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Accueil du site > Equipes > Vecteurs colloïdaux et transport tissulaire (B. Verrier) > Thématiques > Transport d’un antigène particulaire à travers une muqueuse et la matrice extracellulaire > Trans-mucosal delivery of antigen-coated PLA nanoparticles

Trans-mucosal delivery of antigen-coated PLA nanoparticles

Project leader(s) : C. Lethias, C. Primard, B. Verrier

People involved in the project : JY. Exposito, L. Baggetto, P. Mercier, S. Legaz, V. Pavot

Aiming to improve the delivery of PLA nanoparticles carrying antigenic or antiviral molecules, we elaborate multifunctional nanoparticles designed to target and stimulate specific cell sub-populations involved in mucosal immunity. Our secondary goal is also to monitor nanoparticle distribution, at the cell and tissue level, using imaging tools.

Cell targeting is prompted by a bio-inspired strategy using cellular or viral mimetic approaches and is achieved by addition of specific molecules consisting in : i) antibodies (essentially IgA, against DC sign H7 and integrin alpha4beta7), ii) TLR-3 and TLR 7/8 synthetic ligands, and iii) domains from extracellular matrix molecules like collagens, fibronectin or tenascins in order to target -ß1 and alpha4beta7 integrins, and TLR-4 receptors.

We evaluate nanoparticle delivery by monitoring their impact on cell activation and by analyzing their cellular localization. To this end, we use different in vitro biological systems, consisting in dendritic cells and macrophages cultures, and a model of intestinal M cell differentiation (in collaboration with Pr S. Paul from GIMAP in Saint Etienne). The key questions are to decipher the molecular mechanisms of particle endocytosis and to identify intracellular compartments involved, by the use of cell fractionation studies and imaging by confocal microscopy and electron tomography.

Visualization of nanoparticle fate and transport in biological tissues is followed up by using in vivo models such as transgenic mice (CX3CR1egfp, Langerin GFP…), zebrafish and non human primates (in collaboration with the IDMIT du CEA, http://www.idmitcenter.fr/). Localizations are essentially performed by classical and b-iphotonic confocal imaging. Complementary studies include analysis of particle diffusion into polymeric hydrogels mimicking the extracellular matrix.

Fluorescent micrographs obtained from transversal cryosections of mice ileum intestine. In vivo intestinal ligated loop was incubated with red fluorescent PLA nanoparticles. Micrographs were obtained from villus and PP areas for each incubation time. Blue line : epithelium, white line, muscularis, L, lumen. The bright red-fluorescence observed in lumen highlighted a retention of fluoNPs in the mucus. However, the red fluorescence associated to fluoNPs also penetrated the intestine mainly in PP area, and rose to the tissue towards the muscularis.
From C. Primard et al., 2010 - Biomaterials

References :

Intradermal immunization triggers epidermal Langerhans cell mobilization required for CD8 T-cell immune responses.
Rancan F, Todorova A, Hadam S, Papakostas D, Luciani E, Graf C, Gernert U, Ruhl E, Verrier B, Sterry W, Blume-Peytavi U, VogtA
(2012) J Invest Dermatol 132(3 Pt 1):615-25

Stability Of Polylactic Acid Particles And Release Of Fluorochromes Upon Topical Application On Human Skin Explants.
Liard C, Munier S, Joulin-Giet A, Bonduelle O, Hadam S, Duffy D, Vogt A, Verrier B, Combadière B
(2012) Eur J Pharm Biopharm 31 : 6060-8

Traffic Of Poly(lactic Acid) Nanoparticulate Vaccine Vehicle From Intestinal Mucus To Sub-epithelial Immune Competent Cells.
Primard C, Rochereau N, Luciani E, Genin C, Delair T, Paul S, Verrier B
(2010) Biomaterials 31 : 6060-8

Nanoparticle-based Targeting Of Vaccine Compounds To Skin Antigen-presenting Cells By Hair Follicles And Their Transport In Mice.
Mahe B, Vogt A, Liard C, Duffy D, Abadie V, Bonduelle O, Boissonnas A, Sterry W, Verrier B, Blume-Peytavi U, Combadiere B
(2009) J Invest Dermatol 129 : 1156-64

Investigation Of Polylactic Acid (pla) Nanoparticles As Drug Delivery Systems For Local Dermatotherapy.
Rancan F, Papakostas D, Hadam S, Hackbarth S, Delair T, Primard C, Verrier B, Sterry W, Blume-Peytavi U, Vogt A
(2009) Pharm Res 26 : 2027-36

Collaborations within the Institut :

D. Sigaudo-Roussel, P. Sommer, R. Debret

Collaborations et financials :

Pr. Stéphane PAUL & Pr. Christian GENIN
Groupe Immunité des Muqueuses et Agents Pathogènes, GIMAP

Faculté de Médecine Jacques Lisfranc
15 rue Ambroise Paré
42023 Saint-Etienne Cedex 2, France

Cuthivac : Cutaneous and Mucosal HIV Vaccination
Coordinator : Dr. Behazine COMBADIERE
Université Pierre et Marie Curie et INSERM
Paris, France

iNanoDCs : Design of multifunctional nanoparticles targeting TLR or Nod receptors for dendritic cell immune therapy
Coordinator : Dr. Bernard VERRIER
IBCP - FRE 3310
Lyon, France