Imaging Reveals New Pathway for Anti-Cancer Treatment

Researchers have discovered a possible new pathway for anti-tumor drugs to kill cancer cells and proposed how to improve the design of tiny drug-delivery particles for use in "nanomedicine.”

The synthetic "polymer micelles” are drug-delivery spheres 60-100 nanometers in diameter, or about 100 times smaller than a red blood cell. The spheres contain drugs in their inner core and contain an outer shell made of a material called polyethylene glycol.

Researchers showed for the first time how this shell of polyethylene glycol latches onto the membranes of cancer cells, allowing fluorescent probes mimicking cancer drugs to enter the cancer cells, according to Dr. Ji-Xin Cheng, an assistant professor in the Weldon School of Biomedical Engineering and department of chemistry at Purdue University (West Lafayette, IN, USA). "This is an interesting new step in developing nanomedicine techniques in drug delivery,” he said.

The research is being led by Dr. Cheng and Dr. Kinam Park, a professor of biomedical engineering and pharmaceutics. New findings are detailed in two research articles. One study was published in the May 6, 2008 issue of the Proceedings of the [U.S.] National Academy of Sciences (PNAS), and another study was published in the May 2008 issue of the journal Langmuir.

The researchers utilized an imaging technique called Förster resonance energy transfer imaging (FRET) to make two significant findings: how fluorescent molecules mimicking the cancer drug paclitaxel enter tumor cells and how the micelles break down in the blood before they have an opportunity to deliver the drug to cancer cells.

An important feature of micelles is that they combine two types of polymers, one being hydrophobic, and the other hydrophilic, meaning they are either unable or able to mix with water. The hydrophobic core was loaded with a green dye and the hydrophilic part labeled with a red dye.

Experiments demonstrated that "core-loaded” fluorescent molecules mimicking the drug entered cancer cells within 15 minutes, suggesting a new drug-delivery pathway to destroy tumor cells, according to Dr. Cheng. The fluorescent probes produced a green color on the membranes and a yellowish color inside the cells. "So this technique provides a system to monitor in real time how well anti-cancer drug delivery is working,” Dr. Cheng said.

Further findings made by the investigators using mice demonstrate specifically how the drug is released prematurely in the blood. "We first proved that micelles are unstable in the blood, and then we answered why they don't remain intact,” Dr. Cheng said.

The researchers also propose a possible way to correct the problem by "crosslinking,” or reinforcing polymer strands in the micelles with chemical bonds made of two sulfur atoms. This reinforced structure might remain intact in the blood long enough to deliver the micelles to tumor sites, where they would biodegrade, according to Dr. Cheng.

The researchers are the first to use FRET to study drug release from polymer micelles into a tumor cell. Because micelles remain intact in water, researchers had thought the particles were stable in blood, but Canadian scientists in 2003 showed that the micelles are quickly broken down, releasing the drug into the blood. "The reason is very simple,” Dr. Cheng said. "Unlike water, blood has many components like surfactants and lipids and proteins that interact with the whole micelle structure. As a result, the micelles are unstable in blood and the drug is released too soon.”

The Purdue researchers evaluated how stable micelles are in different blood components. Findings indicated that the micelles remained intact in red blood cells and components of blood plasma except for a class of plasma proteins called alpha and beta globulins, which caused the drug to be released. "There could also be other blood components that cause the drug to be released, but our proposal of using crosslinking could prevent this from happening,” Dr. Cheng said.

Future study, according to the researchers, may concentrate on creating micelles that remain intact longer in the blood by using crosslinking.


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