Researchers have developed a lipid-based nanoparticle that can deliver cardiovascular drugs specifically to diseased constricted arteries and spare normal arteries from unwanted drug therapy. Cardiovascular disease is often treated using intravenous injections of vasodilators, but this results in the dilation of both stenotic and normal blood vessels, which can lead to significant side-effects. In contrast, the lenticular (lentil-shaped) liposomes developed by a Swiss team at the University of Geneva, the University Hospitals of Geneva Cardiovascular Division, and the University of Basel, effectively target only diseased stenotic vessels because the increased shear stress forces within the narrowed lumens is enough to cause transient break points in the particles that let the drugs out.
The University of Geneva’s Andreas Zumbhehl, Ph.D., and colleagues report in Nature Nanotechnology on their development and initial tests using an artificial cardiovascular system. The paper is titled “Shear-stress sensitive lenticular vesicles for targeted drug delivery”.
Conventional spherical liposomes are composed of self-assembling phospholipid bilayers and are highly stable to mechanical stress. In order to generate lenticular vesicles, the Swiss researchers engineered the component phospholipid molecules so they contained two amide bonds instead of the ester bonds that link the head and tail portions. This substitution effectively stabilizes the polar region of the resulting bilayer membrane through additional hydrogen bonds.
The resulting amide-bearing 1,3, dipalmitamidopropan-2-yl 2 (trimethylammonio)ethyl phosphate (Pad-PC-Pad) vesicles could be produced with a 3-D lenticular shape that, surprisingly, was still capable of encapsulating 97% of the volume of cargo in comparison with spherical vesicles. Initial tests with fluorophore-loaded nanocontainers confirmed that they were completely stable when not subjected to mechanical force, but leaked their payload when agitated or shaken.
The team then moved on to test the lenticular nanoparticles as a potential vehicle for the targeted delivery of drugs to atherosclerotic arteries, by passing a diluted suspension of fluorescent dye-loaded vesicles through an artificial cardiovascular system. The basic configuration of the system comprised an extracorporeal circulation pump representing the heart, attached to flexible tubing representing the arteries. In one setup tubing with a physiologically normal cross section was used. In another setup 2.5 cm lengths of the artificial artery were constricted by up to 75%, representing atherosclerotic sections. In each case the pressure, flow rates, osmolarity, and temperature were controlled and maintained within physiological ranges.
Tests were carried out using Pad-PC-Pad vesicles to assess the release of vesicle contents after a single pass through the system, and also following a number of circulations through a closed loop setup. The results confirmed that the Pad-PC-Pad vesicles remained stable when passed through the ‘healthy’ arterial system, but released their cargo in the constricted regions where shear stress was much higher. Further analyses indicated that drug release was effected as a result of the development of transient shear-induced pores in the vesicles, rather than their complete destruction. “The lenticular shape of the liposome leads to preferential breaking points along the equator that makes them sensitive to increased shear stresses,” the team writes. “Our results show that the lenticular vesicles preferentially release drugs in a model cardiovascular system, suggesting that such vesicles may potentially be used to treat cardiovascular diseases in a targeted manner.”