Development of ionic liquid-coated PLGA nanoparticles for applications in intravenous drug delivery.

Polymeric nanoparticles (NPs) are a promising platform for medical applications in drug delivery. However, their use as drug carriers is limited by biological (e.g., immunological) barriers after intravenous administration. Ionic liquids (ILs), formed from bulky asymmetric cations and anions, have a wide variety of physical internal and external interfacing properties. When assembled on polymeric NPs as biomaterial coatings, these external-interfacing properties can be tuned to extend their circulation half-life when intravenously injected, as well as drive biodistribution to sites of interest for selective organ accumulation. In our work, we are particularly interested in optimizing IL coatings to enable red blood cell hitchhiking in whole blood. In this protocol, we describe the preparation and physicochemical and biological characterization of choline carboxylate IL-coated polymeric NPs. The procedure is divided into five stages: (1) synthesis and characterization of choline-based ILs (1 week); (2) bare poly(lactic-co-glycolic acid) (50:50, acid terminated) Resomer 504H (PLGA) NP assembly, modified from previously established protocols, with dye encapsulation (7 h); (3) modification of the bare particles with IL coating (3 h); (4) physicochemical characterization of both PLGA and IL-PLGA NPs by dynamic light scattering, 1H nuclear magnetic resonance spectroscopy, and transmission electron microscopy (1 week); (5) ex vivo evaluation of intravenous biocompatibility (including serum-protein resistance and hemolysis) and red blood cell hitchhiking in whole BALB/c mouse blood via fluorescence-activated cell sorting (1 week). With practice and technique refinement, this protocol is accessible to late-stage graduate students and early-stage postdoctoral scientists.

Selective Blood Cell Hitchhiking in Whole Blood with Ionic Liquid-Coated PLGA Nanoparticles to Redirect Biodistribution After Intravenous Injection.

Less than 5% of intravenously-injected nanoparticles (NPs) reach destined sites in the body due to opsonization and immune-based clearance in vascular circulation. By hitchhiking in situ onto specific blood components post-injection, NPs can selectively target tissue sites for unprecedentedly high drug delivery rates. Choline carboxylate ionic liquids (ILs) are biocompatible liquid salts <100X composed of bulky asymmetric cations and anions. This class of ILs has been previously shown to significantly extend circulation time and redirect biodistribution in BALB/c mice post-IV injection via hitchhiking on red blood cell (RBC) membranes. Herein, we synthesized & screened 60 choline carboxylic acid-based ILs to coat PLGA NPs and present the impact of structurally engineering the coordinated anion identity to selectively interface and hitchhike lymphocytes, monocytes, granulocytes, platelets, and RBCs in whole mouse blood for in situ targeted drug delivery. Furthermore, we find this nanoparticle platform to be biocompatible (non-cytotoxic), translate to human whole blood by resisting serum uptake and maintaining modest hitchhiking, and also significantly extend circulation retention over 24 hours in BALB/c healthy adult mice after IV injection. Because of their altered circulation profiles, we additionally observe dramatically different organ accumulation profiles compared to bare PLGA NPs. This study establishes an initial breakthrough platform for a modular and transformative targeting technology to hitchhike onto blood components with high efficacy and safety in the bloodstream post-IV administration.