Evaluation of New Fluorescent Lipophosphoramidates for Gene Transfer and Biodistribution Studies after Systemic Administration

International Journal of Molecular Sciences

Nawal Belmadi²  Mathieu Berchel¹  Caroline Denis²  Wilfried Berthe¹  Yann Sibiril²  Tony Le Gall²  Jean-Pierre Haelters¹  Paul-Alain Jaffres¹  Tristan Montier² 

[1] Plateforme SynNanoVect, Biogenouest, SFR 148 ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, 22 rue Camille Desmoulins, 29238 Brest cedex 3, France;Unité INSERM 1078, Faculté de Médecine, Université de Bretagne Occidentale, Université Européenne de Bretagne, 22 avenue Camille Desmoulins, 29238 Brest cedex 3, France;

关键词: cationic lipids;    administration way;    in situ biodistribution;    in vivo fluorescence;    pegylated formulations;   

DOI  :  10.3390/ijms161125941

来源: mdpi

【 摘 要 】

The objective of lung gene therapy is to reach the respiratory epithelial cells in order to deliver a functional nucleic acid sequence. To improve the synthetic carrier’s efficacy, knowledge of their biodistribution and elimination pathways, as well as cellular barriers faced, depending on the administration route, is necessary. Indeed, the in vivo fate guides the adaptation of their chemical structure and formulation to increase their transfection capacity while maintaining their tolerance. With this goal, lipidic fluorescent probes were synthesized and formulated with cationic lipophosphoramidate KLN47 (KLN: Karine Le Ny). We found that such formulations present constant compaction properties and similar transfection results without inducing additional cytotoxicity. Next, biodistribution profiles of pegylated and unpegylated lipoplexes were compared after systemic injection in mice. Pegylation of complexes led to a prolonged circulation in the bloodstream, whereas their in vivo bioluminescent expression profiles were similar. Moreover, systemic administration of pegylated lipoplexes resulted in a transient liver toxicity. These results indicate that these new fluorescent compounds could be added into lipoplexes in small amounts without perturbing the transfection capacities of the formulations. Such additional properties allow exploration of the in vivo biodistribution profiles of synthetic carriers as well as the expression intensity of the reporter gene.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.