Web Date: January 20, 2016
Two-Step Delivery Method Ups Cancer Drug’s Concentration In Tumors
Researchers report that cancer therapies involving drugs such as Taxol (paclitaxel) might be made more effective if clinicians did the two-step when administering them. The team found that a two-step procedure—delivering a tumor-localizing, drug-absorbing nanoparticle followed by the actual therapeutic—can increase the amount of drug that reaches tumor cells and the amount of time the drug acts on the cells (Scientific Reports 2016, DOI: 10.1038/srep18720).
In the study, Mark W. Grinstaff of Boston University, Yolonda Colson of Brigham & Women’s Hospital, and coworkers first administered a polymer-based nanoparticle to mice with tumors. This nanoparticle swells and becomes a gel in mildly acidic surroundings. Because cancer cells are more acidic than normal cells, when the rodents’ tumors took up the particles, the tiny particles expanded to 10 times their original size and became trapped.
Two days later, the researchers gave the mice Taxol, which concentrated inside the trapped nanoparticles because of its hydrophobicity. Taxol concentrations within the mouse tumors rose to about five times the level attained when researchers gave mice the drug alone. The drug also remained in the tumor longer, giving Taxol more time to kill cancer cells.
The researchers got the idea for the two-step strategy from previous studies in which scientists derivatized drugs with antibodies, nucleic acids, or other binding agents and then administered these conjugates separately from nanoparticles containing complementary binding agents or sites. The new approach is the first to match the chemical properties of drug and nanoparticle so they come together in the body without the need for derivatization.
The new two-step strategy is reminiscent of one-step nanomedicines—drug-laden nanoparticles that aim to deliver therapeutics in a targeted way, cutting down on drug side effects. In fact, when Grinstaff, Colson, and coworkers delivered nanoparticles preloaded with Taxol to mice with cancer, orders of magnitude more drug got to the tumors than was achieved with the two-step procedure. This might be expected because the drug doesn’t have to find the nanoparticles in the body.
But the new approach has a advantage: Nanomedicines preloaded with drugs would be considered new drug entities by the U.S. Food & Drug Administration and would have to pass a full series of clinical trials over many years to be approved. The polymer-based particles, on the other hand, are defined by FDA as medical devices because they do not have chemistry-based therapeutic activity. Taxol is also already FDA-approved. So the two-step strategy could minimize drug-approval complications and expenses and get to patients sooner, the Boston team says.
Cancer nanomedicine expert Joseph M. DeSimone of the University of North Carolina, Chapel Hill, notes that the study “reports a first-of-its-kind result” because the two-step treatment requires neither selective binding interactions between drug and nanoparticle nor an activating event to make the drug start working, either or both of which were required in earlier drug-nanoparticle treatments. “The surprising result was that pretreating mice with a nontherapeutic nanoparticle that passively accumulates in the tumor tissues, followed by treatment with an untargeted drug, resulted in significantly higher tissue-specific drug delivery than treatment with drug alone,” DeSimone says.
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