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Previously at Oncobites, we discussed how small particles such as nanoparticles could be used for delivering drugs against cancer. The nanoparticles can carry the drugs to the tumor taking advantage of the leakiness of blood vessels running through the tumor. The leaky vessels allow the drug-carrying nanoparticles to enter the tumor environment preferentially over normal cells with tighter blood vessels, reducing toxicity, and increasing efficiency of the therapy. However, what serves as an entry route can also act as an exit portal. Recent research suggests that nanoparticles may further enhance the leakiness of blood vessels, allowing cancer cells to escape, and spread through the body.
The study conducted by researchers at the National University of Singapore found that nanoparticles can increase the gaps between endothelial cells – cells lining the surface of blood vessels, resulting in a leaky organization. The scientists found that nanoparticles composed of different materials were able to induce leakiness. On the contrary, bigger particles made with similar materials did not disrupt the vessel structures as seen with particles of nano dimensions. Particle size plays a crucial role in this behavior because particles composed of the same material, but different sizes, disrupt blood vessels differently.
In the lab, when the researchers treated single layers of cancer cells with the nanoparticles, they observed gaps forming between cells, allowing cells or other materials to leak through the gaps. To see if the behavior holds true in animals, the researchers implanted human tumors on a specially engineered lineage of mice, injected the animals with nanoparticles, and monitored them for weeks. The mice that were treated with nanoparticles showed a higher percentage of human cell signatures in the blood over the untreated animals. Further, when animals carrying no primary tumors were injected with both breast cancer cells and nanoparticles, the cancer cells showed a higher tendency to accumulate in the lung over animals that were not treated with nanoparticles.
Together, these results suggest, nanoparticles can potentially facilitate the leakage of cancer cells into blood vessels and subsequently their escape to other organs from the vessels, by increasing gaps between endothelial cells.
Metastasis – the spread of cancer cells from the original tumor site – is a major cause of relapse and mortality in cancer. Thus, the possibility that nanoparticles can increase the chances of metastases should be taken with seriousness. However, some questions need to be answered.
The researchers explored a few nanoparticle platforms to confirm their hypotheses. While the induction of leakiness was true for all the materials tested, it has yet to be seen if the phenomenon is truly universal for particles in the dimension of nanoparticles. Further, nanoparticle formulations of drugs do have advantages in improving the distribution of drugs to intended sites within the body. Metastasis is a common risk in cancer, and we need to evaluate if nanomedicine aggravates the risk. If evidence suggests that nanoparticle exposure is a universal trigger for endothelial leakiness, we should further reflect if the risk of cancer cell escape outweighs the improved therapeutic benefit achievable with nanoparticles as vehicles of drug delivery.
Peng, F., Setyawati, M. I., Tee, J. K., Ding, X., Wang, J., Nga, M. E., . . . Leong, D. T. (2019). Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness. Nat Nanotechnol.
Art created with Biorender. Not to scale