Tumor targeting of functionalized lipid nanoparticles: assessment by in vivo fluorescence imaging.
Lipid nanoparticles (LNP) coated by a poly(oxyethylene) polymer have been manufactured from low cost and human use-approved materials, by an easy, robust, and up-scalable process. The incorporation in the formulation of maleimide-grafted surfactants allows the functionalization of the lipid cargos by targeting ligands such as the cRGD peptide binding to alpha(v)beta(3) integrin, a well-known angiogenesis biomarker. LNP are able to encapsulate efficiently lipophilic molecules such as a fluorescent dye, allowing their in vivo tracking using fluorescence imaging. In vitro study on HEK293(beta3) cells over-expressing the alpha(v)beta(3) integrins demonstrates the functionalization, specific targeting, and internalization of cRGD-functionalized LNP in comparison with LNP-cRAD or LNP-OH used as negative controls. Following their intravenous injection in Nude mice, LNP-cRGD can accumulate actively in slow-growing HEK293(beta3) cancer xenografts, leading to tumor over skin fluorescence ratio of 1.53+/-0.07 (n=3) 24h after injection. In another fast-growing tumor model (TS/A-pc), tumor over skin fluorescence ratio is improved (2.60+/-0.48, n=3), but specificity between the different LNP functionalizations is no more observed. The different results obtained for the two tumor models are discussed in terms of active cRGD targeting and/or passive nanoparticle accumulation due to the Enhanced Permeability and Retention effect.
CEA, LETI-DTBS, Grenoble cedex, France. mathieu.goutayer@gmail.com
Mathieu
M
Goutayer
Sandrine
S
Dufort
Véronique
V
Josserand
Audrey
A
Royère
Emilie
E
Heinrich
Françoise
F
Vinet
Jérôme
J
Bibette
Jean-Luc
JL
Coll
Isabelle
I
Texier
D000818:Animals; D016503:Drug Delivery Systems; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D007275:Injections, Intravenous; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013501:Surface-Active Agents / Q000737:chemistry; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D005456:Fluorescent Dyes; D039302:Integrin alphaVbeta3; D008055:Lipids; D008301:Maleimides; D010456:Peptides, Cyclic; D013501:Surface-Active Agents; C507169:cyclic arginine-glycine-aspartic acid peptide; C043592:maleimide