79957208 Session4 Drug Delivery Systems

7/28/2019 79957208 Session4 Drug Delivery Systems

1/20

NANOCARRIERS :

ACTIVE VERSUS PASSIVE TARGETING

Catherine PASSIRANI

Inserm U646

Ingnierie de la Vectorisation ParticulaireUniversit dANGERS

Intensive Training for earlier Exposure to

Research : From chemistry to clinical trial

06/07/2010

1


2/20

Physico-chemistry

of collodal systems

Interface study

Pharmaceuticaltechnology

Cancers

In vitro / in vivointeractions

Neurobiology

Imagery,radiotherapy and diagnostic

Clinical andindustrial

applications

Ingnierie de la Vectorisation Particulaire

2


3/20

CANCER THERAPY

| Cancer : 10 millions new cases every year !

|

Decrease since 2005y Tumor biology

y Better diagnostic devices

y Improved treatments :

3

SURGERY RADIATION CHEMOTHERAPY

BUT

Healthy cells not avoided by drugs

TOXICITY


4/20

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

4

Action site

Immune

System

Toxicity

site

ACTION SITE

Toxicity

site4

Immune

System


5/20

NANOCARRIER

Log Scale (nm)

Micelles

Liposomes

SUV

LiposomesMLV

Nanoparticles

10 100 1000

Lipid

nanocapsules

5

Gold NP

Polymer

conjugates
http://images.google.fr/imgres?imgurl=http://www.iecb-polytechnique.u-bordeaux.fr/images/ml2.gif&imgrefurl=http://www.iecb-polytechnique.u-bordeaux.fr/pole1/erechml.html&h=440&w=450&sz=84&tbnid=0s3ZJlyySVMJ:&tbnh=121&tbnw=124&hl=fr&start=4&prev=/images?q=micelles&hl=fr&lr=http://images.google.fr/imgres?imgurl=http://www.exopol.com/autovac/figuras/liposoma.JPG&imgrefurl=http://www.exopol.com/autovac/liposomas.html&h=212&w=227&sz=11&tbnid=uGzhpwvv9gwJ:&tbnh=96&tbnw=103&hl=fr&start=2&prev=/images?q=liposomes&hl=fr&lr=&sa=G


6/20

Plasma proteins (opsonins)

NUMEROUS BARRIERS AFTER SYSTEMIC

INJ ECTIONMPS cells

6

A : non

specific

uptake byMPS cells


7/20

LONG-CIRCULATING OR STEALTH NANOCARRIER

| Opsonization and phagocytosis mainly affected by

y Size (ideal range 70-200 nm)

y Surface charge (not too negative and not too positive)

y Hydrophilicity / hydrophobicity

Chemical modification ofnanocarrier surface

Small hydrophilic neutral nanocarrier

7

Polymers


8/20

| Inert in biological environment

| Highly hydrophile

| Highly flexible

steric stabilization effects

stealth properties

targeting properties

Water cloud

(hydrogen bonds)

8

POLY(ETHYLENE GLYCOL) OR PEG

Hydrophobic surface

PEG
http://upload.wikimedia.org/wikipedia/en/a/a7/Polyethylene_glycol_chemical_structure.png


9/20

Plasma proteins (C3, opsonins,

nucleases)


INJ ECTIONMPS cells

9

B :

extravasation


10/20

EXTRAVASATION THROUGH BLOOD VESSELS

| MPS organs

| Increased permeability

of the endothelium bypathological processes

y Inflamed tissues

y

Solid tumors

DISSE space

100 nm

Kupffer cell

Hepatocytes

c) Discontinuous endothelium

10

a) Continuous endothelium b) Fenestrated endothelium50 nm

Majority of the organes Gastrointestinal mucosaThyroid, Hypophysis


11/20

EXTRAVASATION THROUGH BLOOD VESSELS

| In solid tumors

y

Extensive angiogenesisy Defective vascular architecture

y Production of permeability mediators

y

Impaired lymphatic drainage

Enhanced Permeability andRetention effect (EPR)

11Maeda 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.


12/20

12

PASSIVE TARGETING

Angiogenic

vessels

Limitedlymphatic

drainage


13/20

13

PASSIVE TARGETING

Angiogenic

vessels

Limitedlymphatic

drainage

| Ubiquitous targeting :

y Lack of control

y Nanocarrier/Drug diffusion limitation

| No EPR effect in some tumors (low vascularisation)

| Differences of permeability of the vessels throughout

a tumor and between different types of tumor


14/20

Plasma proteins (C3, opsonins,

nucleases)


INJ ECTIONMPS cells

14

C, D :

active binding

to specific cells


15/20

15


Angiogenic

vessels


16/20

ACTIVE TARGETING

| Ligand conjugation

|

Binding to specific receptorson the cell surface

y Ligand-receptor interaction

|

High selectivity to receptorsy uniquely expressed on the cell

surface

y over-expressed on target cells

relative to normal cells

16

PEG

Longer PEG chains

Active chemical

group

LIGAND

High surface area to volume High ligand density


17/20

TYPES OF TARGETING AGENTS

17

Sugars (galactose, )

Antibodies and

their fragments

Nucleic acids

(aptamers)

Proteins (epidermal

growth factor EGF,Transferrin)

Vitamins (folic acid, )

Peptides (RGD, )

ECM receptors (heparin

sulphate, chondroitin

sulphate, hyaluronan) 17


18/20

DRUG RELEASE IN DRUG TARGETING

18

(1)

(2)(3)

Receptor

Non-internalizing

receptor

Nucleus

| Multivalent binding effects

(avidity)

| Higher binding affinityy targeting efficacy

y if binding-site barrier


20/20

NANOCARRIER-BASED DRUGS ON THE MARKET*

Compound Commercial

name

Nanocarrier Indications

Daunorubicin

Doxorubicin

Doxorubicin

Paclitaxel

DaunoXome

Myocet

Doxil/Caelyx

Abraxane

Liposomes

Liposomes

PEG/Liposomes

Albumine

nanoparticles

Kaposis sarcoma

KS, breast and

ovarian cancers

KS, breast and

ovarian cancers

Metastatic breast

cancer

*Except : polymer-protein conjugates, immunotoxins, chemo or radio-

immuno-conjugates, antibodies, micelles

20

Documents

79957208 Session4 Drug Delivery Systems