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Design of vascular-targeted carriers for optimal performance in humans: bringing blood cells and hemorheology into the game

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Written by Hope Sisley

Posted on 20 April 2014

On March 7, Mines hosted Dr. Omolola Eniola-Adefeso, the director of chemical engineering at the University of Michigan, Ann Arbor. She spoke on vascular-targeted drug delivery - that is, the transport of medical drugs directly to the wall of the blood vessels at a specific point in the body, using a man-made carrier with a built-in drug-release trigger. The carriers are modelled after white blood cells. By using targeted delivery to treat something such as cancer, the doctors ensure that the drugs - which are often toxic to humans - are sent straight to the tumor without harming the patient's other cells. This "localization" of drug delivery requires efficiency, and in order to make delivery as efficient as possible, the behaviour of the carrier must be well known. This behaviour depends on the type, shape, and size of the carrier, as well as the properties of the target (the wall of a blood vessel, in this case) and the rheology of blood, which is a complex fluid. Red blood cells (erythrocytes) tend to concentrate in the center of blood flow, while other cells are pushed to the vessel walls. Because the walls are the target, the drug carrier must behave like these other cells, not like an erythrocyte. Furthermore, the nature of the target and the delivery path depends on the disease being treated. Arteriosclerosis, for instance, involves large blood vessels, while cancer involves capillaries, the tiniest blood vessels of all. Different sizes of blood vessel will have different flow regimes, and will be able to accommodate different sizes of drug carrier. Thus, Eniola-Adefeso set out to determine how the size of the carrier affects the efficiency of drug delivery.

As a proxy for delivery efficiency, the researchers tested the adhesion of carrier particles to epithelial cells in the midst of human blood flow. First Eniola-Adefeso and her colleagues tested a larger blood vessel. They found that, in general, larger particles bind better than smaller (for example, ten microns in diameter as opposed to 0.1 micron). This relationship held true at a higher rate of input, but at higher speeds five microns was better than ten. To negate the effects of gravity, the tests were repeated upside-down, and yielded the same results. Because arteriosclerosis is caused by plaque building up on the wall of blood vessels, it can cause flow separation or create regions of flow stagnation; these irregularities were simulated and found to favor carriers of five microns as well.

Next, Eniola-Adefeso and her colleagues conducted the same tests in a capillary-sized blood vessel, simulating microvessels in a cancer tumor. While five microns was found to be too big, leading to collisions with red blood cells, the efficiency of the very tiny particles (fractions of microns in size) was not improved from that seen in the large vessel. The small particles fit easily between the erythrocytes, so they are unable to leave the flow, while particles one and two microns in size get pushed to the wall by shear forces in the flow. Two microns was found to be the best diameter for efficient adhesion. As the concentration of the carrier is increased, adhesion increases across sizes, but not at a one-to-one return, and not to the same degree for all sizes.

The next suite of tests involved the fluid itself. These tests had involved slightly-diluted human blood; the same tests were run with a cell-free saline buffer solution, and the presence of blood cells was found to be the controlling factor on behavioral differences between carrier sizes. In order to determine which cells exactly were having the greatest effects, serum containing each of the three main cell types found in blood was tested. Platelets, which cause clots and scabs to form in the event of injury, were found to have no effect. Red blood cells favored two microns, while detrimenting the efficiency of five microns; this effect was greater in pulsed flow. White blood cells (leukocytes) gave similar (though much less pronounced) results in steady flow, but in pulsed had a negative effect on adherence for all carrier sizes. This is because the particles stick to the leukocytes as well as to the blood vessel's wall, and as the leukocytes roll by they rip the carrier particles off of the walls. The type of ligand, or binding protein, used on the carrier does not affect this behaviour, so Eniola-Adefeso determined that the solution was to simply add more ligand to the particles so that they will adhere more strongly to the vessel wall.

At this stage in the experiment, the researchers are testing different shapes of carrier. The ones used in all of the tests so far were spherical; rod-shaped carriers, however, were found to be better carriers (though still most efficient at two microns). The more elongate the particle, the better a carrier it makes, with the difference between shapes being greater in larger particles. Eniola-Adefeso is currently testing discoid carriers.

When the tests were run in living lab mice, the two-micron carrier was again found to be most efficient. Other concerns which will be tested in the future include the effects on carrier behaviour of the type of blood involved - in other words, whether mice can be considered an accurate proxy for humans in these experiments - and the effects of density, as all the tests described in Eniole-Adefeso's talk were density-neutral. As the variables are narrowed down, slowly she and her colleagues are moving towards a drug-delivery system that will be more efficient than any in existence, ensuring that ill people the world over can get the best treatment possible.
Colorado School of Mines

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