Ionic liquids (ILs) and deep eutectic solvents have shown great promise in drug delivery applications. Choline‐based ILs, in particular choline and geranic acid (CAGE), have been used to enhance the transdermal delivery of several small and large molecules. However, detailed studies outlining the design principles of ILs for transdermal drug delivery are still lacking. Using two model drugs of differing hydrophilicities, acarbose and ruxolitinib and 16 ILs, the dependence of skin penetration on the chemical properties of ILs is examined. First, the impact of ion stoichiometry on skin penetration of drugs is assessed using CAGE, which evidences that a molar ratio of 1:2 of choline to geranic acid yields the highest delivery. Subsequently, variants of CAGE are prepared using anions with structural similarity to geranic acid and cations with structural similarity to choline at a ratio of 1:2. Mechanistic studies reveal that the potency of ILs in enhancing transdermal drug delivery correlates inversely with the inter‐ionic interactions as determined by 2D NMR spectroscopy. Using this understanding, a new IL is designed, and it provides the highest delivery of ruxolitinib of all ILs tested here. Overall, these studies provide a generalized framework for optimizing ILs for enhancing skin permeability.

Transdermal delivery offers a patient-friendly method of drug administration. An ideal formulation for transdermal drug delivery should have high potency to enhance skin permeation and low tendency to induce skin irritation. Ionic liquids (ILs) and deep eutectic solvents (DESs) have recently been proposed to serve as an excellent platform to enable transdermal delivery of various therapeutics including proteins and siRNA. In spite of their success, general safety-efficacy behavior of ILs/DESs is not reported. Using safety and efficacy as two design criteria, a Fourier transform infrared (FTIR) spectroscopy study is conducted to compare the performance of 31 ammonium-based ILs/DESs and 44 conventional chemical permeation enhancer (CPE) molecules. FTIR analysis of skin stratum corneum exposed to ILs/DESs and CPEs is performed to extract features indicative of their safety and efficacy. ILs/DESs, as a class, outperformed conventional CPEs in terms of both potency and safety. Analysis of ILs/DESs and CPEs based on Hansen solubility parameters indicates that ILs/DESs possess solubility parameters close to those of skin, which may explain their superiority over CPEs. These studies support ILs/ DESs as promising materials for novel drug delivery systems.

Vaccinia virus (VV) is a powerful tool for cancer treatment with the potential for tumor tropism, efficient cell-to-cell spread, rapid replication in cancer cells, and stimulation of anti-tumor immunity. It has a well-defined safety profile and is being assessed in late-stage clinical trials. However, VV clinical utility is limited by rapid bloodstream neutralization and poor penetration into tumors. These factors have often restricted its route of delivery to intratumoral or intrahepatic artery injection and may impede repeat dosing. Chemical stealthing improves the pharmacokinetics of non-enveloped viruses, but it has not yet been applied to enveloped viruses such as VV. In the present study, amphiphilic polymer was used to coat VV, leading to reduced binding of a neutralizing anti-VV antibody (81.8% of polymer-coated VV [PCVV] staining positive versus 97.1% of VV [p = 0.0038]). Attachment of anti-mucin-1 (aMUC1) targeting antibody, to give aMUC1-PCVV, enabled binding of the construct to MUC1. In high MUC1 expressing CAPAN-2 cells, infection with PCVV was reduced compared to VV, while infection was restored with aMUC1-PCVV. Pharmacokinetics of aMUC1-PCVV, PCVV, and VV were evaluated. After intravenous (i.v.) injection of 1 × 10 8 viral genomes (VG) or 5 × 10 8 VG, circulation time for PCVV and aMUC1-PCVV was increased, with ~5-fold higher circulating dose at 5 min versus VV.

Originally developed for diagnostic purposes and already approved for clinical use, lipid and protein-shelled microbubbles were a natural choice as initial nucleation agents for cavitation-based therapies entering the clinic. However, several emerging therapeutic ultrasound applications require nuclei that: (i) are significantly smaller in size, in order to overcome a particular biological barrier such as the leaky vasculature of tumours or the stratum corneum; (ii) offer greatly increased cavitation persistence, both during a single extended ultrasound pulse and in terms of extended circulation following intravenous administration; (iii) have better resilience to sudden ambient pressure changes in order to enable direct injection without nuclei destruction into tissue targets via a needle and syringe; and (iv) are made of materials or have an increased payload or surface area that can interact beneficially with the relevant tissue target during or following cavitation. Gas-stabilizing solid particles will be reviewed in this context, providing an overview of their known characteristics in terms of size distribution, associated acoustic emissions, cavitation thresholds, cavitation persistence and circulation. The relationship between this acoustic characterization and associated bioeffects including drug and vaccine delivery, and immunomodulation will subsequently be explored.