"Smart" Drugs Target Cancer Cells

One of the bitter ironies of cancer therapy is that any treatment powerful enough to kill tumor cells also harms healthy ones, causing undesirable side effects.

Researchers at the University of Michigan's Center for Biologic Nanotechnology are developing "smart" drug delivery systems that will hopefully help prevent that problem by knocking out cancer cells with lethal doses while leaving normal cells unharmed.

The U-M group is using lab-made molecules called dendrimers—also known as nanoparticles—as the backbones of their delivery system, according to U-M graduate student Almut Mecke, who reported on the group's progress at the APS March Meeting in Montréal.

Dendrimers are tiny spheres that have been carefully engineered to have several loose ends, to which other molecules can be attached, such as a targeting agent that can recognize a cancer cell and distinguish it from a healthy cell, or a drug that kills cancer cells. This turns the dendrimer into a cancer-fighting Trojan horse. "If you have both of these functions on the same molecule, then you have a smart drug that knows which cells to attack," said Mecke.

In order for this approach to be successful, the bare dendrimer should not be toxic and should not be able to break into healthy cells, only cancerous ones. So Mecke investigated the interaction of dendrimers with cell membranes. She found that certain kinds of dendrimers are able to disrupt membranes by literally punching holes in them—not a desirable attribute, since they do not distinguish between cancerous and healthy cells. The underlying mechanism seems to arise from the membrane wrapping itself around the dendrimer, leaving a hole.

This happens because both the dendrimers and cell membranes are charged, causing the two to bind. Mecke's group modified the dendrimers chemically so that they became uncharged, and no longer punched holes in membranes. Of course, uncharged dendrimers don't attack any cells at all, so cancer-detecting targeting agents must be attached.

Mecke's group is working with a type of dendrimer called polyamidoamine, which is modified to identify cancer cells containing specific markers on their membrane surface. This causes the cancer cell to ingest the dendrimer. Once inside the cell, it releases the attached anti-cancer drug.

The data Mecke gleaned through atomic force microscopy is supported by recent research on live human cancer cells in-vitro, as well as animal tests conducted by team members. Initial results on mice have shown a greater efficiency and reduced side effects when cancer is treated nano-therapeutically.

The researchers hope next to add more functions to their dendrimer-drug devices, such as biosensors that can report on cancer cell death, indicating how successful a particular treatment has been.