Microfluidic self-assembly of a combinatorial library of single- and dual-ligand liposomes for in vitro and in vivo tumor targeting.

Abstract

Precise engineering of nanoparticles with systematically varied properties (size, charge surface properties, targeting ligands, etc.) remains a challenge, limiting the effective optimization of nanoparticles for particular applications. Herein we report a single-step microfluidic combinatorial approach for producing a library of single and dual-ligand liposomes with systematically-varied properties including size, zeta potential, targeting ligand, ligand density, and ligand ratio. A targeting ligand folic acid and a cell penetrating peptide TAT were employed to achieve the optimal synergistic targeting effect. In 2D cell monolayer models, the single-ligand folic acid modified liposome didn't show any enhanced cellular uptake, while the incorporation of TAT peptide "switched on" the function of folic acid, and induced significant elevated cellular uptake compared to the single ligand modified liposomes, showing a strong synergistic targeting effect. The folic acid and TAT peptide dual-ligand liposome also demonstrated enhanced tumor penetration as observed using 3D tumor spheroid models. The in vivo study further confirmed the improved tumor targeting and longer tumor retention (up to 72 h) of the dual-ligand liposomes. Our work not only proved the versatility of this microfluidic combinatorial approach in producing libraries of multifunctional liposomes with controlled properties but also revealed the great potential of the optimized liposome formulation for synergistic targeting effects.

• Authors: Rui Ran, Haofei Wang, Yun Liu, Yue Hui, Qi Sun, Arjun Seth, David Wibowo, Dong Chen, Chun-Xia Zhao
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 130 Pg. 1-10 (Sep 2018) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 29908938 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Cell-Penetrating Peptides
• Gene Products, tat
• Ligands
• Liposomes
• Folic Acid

Topics

• Animals
• Cell Line, Tumor
• Cell-Penetrating Peptides (administration & dosage, chemistry)
• Drug Delivery Systems
• Folic Acid (administration & dosage, chemistry)
• Gene Products, tat (administration & dosage, chemistry)
• Humans
• Ligands
• Liposomes
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microfluidics (methods)
• Nanoparticles
• Particle Size
• RAW 264.7 Cells
• Time Factors