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Posted: Feb 08, 2007

Medicine of the future: cell-like nanofactories inside the body

(Nanowerk Spotlight) Without doubt, nanotechnology is having a major impact on medicine and the treatment of disease, notably in imaging and targeted drug delivery. Nanotechnology promises us a radically different medicine than the cut, poke and carpet bomb (think chemo therapy) medicine of today. The two major differences of nanomedicine will be a) the tools it uses - the main workhorse will be multifunctional nanoparticles (see Nanowerk Spotlight "Creating the nanotechnology wunderkind in pharmaceutics: multifunctional nanocarriers") and b) it will enable a perfectly targeted and individual treatment: organs and bones, really any body tissue, can be diagnosed and treated on a cell by cell basis with precise dosing and monitoring through the use of biomolecular sensors. Notwithstanding the huge amount of research going into this field, nanomedicine by and large is still in the basic research stage. Some fundamental problems like the targeting of nanoparticles in vivo, the transport of unstable drugs, and the dosage control of drug-carrying nanoparticles lead some scientists to think even one step further. Rather than delivering external drugs into the body, they conceptualize "pseudo-cell" nanofactories that work with raw ingredients already in the body to manufacture the proper amount of drug in-situ under the control of a molecular biosensor.
"This approach draws its inspiration from the ability of the human body to self-medicate by actively adapting molecular production in response to its intrinsic biochemistry" Philip R. LeDuc explains to Nanowerk. "This new approach proposes that molecular machinery could, in principle, be introduced into the body to convert pre-existing materials into therapeutic compounds, or to change molecules that a patient is unable to process, owing to some medical condition, into other compounds that the body can process."
LeDuc, an assistant professor of mechanical engineering at Carnegie Mellon University, is first author of a paper in this month's issue of Nature Nanotechnology ("Towards an in vivo biologically inspired nanofactory") that proposes this, potentially high-impact, new concept of an in vivo "pseudo-cell factory".
What would such a nanofactory look like, and what would it do?
"We would need six essential components for realizing a biochemical/biomaterials-based pseudo-cell factory" says Michael S. Wong, assistant professor in chemical and biomolecular engineering at Rice University and co-lead author of the paper: "(1) a structural shell or scaffold; (2) transport to convey biomolecules to and from the environment; (3) sensing functionality; (4) encapsulation of biochemical machinery; (5) targeting of the factory within the body; and (6) externally triggered "kill switch" to terminate a treatment in a controlled fashion."
Schematic of the six elements required for the nanofactory (Image: Reprinted with permission from the Nature Publishing Group)
One of the most challenging aspects of the nanofactory will be the mechanism that facilitates the movements of the required molecules into and products out of the artificial cell.
"Biological cells closely regulate the transport of materials across their wall through a variety of complex mechanisms including channels, endocytosis, and lipid rafts" says Wong. "There is no obvious solution to this challenge at present, but research into synthetic approaches to cellular-based transport provides some insight. Potential solutions include the development of active artificial carrier proteins or the use of passive channels that allow transport across the membrane."
The outer structure of the artificial cell could be designed based on a variety of encapsulation systems that are already in the experimental stage such as liposomes or hybrid organic/inorganic composites. Whatever its composition, a key task of the shell structure will be its ability to evade the body's immune system for a sufficiently long period of time.
Also part of the outer shell would have to be some kind of sensing mechanism that recognizes the required biomolecules. However, the authors note that although sensing of molecules in applications such as drug delivery in vivo has been successful, there is a dearth of effective approaches for the in vivo sensing of biological moieties.
Once biomolecules enter the nanofactory they need to be modified in order to create the desired end product. This could be done with encapsulated modifiers such as enzymes and vesicles as the compartment material (see: "A vesicle bioreactor as a step toward an artificial cell assembly").
The ability to localize the factories to a specific area in vivo could be essential for their success. Although targeting on the nanoscale has been investigated a lot already, especially for drug delivery, the authors point out that the success of this component will require advances on many fronts.
Finally, the last component would be a "kill switch" that allows an external operator to stop the operation of the nanofactory, for instance through ultrasonic stimulation, and have it break down into smaller parts. The goal here is not only to stop the production of the nanofactory's output, but also prevent the disassembled parts from causing any unwanted side effects.
The artificial cell concept has a long history, including research into developing systems that mimic living cells as well as using cells in an artificial environment or device. Efforts to mimic live cells focus on how to generate vesicles with cellular functionality. Such structures would be considered "living" if they could replicate, self-heal and evolve.
"When comparing the use of an artificial cell system with living cells, there are benefits and risks to both" says Wong. "Living cells are wonderfully adapted to performing a wide variety of tasks. Yet, the ability to engineer control of a cell to produce billions of molecules for a specific function has limitations."
"So, rather than reverse engineering an extremely complex system, generating an artificial cell provides a robust platform where researchers can add functionality in a component-by-component process" says LeDuc. "Furthermore, artificial approaches may be more controllable as living cells can respond in unanticipated ways."
There are many challenges that exist in developing this type of system including issues with fabrication, immunological response and safety. If successful, though, this could become an important platform technology that could benefit a variety of therapeutical approaches.
Not only would it allow to cure cancer by repairing or destroying malignent cells one by one but it would revolutionize gene therapy as well. Even NASA is looking into the nanofactory concept for the prevention of radiation-induced cancer in astronauts during long space missions.
By , Copyright Nanowerk LLC

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