Peptide-guided delivery improves the therapeutic efficacy and safety of glucocorticoid drugs for treating acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions with excessive inflammation in the lung. Glucocorticoids had been widely used for ALI/ARDS, but their clinical benefit remains unclear. Here, we tackled the problem by conjugating prednisolone (PSL) with a targeting peptide termed CRV. Systemically administered CRV selectively homes to the inflamed lung of a murine ALI model, but not healthy organs or the lung of healthy mice. The expression of the CRV receptor, retinoid X receptor ß, was elevated in the lung of ALI mice and patients with interstitial lung diseases, which may be the basis of CRV targeting. We then covalently conjugated PSL and CRV with a reactive oxygen species (ROS)-responsive linker in the middle. While being intact in blood, the ROS linker was cleaved intracellularly to release PSL for action. In vitro, CRV-PSL showed an anti-inflammatory effect similar to that of PSL. In vivo, CRV conjugation increased the amount of PSL in the inflamed lung but reduced its accumulation in healthy organs. Accordingly, CRV-PSL significantly reduced lung injury and immune-related side effects elsewhere. Taken together, our peptide-based strategy for targeted delivery of glucocorticoids for ALI may have great potential for clinical translation.

Neurotensin receptor 1 facilitates intracellular and transepithelial delivery of macromolecules.

G protein-coupled receptors are expressed on the surface of eukaryotic cells and internalise in response to ligand binding. The actions of the hormone and neurotransmitter neurotensin (NT) are predominantly mediated by specific interactions with one such receptor, neurotensin receptor 1 (NTS1), which is upregulated in a variety of cancers, including pancreatic and breast tumours. NTS1 could therefore serve as a target for selective delivery of therapeutics. This study characterised the expression of NTS1 in HEK293 cells, as well as both polarised and non-polarised intestinal epithelial Caco-2 cells. NT-conjugated fluorophores were internalised in NTS1-expressing HEK293 and Caco-2 cells in a receptor-mediated fashion. Confocal microscopy revealed fluorophore localisation in the perinuclear region. Cell uptake and transport across the Caco-2 intestinal model of two NT-conjugated fluorophores (GFP and fluorescein) were compared to evaluate the effect of cargo size on cellular uptake. This work demonstrates that NT ligand conjugation is able to deliver relatively large macromolecular cargoes selectively into cells overexpressing NTS1 and the system is able to effectively translocate macromolecules across an intestinal epithelial model. NTS1 therefore shows potential as a drug delivery target not only for targeted but also non-invasive (oral) delivery of biotherapeutics for cancer.