Many patients must take more than one drug to keep their disease in check. This so-called combination drug therapy is generally more effective than single-drug approaches because each drug affects a distinct target. For example, one drug may attack the cell’s ability to make protein, and another may reduce its ability to replicate DNA. Using drugs that work on different targets is also helpful in combating drug resistance, which occurs when the cell uses alternate molecular pathways to override the effects of a drug.
Designing a Smart Drug Delivery Vehicle
Securing the best outcome for patients requires delivering correct doses of drugs, in correct ratios, to the correct site in the body. Thus far, it has been impossible to satisfy all those factors with conventional combination chemotherapy where each drug is given individually. But investigators from Brigham and Women’s Hospital/Harvard Medical School and the Massachusetts Institute of Technology (MIT) have engineered a nanoparticle platform that rises to the challenge. The research team is led by Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s Hospital and associate professor at Harvard Medical School; Robert Langer, David H. Koch Institute Professor at MIT; and Stephen Lippard, Arthur Amos Noyes Professor at MIT.
The team chose to work with nanoparticles made of a biocompatible, FDA-approved polymer material called PLGA-PEG, as these nanoparticles are stable and can be densely loaded with a drug, and the rate of drug release is controllable. A molecular tag was added to the nanoparticle’s surface so each nanoparticle can navigate itself to the molecular “bait,” a protein present on most solid tumor cells.
In the Same Place – Like It or Not
Because water-repelling (hydrophobic) and water-attracting (hydrophilic) molecules like to be in different places, first-generation polymeric nanoparticles could be loaded with multiple drugs only when all the drugs were chemically and physically similar. This limited the range of possible drug combinations and the potential use of nanoparticle therapy. However, the research team devised a clever strategy to put a water-repelling and a water-attracting drug together in the same particle: first, water-attracting drug molecules are chemically bound to the polymer used to construct nanoparticles (hanging like pearls on a string), and then the water-repelling drug becomes encapsulated during nanoparticle self-assembly. “The key innovation was creating relatively short polymers on which the first drug [cisplatin] is hanging, so that the drug doesn’t have a choice but to be there. By blending this cisplatin-bearing polymer with a second hydrophobic polymer during the nanoparticle synthesis process, the amount of cisplatin in the nanoparticle was precisely controlled. At the same time, a second drug [docetaxel] was encapsulated using traditional methods for encapsulating hydrophobic drugs,” says Farokhzad.
The nanoparticle platform enables precise control of the dose, ratio, and rate of release of the two drugs. Farokhzad explains that a drug encapsulated in a polymeric nanoparticle is like ink absorbed in a sponge. Because the ink molecules are not chemically bound to the sponge, they can easily seep through its pores. This process, known as diffusion, is the principal way docetaxel leaves the nanoparticle. The rate of drug release can be adjusted as desired by changing the size of the pores; the larger the pores in the nanoparticle, the faster the rate of drug release. “Pore size is controlled by the choice of material and processing,” explains Farokhzad. On the other hand, cisplatin, which is chemically bound to the polymer, is released after the nanoparticle enters the cell and is biodegraded.
The nanoparticle was engineered to release the two drugs over a period of 48-72 hours. In cell culture experiments, the dual-drug-targeted nanoparticle was twice as effective in killing prostate cancer cells as the non-targeted version of the nanoparticle and up to ten times as effective as the single-drug-targeted nanoparticles.
When Less Is More
Encapsulating drugs in targeted nanoparticles enables more drug to reach the tumor, and up to 20 times more drug reaches the tumor when compared with free (unencapsulated) drug. In fact, Farokhzad says that if you tried to give enough unencapsulated drug to match the drug concentration in the tumor that nanoparticles deliver, the patient would receive a lethal dose.
Farokhzad and Langer have previously reported the development of various targeted nanoparticle technologies that deliver drugs to tumors, diseased arteries, or immune cells. Their technologies formed the foundation for a recently initiated clinical trial to test the safety of a targeted nanoparticle delivering docetaxel in patients with solid tumors.
Delivering multiple drugs in the same nanoparticle is a powerful new method to ensure that drugs reach the disease site in the correct ratio. In the near future, it may be possible to encapsulate more than two drugs in the same particle. “It gets more complex the more you try to do. One is hard enough, two is very hard, and the more you go up, the harder it gets,” says Langer. “We’re hopeful that we can advance our drug-polymer blending technology toward clinical application in the near future,” he adds. This relatively simple platform technology will allow scientists to rapidly build a library of many different nanoparticles with drug combinations and to screen for the most effective drugs, doses, and release rates.
This work is supported by the National Institute of Biomedical Imaging and Bioengineering, the National Cancer Institute, and the David Koch-Prostate Cancer Foundation Award in Nanotherapeutics.
Kolishetti N, Dhar S, Valencia PM, Lin LQ, Karnik R, Lippard SJ, Langer R, Farokhzad OC. Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy. Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):17939-44.