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A new kind of gatekeeper
HOUSTON—Leaks are not usually something you want, but in the case of drug delivery, it could be a new option for targeting hard-to-reach tissues. Gang Bao of Rice University and his team, along with collaborators at Emory University and the Georgia Institute of Technology, have found a way to make blood vessels “leaky” by using magnets and iron-oxide nanoparticles to increase their permeability and allow large-molecule drugs through.
This work was published in Nature Communications, in a paper titled “Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions.”
As noted in the paper, “Transport across the vascular endothelium can occur via either transcellular or paracellular route. Both are tightly regulated through a complex network of signaling pathways to maintain the homeostasis of tissue microenvironment.” The authors explain that large drug molecule delivery is dependent on the vascular endothelium or incidents of increased permeability of the endothelial cells. For example, “[C]urrent drug delivery strategies are primarily aimed at treating solid tumors, in which large pores are opened along the endothelium of angiogenic vessels. Nevertheless, the success of delivering anticancer drugs is often impeded by the inherent heterogeneity in vascular permeability due to the complex interplay between the vessels and the tumor microenvironment. In many other diseases, such as cardiovascular diseases and central nervous system diseases, the vascular endothelium maintains its structural and functional integrity, preventing sufficient drug delivery into the tissue space.”
"For many diseases, systemic delivery through the blood stream is the only way to deliver molecules to the site," Bao said. "Small molecules can penetrate the blood vessel and get into the diseased cells, but large molecules like proteins or drug-loaded nanoparticles cannot pass the endothelium effectively unless it is leaky."
For this work, the team developed a microfluidic flow chamber to mimic the vascular system and lined the tubes with endothelial cells. When they applied a magnetic field to the cells, which had been infused with nanoparticles, gaps opened, and when the force was relaxed, most gaps closed after 12 hours. It was found that in the absence of a magnetic field, the nanoparticles were evenly distributed in the mock blood vessel; when a magnetic field was applied, the particles redistributed themselves, and that force warped the cytoskeleton enough to create gaps. In addition, Bao noted that the magnetic force produces a biological signal that alters the cytoskeletal structure, which also increases the “leakiness,” though they haven't pinpointed the exact nature of the signal or how cells respond.
"Our initial idea was to deliver magnetic nanoparticles into stem cells and then use a magnet to attract the stem cells to a particular location," he explained. "In doing so, we also discovered that by applying a magnetic field, we could generate changes in the cell's skeletal structure in terms of the actin filament structures." Those structures are what give cells their shape and keep surrounding endothelial cells compacted.
They also tested this in vivo in the tail of a mouse. As noted in the paper, “[Magnetic iron-oxide nanoparticles] were injected into the systemic circulation from the distal end of a mouse lateral tail vein, and the opposite lateral tail vein was placed along an NdFeB block magnet. Our initial studies and computational numerical simulations showed that magnetic targeting in the lateral tail vein required a higher field gradient and larger MNPs due to the increased venous blood velocity and a longer distance from the vessel to the magnet.”
“In contrast to ultrasound-based methods, magnetic fields are not attenuated by biological tissues, enabling better control of targeted delivery into deep tissue,” the authors added. “In addition, the pharmacokinetics and interactions of MNPs with the vascular endothelium can be optimized by fine-tuning nanocrystal synthesis and surface modification, owing to a large repertoire of nanofabrication techniques.”
Bao noted that his group is collaborating with the lab of Dr. Johnny Huard, a professor of orthopedic surgery at the University of Texas Health Science Center at Houston, on knee repair—specifically, looking at injecting nanoparticle-laden therapeutic stem cells into the knee, then surrounding the joint with magnets to attract the cells to the required area.
“But if you want to treat the heart or liver, you’d need a pretty large device to have the required magnetic field,” he said. “We don’t have that yet. To drive this to a clinical setting will be a challenge.”
As for moving this from the lab to the clinic, the authors write that “There are two major aspects concerning the potential clinical application of the method developed in this study. The first is to deliver MNPs to the targeted endothelium, of which magnetic targeting is just one of the many ways. Other approaches include conjugating targeting ligands or cell-penetrating peptides to MNPs and direct injection (when permitted). The second is to apply magnetic force to intracellular MNPs in vivo (in deep tissue), possibly using a clinical-grade magnetic device in which multiple magnets of different strengths can be placed on the patient at specific anatomic sites to yield the optimal magnetic field strength and distribution to enhance delivery at the desired location. Magnetic enhancement of vascular permeability thus has the potential to be applied to any tissue or organ of interest, regardless of the pathophysiological state.”