Endothelium-targeted delivery of dexamethasone by anti-VCAM-1 SAINT-O-Somes in mouse endotoxemia

Abstract

Microvascular endothelial cells play a pivotal role in the pathogenesis of sepsis-induced inflammatory responses and multiple organ failure. Therefore, they represent an important target for pharmacological intervention in the treatment of sepsis. Glucocorticosteroids were widely used in the treatment of sepsis but vast evidence to support their systemic use is lacking. The limited effects of glucocorticoids in the treatment of sepsis may be explained by differential effects of drug initiated NF-κB inhibition in different cell types and insufficient drug delivery in target cells. The current study aimed therefore to investigate the effects of an endothelial targeted delivery of dexamethasone in a mouse model of endotoxemia induced by two consecutive i.p. injections of lipopolysaccharide (LPS). To achieve endothelial cell specific delivery of dexamethasone, we modified SAINT-O-Somes, a new generation of liposomes that contain the cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl) methyl-pyridinium chloride, with antibodies against vascular cell adhesion molecule-1 (VCAM-1). In LPS challenged mice, the systemic administration of free dexamethasone had negligible effects on the microvascular inflammatory endothelial responses. Dexamethasone-loaded anti-VCAM-1 SAINT-O-Somes specifically localized at VCAM-1 expressing endothelial cells in the microvasculature of inflamed organs. This was associated with a marginal attenuation of the expression of a few pro-inflammatory genes in kidney and liver, while no effects in the lung were observed. This study reveals that, although local accumulation of the targeted drug was achieved, endothelial targeted dexamethasone containing anti-VCAM-1 SAINT-O-Somes exhibited marginal effects on inflammatory endothelial cell activation in a model of endotoxemia. Studies with more potent drugs encapsulated into anti-VCAM-1 SAINT-O-Somes will in the future reveal whether this delivery system can be further developed for efficacious endothelial directed delivery of drugs in the treatment of sepsis.

Targeted delivery of celastrol to glomerular endothelium and podocytes for chronic kidney disease treatment

“…Based on above PLNs, we designed a positively charged drug delivery system (DDS) for glomerulus delivery. VCAM-1 is reported to be highly expressed on glomerular cell surface under inflammatory conditions [18,29,37,38]. Indeed, we confirmed that the expression of VCAM-1 did significantly increase on the surface of MRGEC (glomerular endothelial cell) and MPC5 (podocytes) cells after LPS treatment (which induces inflammation) (Figs.…”

“…7). It was reported that TNF-α can upregulate VCAM-1 through the NF-κB pathway [30,[41][42][43], but CLT could act as an inhibitor of NF-κB [9,12,15,16,[36][37][38][39]. Hence, it is possible that CLT inhibit the expression of downstream VCAM-1 via downregulating both TNF-α and NF-κB pathway.…”

Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood–brain barrier

“…In contrast, the key priorities in drug delivery pursued in our study include ratio of uptake in the target organ to that in other organs (e.g., brain to liver), the kinetics of drug delivery and postdelivery fate/activity of the pharmacological cargo (controlled by its release or/and interaction in the target), cellular and subcellular localization, the dose of drug delivered, and amplitude and duration of its effect. It might seem logical in retrospect that targeted drug delivery to VCAM-1-a selective yet scarce target-afforded no improvement in treatment of acute vascular inflammation in animal studies (63). Therefore, VCAM-1 targeted cerebrovascular pharmacological intervention documented in the present study represents the important outcome advancing the field of drug delivery to the brain.…”

Genetically engineered cell membrane–coated nanoparticles for targeted delivery of dexamethasone to inflamed lungs

“…Along these lines, the targeted delivery of antiinflammatory agents to the vasculature of affected sites via cell adhesion molecules represents a promising strategy (12)(13)(14). Using inflammation as the cue, a diverse range of nanodelivery systems have been designed to target upregulated markers such as VCAM1 and ICAM1 (15)(16)(17)(18)(19)(20), and this approach has been leveraged to treat conditions such as cancer and cardiovascular diseases (21)(22)(23). More recently, cell membrane coating technology has garnered considerable attention in the field of nanomedicine (24,25).…”