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

• DOI: 10.1016/j.ejpb.2018.06.017
• Publication Date: 2018-06-15T05:05:28Z
• Authors: Rui Ran; Haofei Wang; Yun Liu; Yue Hui; Qi Sun; Arjun Seth; David Wibowo; Dong Chen; Chun-Xia Zhao
• Keywords: 0301 basic medicine; Time Factors; Folic acid; Dual-ligand liposomes; Nude; Microfluidics; 3003 Pharmaceutical Science; microfluidics; Mice, Nude; cell penetrating peptides; Cell-Penetrating Peptides; Ligands; Cell Line; Biologically active molecules; Biomaterials; folic acid; Mice; 03 medical and health sciences; Drug Delivery Systems; Folic Acid; synergistic effect; Cell Line, Tumor; Gene Products; Animals; Humans; tat; Particle Size; Inbred BALB C; Mice, Inbred BALB C; Tumor; Cell penetrating peptides; tumor targeting; 500; Tumor targeting; Nanomedicine; Pharmacology and pharmaceutical sciences; RAW 264.7 Cells; Gene Products, tat; Liposomes; Synergistic effect; 1305 Biotechnology; Nanoparticles

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.