Ionic liquid-functionalized linear-dendritic block copolymer nanoparticles show facile assemblies and red blood cell hitchhiking in whole blood.

No abstract

Macrophages play a diverse, key role in many pathologies, including inflammatory diseases, cardiovascular diseases, and cancer. However, many therapeutic strategies targeting macrophages suffer from systemic off-target toxicity resulting in notoriously narrow therapeutic windows. To address this shortcoming, the development of poly(propylene sulfide)-b-poly(methacrylamidoglucopyranose) [PPS-b-PMAG] diblock copolymer-based nanoparticles (PMAG NPs) capable of targeting macrophages and releasing drug in the presence of reactive oxygen species (ROS) is reported. PMAG NPs have desirable physicochemical properties for systemic drug delivery, including slightly negative surface charge, ≈100 nm diameter, and hemo-compatibility. Additionally, due to the presence of PPS in the NP core, PMAG NPs release drug cargo preferentially in the presence of ROS. Importantly, PMAG NPs display high cytocompatibility and are taken up by macrophages in cell culture at a rate ≈18-fold higher than PEGMA NPs-NPs composed of PPS-b-poly(oligoethylene glycol methacrylate). Computational studies indicate that PMAG NPs likely bind with glucose transporters such as GLUT 1/3 on the macrophage cell surface to facilitate high levels of internalization. Collectively, this study introduces glycopolymeric NPs that are uniquely capable of both receptor-ligand targeting to macrophages and ROS-dependent drug release and that can be useful in many immunotherapeutic settings.

Bacteria are constantly developing greater antibiotic resistance; therefore, safe, efficacious, and cost-effective antibiotics are urgently needed. Ionic liquids (ILs) show great promise as antimicrobial agents because of their ability to disrupt bacterial membranes. In this study, a library of choline carboxylic acid-based ionic liquids were synthesized and utilized in vitro to discern their antimicrobial activity against Escherichia coli and methicillinresistant Staphylococcus aureus (MRSA). Here, choline was combined with carboxylic acids of varying alkyl chain lengths, degrees of saturation, and mole ratios and then added to E. coli and MRSA at different concentrations to determine the minimal bactericidal concentration (MBC). The MBC is linked to the presence of the anion because, when the cation is held constant, increasing the alkyl chain to its peak length, doubling the mole ratio, and removing the π bonds with respect to the anion tend to decrease MBC values, illustrating greater killing efficacy. This investigation provides insight into how the identity of the anion impacts the biocompatibility of the IL and the growth inhibition and morphology of the bacteria, ultimately establishing this class of materials as an effective, human-safe, and low-cost option for eradication of Gram-positive and Gram-negative bacteria.

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 <100℃ 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.