Researchers at Purdue University 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," according to new research findings published online April 29 in the Proceedings of the National Academy of Sciences.
The researchers used an imaging technique called Förster resonance energy transfer imaging (FRET) to make two key discoveries: how fluorescent molecules mimicking the cancer drug paclitaxel enter tumor cells and how the micelles break down in the blood before they have a chance to deliver the drug to cancer cells, according to Ji-Xin Cheng, an assistant professor in the Weldon School of Biomedical Engineering and Department of Chemistry, one of the lead investigators for the research.
Cheng and colleagues said that synthetic polymer micelles are drug-delivery spheres 60-100 nanometers in diameter, or roughly 100 times smaller than a red blood cell. The spheres harbor drugs in their inner core and contain an outer shell made of a material called polyethylene glycol.
Micelles 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 portion labeled with a red dye, according to the researchers.
Experiments showed that core-loaded fluorescent molecules mimicking the drug entered cancer cells within 15 minutes, suggesting a new drug-delivery pathway to kill tumor cells.The fluorescent probes produced a green color on the membranes and a yellowish color inside the cells, providing a system to monitor in real-time how well the drug delivery is working, Cheng said.
The researchers said they are the first to use FRET to study drug release from polymer micelles into a tumor cell. Another research paper on the topic also will appear in May in Langmuir, which reveals, using mice, specifically how the drug is released prematurely in the blood.
Because micelles remain intact in water, researchers had thought the particles were stable in blood, but previous research showed that the micelles are quickly broken down, releasing the drug into the blood.
"The reason is very simple," 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 tested 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,” Cheng said. Future research may concentrate on creating micelles that remain intact longer in the blood by using the crosslinking.
The Oncological Sciences Center in Purdue's Discovery Park, the National Science Foundation and the National Institutes of Health funded the study.