The development of tumor-targeting, drug-bearing micelles may enable metronomic chemotherapy, a new approach that works to control cancer, not completely eliminate it. [Oregon State University]
The development of tumor-targeting, drug-bearing micelles may enable metronomic chemotherapy, a new approach that works to control cancer, not completely eliminate it. [Oregon State University]

The war on cancer may become a cold war, now that a new drug-delivery system has shown that it is possible to combine careful targeting with small, frequent dosing. With such a system, it may be possible to avoid the usual rollback approach, the administration of “maximum tolerable doses” of chemotherapeutic drugs. Because all-out hostilities against cancer are hard to sustain, and may require rest periods that allow cancer to develop resistance, low-level conflict, patiently sustained, may actually be more effective.

That’s the argument raised by researchers based at Oregon State University. These researchers say that they have found a way to realize a promising anticancer approach called metronomic chemotherapy. This approach calls for using significantly lower doses of chemotherapeutic drugs but at more frequent time intervals. A metronomic drug regimen, the scientists point out, could accomplish several goals at once—kill cancer cells, create a hostile biological environment for the growth of cancer, reduce toxicity from the drug regimen, and avoid the development of resistance to the cancer drugs being used.

Metronomic drug systems, however, have been hard to implement because drug-delivery systems have been lacking. To address this problem, the researchers designed and evaluated paclitaxel (PTX) and rapamycin (RAP) micellar systems that can be tailored for various dosing regimens and target tumor microenvironment.

These new systems were detailed August 10 in the journal Chemistry of Materials, in an article entitled, “Combinatorial Polymeric Conjugated Micelles with Dual Cytotoxic and Antiangiogenic Effects for the Treatment of Ovarian Cancer.” The article describes how a metronomic drug-delivery system could be used to control cancer, as opposed to eliminating it.

“Individual and mixed PTX/RAP (MIX-M) micelles are prepared by conjugating drugs to a poly(ethylene glycol)-block-poly(β-benzyl l-aspartate) using a pH-sensitive linker,” wrote the article’s authors. “The micelles release the drug(s) at pH 5.5 indicating preferential release in the acidic endosomal/lysosomal environment. Micelles exhibit antiproliferative effects in cancer cell lines … and inhibit endothelial migration and tube formation.” In healthy mice, the regimens that were applied did not appear to induce toxicity.

Essentially, the drug-delivery system developed in this research attaches anticancer drugs to polymer nanoparticles that migrate specifically into cancer cells and are designed to release the drugs at a particular level of acidity common to those cells. The low doses, careful targeting of the drugs, and their ability to work in synergy at the same time appeared to increase their effectiveness greatly, while almost completely eliminating toxicity.

The researchers administered two drugs—paclitaxel and rapamycin—that are already common in ovarian cancer treatment, but did so at levels a tenth to a third of the maximum tolerable dose. One drug attacks cancer cells, and the other inhibits cancer cell formation and the growth of blood vessels at tumor sites.

“This new system takes some existing cancer therapy drugs for ovarian cancer, delivers both of them at the same time, and allows them to work synergistically,” said Adam Alani, Ph.D., an associate professor in the Oregon State University/Oregon Health & Science University College of Pharmacy, and lead author on the new study.

“Imagine if we could manage cancer on a long-term basis as a chronic condition, like we now do for high blood pressure or diabetes. This could be a huge leap forward.”

The new approach is still in trial stages, Dr. Alani noted, but shows promise. “Our goal is to significantly reduce tumors, slow or stop their regrowth, and allow a person's body and immune system time to recover its health and natural abilities to fight cancer. I'm very optimistic this is possible, and that it could provide an entirely new approach to cancer treatment.”








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