLOOD VESSELS

a) Continuous endothelium b) Fenestrated endothelium
50 nm

Majority of the organes

Gastrointestinal mucosa Thyroid, Hypophysis

c) Discontinuous endothelium
Kupffer cell 100 nm DISSE space

MPS organs | Increased permeability of the endothelium by pathological processes

|

Inflamed tissues y Solid tumors

y

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Hepatocytes

EXTRAVASATION THROUGH BLOOD VESSELS

In solid tumors
y y y y

Extensive angiogenesis Defective vascular architecture Production of permeability mediators Impaired lymphatic drainage

Enhanced Permeability and Retention effect (EPR)

11

Maeda et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000 Mar 1;65(1-2):271-84.

PASSIVE TARGETING

Limited lymphatic drainage

Angiogenic vessels 12

PASSIVE TARGETING

Limited lymphatic drainage

Ubiquitous targeting :
y y

Lack of control Nanocarrier/Drug diffusion limitation

Angiogenic | No EPR

effect in some tumors (low vascularisation) vessels | Differences of permeability of the vessels throughout a tumor and between different types of tumor

13

NUMEROUS BARRIERS AFTER SYSTEMIC

INJECTION
MPS cells

Plasma proteins (C3, opsonins, nucleases)

C, D : active binding to specific cells

14

ACTIVE VERSUS PASSIVE TARGETING

Angiogenic vessels 15

ACTIVE TARGETING
Ligand conjugation | Binding to specific receptors on the cell surface
| y |

LIGAND Active chemical group Longer PEG chains PEG

Ligand-receptor interaction

High selectivity to receptors

uniquely expressed on the cell surface y over-expressed on target cells relative to normal cells
y

High surface area to volume

High ligand density

16

TYPES OF TARGETING AGENTS

Vitamins (folic acid, ) Sugars (galactose, ) Proteins (epidermal growth factor EGF, Transferrin)

Peptides (RGD, )

Nucleic acids (aptamers) Antibodies and their fragments

ECM receptors (heparin sulphate, chondroitin sulphate, hyaluronan)

17 17

DRUG RELEASE IN DRUG TARGETING

(1)
Receptor

Multivalent binding effects (avidity) | Higher binding affinity

| y y

targeting efficacy if binding-site barrier

Nucleus

(3)

(2)
Non-internalizing receptor
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ACTIVE VERSUS PASSIVE TARGETING

Passive targeting Active targeting

Easy to formulate | Tumor accumulation | On the market

|

Specfic targeting | Drug efficacy | Lower toxicity

|

but

but

Non specific targeting | Not always EPR effect | Differences of vessel permeability | Cell internalisation prevented by PEG | Multi Drug Resistance
|

Receptors also expressed in healthy cells | Different degree of receptor expression | Binding ligand affinity | High densities of ligand : accelerated elimination 19
|

NANOCARRIER-BASED DRUGS ON THE MARKET*

Compound Daunorubicin Doxorubicin Commercial name DaunoXome Myocet Nanocarrier Liposomes Liposomes Indications Kaposis sarcoma KS, breast and ovarian cancers KS, breast and ovarian cancers Metastatic breast cancer
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Doxorubicin

Doxil/Caelyx

PEG/Liposomes

Paclitaxel

Abraxane

Albumine nanoparticles

*Except : polymer-protein conjugates, immunotoxins, chemo or radioimmuno-conjugates, antibodies, micelles