Next-Gen Nano Composite Devices Aim To Reduce Complexity for NanoMedicine
Researchers at the Roswell Park Cancer Institute (Buffalo, NY), are working on a new generation of nanodevices to improve imaging and treatment of cancer and other diseases.
The work of Drs. Mohamed K. Khan, M.D., Ph.D. and Lajos P. Balogh, Ph.D., co-directors of the NanoBiotechnology Center of Roswell Park’s Department of Radiation Medicine, focuses on Composite NanoDevices (CNDs), an emerging class of hybrid nanoparticulate materials. CNDs are composite nanodevices made from dendrimer-based polymers, for example from poly(amidoamine) [(PAMAMs)].
To visualize the device, Dr. Balogh says simply think of nanoscale, dense, but soft ‘tumbleweed,’ where clusters of inorganic materials (such as gold) can be trapped inside. The CND “tumbleweed” device can be made in discrete sizes, carry different electric charges and can encapsulate different materials inside. This design offers researchers a wider choice of size, surface functionality, and payload than traditional small in vivo devices where the agent is conjugated directly to the surface, Dr. Khan told NWN.
This research started out with funding from the U.S. Department of Energy, and is being continued by support from the National Institutes of Health and the U.S Department of Defense.
At Nanotech 2007, Mohamed K. Khan, M.D., Ph.D. and Lajos P. Balogh, Ph.D. will discuss their CND experiments. (Click here for more on Nanotech 2007; May 20-24 – Santa Clara, CA (www.nsti.org/Nanotech2007/).
The CND approach allows researchers to place imaging or therapy agents inside the device rather than on top, which frees the surface for functionalization for other agents, anything from sensors for imaging, targets for directing the device and even the therapy/drug itself. “Once we fashion the tumbleweed together, we can embed materials within [the mesh], which traps the [inorganic] material inside the device,” Dr. Khan said.
“Modifiable terminal functionalities of the dendrimer component offer a multipurpose mode to covalently attach drugs, diagnostic/imaging modules and targeting moieties. They can be converted to targeted ‘nanodevices’ to deliver anticancer drugs to specific organs and tissues,” Dr. Balogh added.
Composite Nanodevices’ Unique Benefits
Researchers say the CND’s “tumbleweed” architecture makes it suitable for both diagnosis and therapy. The scientists’ work at Roswell Park on CNDs reflects nearly 8 years of research.
“We think of [the CND] as a simplified and multi-functional platform,” Dr Balogh said. “Today, when [researchers] want to carry out a job [with a conventional bio-nanodevice], they need to put something on the surface. And, depending on the job you want to do that can get very complicated, very fast.” The ability to replicate or characterize multiple [chemical] groups onto a device can also be problematic, he added. “Because CNDs can carry multiple functions within and not on the surface, many of these complications disappear,” Dr. Balogh said.
CNDs are also exhibiting some very intriguing properties, which Drs. Khan and Balogh admit they yet don’t fully understand. They described one “Eureka moment” in a recent paper.
“One of the things we’re teasing out [from our research] is how small changes in [CND] sizes can affect how they move, and small changes in [CND] charge can change how they move throughout the bodies,” Dr. Khan said, and points to numerous experiments. “While it may look like for all the world we are targeting an organ, we have found CNDs move to a particular organ just based on their size and charge – no active agents,” he added.
“Our current goal is to send these devices to the microvasculature or to bind them to targets on a tumor’s angiogenic microvascular system,” Dr. Khan said.
When a tumor grows beyond 1 mm in size, it needs more blood supply and so it says ‘Build me more capillaries,’” Dr. Khan said. To look at the tumor’s blood vessel growth, called angiogenesis, the researchers are looking to send CNDs through the “leaks” in these growing vessels or to target one of the specific receptors in the angiogenic tumor vessels or on tumor cells themselves using small peptides or molecules on the CND’s surface. The CND can contain different isotopes or metals, depending on the target organ or the function (drug delivery or imaging). “The same platform or the same device with different metal could have different effects,” Dr. Khan said.
For example, Dr. Khan notes a CND at 11-nanometer and negatively charged will go into the liver in extremely high levels. A CND at 5 nm seems to be highly tuned to go to the kidney, and goes evenly into many other organs. The finding is promoting a new question for bio-nano devices overall. “When people say they are targeting an organ with a device, the question might now have to be asked ‘is it the targeting component of the agent or just the device’?”
The Outlook for CND’s Future
Today, Drs. Khan and Balogh main thrust is to try to target or direct CNDs to look at how cancer tumors move, grow and even feed themselves – throughout the body and even inter-cellularly -- within the tumor itself, both for improved imaging and therapy of tumors.
“We have synthesized water-soluble, fluorescent, and stable dendrimer/silver nanocomposite particles, [FA-{Ag}] with folic acid as targeting moieties, for cell labeling and selective destruction studies,” Dr. Balogh said.
“A group of University of Michigan researchers at the Department of Biomedical Engineering, Drs O’Donnell, Tse, and Ye, have tested these optically active nanodevices,” he added. “Through this work, they have found: Irradiation of {Ag} solutions by femto-second pulsed lasers results in laser-induced optical breakdown (LIOB) localized to the composite particles. The work monitored plasma formation and cavitation bubbles using HF ultrasound imaging. Microbubble formation occurs at much lower energy values as of the breakdown threshold of human tissue. This unique phenomenon can also be utilized for imaging or selective destruction of cells.”
“We have also developed an angiogenic tumor microvascular targeted composite nanodevice, partly designed based on the nanodevice biodistribution data above,” Dr. Khan added. This is being developed now for the improvement of several types of tumor imaging.
With another of their long-term collaborators, Dr. Leah Minc at the Oregon State Nuclear Reactor, these CNDs are also being developed for novel forms of radiation therapy, both nanobrachytherapy, where they directly inject radioactive CNDs into tumors, and systemic targeted radiation therapy (STaRT) approaches, where they inject CNDs into the blood that then specifically target and kill the tumors or tumor vessels throughout the entire body.
