Tackling physiological resistances to drug delivery

Elias FattalUniversité Paris-Sud

Institut Galien Paris-Sud

UMR CNRS 8612

Maurice-Marie Janot1903-1978

Maurice-Marie Janot Award and Lecture11th World Meeting

on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology19 March to 22 March 2018

Granada, Spain

2

Physiological resistances to drug delivery

Degradation

Intracellular penetrationSubcellular distribution

Tissue distribution

Absorption

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1986: joining the drug delivery group in Châtenay-Malabry

Francis Puisieux, Patrick Couvreur and Nicholas Peppas (visiting

Professor in 1986)

1985

Patrick Couvreur at the French Academy of Sciences in

2016

4

Hepatocarcinoma

The polyl(alkylcyanoacrylate) « school »

Polylalkylcyanoacrylate nanoparticles are taken up by the monocyte phagocytic system

Intracellular infections

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Ampicillin-loaded PACA Nanoparticles

Antimicrobial Agents and Chemotherapy, 33(9), 1540-1543, 1989 Antimicrobial Agents and Chemotherapy, 35(4), 770-772, 1991

Mice infected with Salmonella typhimurim

Nanoparticle

Intracellular bacterium

E

E

Nucleus

PL

PACA nanoparticles increase by 100 the amount of antibiotic reaching the liver and by 10 the one entering macrophage

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Antisense Oligonucleotide-loaded PACA Nanocapsules

Claude Malvy(IGR – Villejuif)

PACA nanoparticles are only active after local (intratumoral administration)

Journal of Controlled Release, 53(1-3), 137-143, 1998

Advanced Drug Delivery Reviews, 47(1), 99-112, 2001

Pharmaceutical Research, 17(6), 707-714, 2000

Biochemical and Biophysical Research Communications, 279(2), 401-406, 2000

EWS-Fli in Ewing Sarcoma

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Ideas are invented only as correctives to the past

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Lessons from the pastInfectious diseases

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Peyer’s Patches a pathway for oral vaccine

• Expert Opinion on Drug Delivery, 1(1), 141-163, 2004• European Journal of Pharmaceutics and Biopharmaceutics,

61(1-2), 1-13, 2005

PP

PP

X10 X63

X10 X63

1 h

48 h0

100

200

300

400

500

600

700

1 h 4 h 24 h 48 h

N°

de

pa

rtic

ule

s/1

5 c

ryo

se

ctio

ns

PLGA-PVA 3 µm

PLGA-PEI 3 µm

PVA-coated microparticles are taken up by Peyer’s Patches

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Prevention of infectious diseases: oral vaccine

• Infection and Immunity, 65(3), 853-857, 1997• Vaccine, 16(7), 685-691, 1998

5 µm

Phosphorylcholine

Mice infected with Salmonella typhimurimPoly(lactide-co-glycolide)

Thyroglobuline

0

10

20

30

40

% o

f P

C-t

hyr

rel

ease

d

0 60 120 180 240

Time of incubation (mn)

PC-Thyr

concentration

(mg/ml)

Average size

(µm)

Encapsulation

efficiency

(%)

40 3.2 86.2

120 3.4 87.6

200 3.2 76.5

Stimulation of mucosal immunity and protection against oral infection by S. typhimurium

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0

100

200

300

400

500

600

700

800

900

1000

1100

1200

0

12

0

24

0

36

0

48

0

60

0

72

0

84

0

96

0

10

80

12

00

13

20

14

40

Cip

roflo

xacin

pla

sm

a c

once

ntr

atio

n

(ng

/ml)

Time (minutes)

Free ciprofloxacin 50mg/Kg

Free ciprofloxacin 50mg/kg + uncoated AC beads

ø : ~ 1,5 mm. m : ~ 1,25 mg

Active charcoal : 65% Pectin: 35%

coating with Eudragit RS.

AC uniformly distributed

Preventing resistance to antibiotics

Huguet H., N. Tsapis, A. Andremont, E. Fattal WO 2006/122835 Fattal E., N. Tsapis, F. Reynaud WO/2011/036400

Huguet H., N. Tsapis, A. Andremont, E. Fattal. WO/2012/0107367 International Journal of Pharmaceutics, 379(2), 251-259, 2009

European Journal of Pharmaceutical Sciences, 41(2), 281-288, 2010

Reduction of CPX concentration in fecesNo modification of CPX of antibiotics

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Future research: Mimicking Mycobacterium tuberculosis to enhance

macrophage uptake of antitubeculosis drugs

Mycobacteriumtuberculosis

Alveolar macrophage

MTb-mimickingNP

SP-A

+

Journal of Controlled Release, 128(1), 41-49, 2008

Molecular Pharmaceutics, 13(12):4168-4178, 2016

Colloids and Surfaces B: biointerfaces, 139, 219–227, 2016

Nanotoxicology, 10(3):292-302, 2016

Surfactant protein A-covered PLGA nanoparticles……are more internalized by alveolar macrophages

Lung nanotoxicity of PLGA v/s TiO2 and PLS

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Lessons from the past

Nucleic acid delivery

15

Francine Behar Cohen

(Ophtalmology)

Progress in Retinal and Eye Research, 19(2), 131-147, 2000

Biomacromolecules 4, 529-536 , 2003

Advanced Drug Delivery Reviews, 58(11), 1203-1223, 2006

Pharmaceutical Research 23(4)770-781 2006.

Journal of Controlled Release 112, 3, 369-381, 2006

PLGA Trojan microparticle for intraocular delivery of antisense oligonucleotides

Effective TGFβ2 knock-down and growth inhibition for more than one month

TGF-β2

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The years in UCSF and training in liposomal gene delivery

pH-sensitive amphipathic peptides (GALA) induces phospholipid

flip-flop as part of the mechanism of membrane fusionUniversity College of San Francisco

Francis Szoka Jr.

Mentor and most inspiring Scientist

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CD44-targeted delivery of nucleic acids

(Margot Zoller., 2011)

CD44 targeting

Molecular Pharmaceutics, 6(4), 1062-1073, 2009Journal of Controlled Release, 162(3), 545-552, 2012

Nucleic Acid Therapeutics, 23(6), 401-407, 2013 Bioconjugate Chemistry, 26 (7), 1307–1313, 2015

Langmuir, 31(41):11186-11194, 2015Nanomedicine, 12(1):135-46, 2016

Advanced Drug Delivery Reviews 97:204-36, 2016

DOPE-Hyaluronic acid

SiRNA

Cationic lipid

Targeting Ligand

Cationic core

« Protective » layer

Silvia Arpicco (U. Turin)

Said Ismail (U. Amman)

Hyaluronic acid

Aptamer

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Hyaluronic or Aptamer-bearing nanomedicinefor siRNA delivery to CD44 expressing tumor cells

A 549

Journal of Controlled Release,271, 198-106, 2018

Time (h)

MF

I

1 3

0

10000

20000

30000FITC-siRNA/prot lip-Apt1

FITC-siRNA/prot lip

MDA-MB 231

International Journal of Pharmaceutics. 514(1):103-111, 2016

Inhibition of luciferase in

orthotopic lungA549 metastasis

Inhibition of luciferase in orthotopic breast cancer

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Lessons from the past

Nanomedicine and Imaging

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Polymer-based system for contrast agent

Pharmaceutical Research, 27(1):1-16., (2010).

Polymeric shell of PLGA

& PLA-PEG

Perfluorooctyl bromide (PFOB)

Liquid at room T

biocompatible

stable, inert

Insoluble in water

Ultrasonography19F MRI

Biodegradable and biocompatible

No toxicity - No inflammation

Ability to be chemically modified

Nicolas TsapisIGPS

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200nm

Freeze-fracture

100 nm

TEM

Significant enhancement in the tumor

Before IT injection After IT injection

Sequoiaf=14MHz

Transducer

Gel

Advanced Functional Materials 18, 19, 2963–2971, (2008).Biomaterials,30(8):1462-72, (2009).

Biomaterials, 31(7),1723-31, (2010).

PFOB Nanocapsules as ultrasound contrast agents

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19F Magnetic Resonnance Imaging19F

Stable element -> stability of molecules containing fluorine

Virtually absent from biological samples -> no endogenoussignal

19F MRI : Tumor accumulationCT26 subcutaneous allograft into nude micet=0 intravenous injection of nanocapsules, t=7h 19F MRIacquisition

Liver

Tumor

Spleen

Biomaterials, 33(22), 5593-5602, 2012Journal of Controlled Release, 264, 219-227, 2017

Tumor Imaging and delivery of Paclitaxel

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CollaborationsAffiliation Country

Stefaan De Smedt Ghent University Belgium

Helder Teixeira/Silvia Guterres University of Rio Grande do Sul Brazil

Mingshi Yang/Camilla Foged University of Copenhagen Denmark

Claus Michael Lehr University of Saarland Germany

Massimo Fresta University of Catanzaro Italy

Anna Maria Fadda Univeristy of Cagliari Italy

Silvia Arpicco University of Turin Italy

Franco Alhaique University of Rome Italy

Giuseppe De Rosa University of Naples Italy

Paolo Colombo University of Parma Italy

Said Ismail University of Amman Jordan

Maria José Alonso University of Santiago de Compostella Spain

Ozgern Ozer Ege University Turkey

Richard Guy University of Bath UK

Justin Hanes John Hopkins University USA

Frank Szoka University of California San Francisco USA

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People from the past…

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Present and future….

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