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# Infernal MechanismPUBLIC ACCESS

At the Nanoscale, The Way that Cancer Spreads and Kills can Best be Understood as Mechanical Processes. Nanotechnology and Nanoscale Mechanical Engineering may soon Lead to a Revolution in Oncology.

[+] Author Notes

Mauro Ferrari is a professor and chairman of the Department of Nanomedicine and Biomedical Engineering at the University of Texas Health Science Center – Houston. Ferrari also holds positions with M.D. Anderson Cancer Center, Rice University, and the University of Houston.

Mechanical Engineering 132(03), 24-28 (Mar 01, 2010) (5 pages) doi:10.1115/1.2010-Mar-1

This article explores the new generation of nanotech-based therapeutic agents that have entered the fight against cancer. In 2005, a class of albumin-based nanoparticles was approved for delivery of taxanes for breast cancer, and then later for ovarian cancer. Therapeutic and imaging contrast nanoparticles now have a market size exceeding 5 billion per year, and many higher functionality nanodrugs are awaiting approval in the regulatory pipeline. An essential role of nanoparticles in cancer mechanics is in the building of the necessary tools for experimental studies of transport. The research carried out so far on cancer transport differentials has employed nanoparticles as test probes. In order to overcome the multitude of biological barriers, scientists have introduced a system of nanoparticles, designed to address the barriers in their time sequence of presentation called multistage vectors, which consist of nested particles that release consecutively. The level of specificity that can be achieved through the use of the conceptual model of cancer as a mechanical disease—and through the power of the mechanical engineering design process—will result in greater therapeutic efficacy with reduced side effects. ## Article The healing arts are often held up as a field in which the cold calculus of mechanical engineering has little purchase. Instead, we are told, medicine is a place where biology and chemistry hold the key insights. Sure, a bioengineer could fashion an artificial hip, but how could mechanical engineering hope to remedy the common cold, or cure cancer? But in truth, engineering mechanics and mechanical engineering have long been present in oncology and cancer research. The last decade has provided ample illustrations of the diversity and depth of the mechanics-to-cancer connection. For instance, Arun Majumdar in the Department of Mechanical Engineering at the University of California at Berkeley used micro machined cantilever beams to provide a means for the early and accurate diagnosis of cancer from biological fluid samples. With his team, Majumdar fabricated arrays of micro-beams using techniques employed in the field of micro electromechanical systems, then decorated their surfaces with antibody molecules that link specifically to conjugate molecules—so-called antigens. Certain proteins are markers of cancer because they are overexpressed in the blood and other fluids of cancer patients. Majumdar observed that the micro-beams deflect and change their resonant frequencies when antibodies bind to the antigen proteins. From such observations his team proved that it is possible to determine the quantity of several cancer markers in a blood sample, and thus produce a diagnosis with an accuracy and rapidity that is unmatched by conventional medical laboratory techniques. Thus, structural mechanics entered cancer diagnostics. In a second example, Rakesh Jain and his team at Harvard University and Massachusetts General Hospital demonstrated that cancers and the surrounding tissues (what is known as the “cancer microenvironment”) generally develop internal hydrostatic pressure distributions that oppose the transport of therapeutic drugs from the blood stream into the cancer. This results in greatly diminished efficacy of treatment for cancer drugs, and calls for the development of new therapeutic approaches that can overcome the pressure gauntlets. Thus, solid and fluid mechanics entered cancer therapy. Anticancer therapy may soon be carried out using highly designed, multi-stage nanoscale particles. These particles would home in on tumors by seeking out cells that possess mechanical properties unique to cancers. Our own laboratories in Berkeley, Ohio State, and now in Houston have been active for many years in the field of mass transport inside nanopores and nanochannels, and have pioneered the field of nanofluidics. We developed novel methods for the fabrication of nanochannels in silicon membranes, with dimensional controls that are much better than those of the conventional photolithography used in MEMS. We employed sacrificial layer techniques to attain the goal of reproducibly fabricating channels with minimum dimensions of as few as five nanometers, and essentially with no upper dimensional limit. Over more than 10 years we established new predictive, mechanical laws that apply to these nano-environments, such as non-Fickian diffusion equations, and nonlinear osmotic pressure relations. Nanofluidics has a direct application to cancer therapy. For instance, we demonstrated that these nanochannel systems can be embedded into capsules implanted in the body to release anticancer drugs with the time control that is necessary to attain maximum efficacy with greatly reduced or eliminated adverse side effects. Controlled release with a constant rate can be attained with passive devices, just by exploiting the non-Fickian diffusion profiles. A time-variable rate of release can be obtained by applying a potential across the nanochannels, and employing the phenomenon of electro-osmosis, which becomes significant only in channels of nanometric dimensions. This affords the release of drugs in accordance with a preprogrammed profile, or by external activation, or ultimately, in a self-regulated manner that comprises on-board sensors, intelligence, and the release actuators. Such a device can be thought of as a biomimetic, mechanically engineered “nanogland.” In addition to the increased efficacy and diminished adverse side effects that accompany the release of drugs only when needed, and at the small local concentration required at the site of the implant (rather than flooding the body), these personalized medicine nanoglands further afford the benefit of providing therapy away from the hospital setting. Such off-site treatment is particularly crucial for populations in remote and under-served geographical areas, or in such extreme settings as military combat zones, humanitarian relief missions, and space travel. Indeed, this potential has caught the interest of researchers in broad areas of medicine outside of oncology. Proteins produced by cancer cells can be detected quickly using a cantilever device coated with specific antigens. When the proteins bind with the antigens, it changes the cantilever's oscillation rate. Supported by our recent Heinlein Award, our maiden voyage in orbit will take place later in 2010, aboard a Space-Exploration company spaceship. It will be the first-ever scientific experiment in space in a private-sector spacecraft. These are but three examples of how mechanical engineering at the nanoscale is aiding cutting-edge applications in oncological diagnosis and treatment. And if that was all there was, it would still demonstrate that cancer care is greatly benefiting from insights and applications drawn from mechanical engineers. But, in fact, an even deeper connection between mechanics and cancer has recently emerged. One of the fundamental concerns of mechanics since the discovery of simple machines is the transport of mass. If we use the word mechanical in this sense, rather than in a way typical in medicine or relating to mechanisms of biological action, then I can make a radical and potentially revolutionary statement: Cancer is a disease of mass transport dysregulation. Simply put, cancer is a mechanical disease. CANCER IS A BROADLY SWEEPING TERM THAT ENCOMPASSES OVER 200 DIFFERENT DISEASES. In accordance to a nomenclature introduced by the French in the mid-1800s and still in use, different cancers are typically grouped by site of origin, such as brain, breast, lung, and so on. In this age of molecular medicine, it has become apparent that cancers are best identified by over- and underexpression of biological molecules, such as proteins, in cells and on cell surfaces. These “molecular signatures” frequently transcend distinctions based on site of origin. If we were to classify cancers based on molecular profiles, however, we might well have as many classifications as there are individual cancer patients. Like malignant snowflakes, no two cancers are exactly alike. So, what makes a cancer a cancer? About ten years ago Douglas Hanahan, now at the University of California, San Francisco, and Robert A. Weinberg, a professor of cancer research at MIT, identified six major hallmarks of cancer. Their view that diseases that share those characteristics should be classified as cancers is now widely accepted. The first hallmark is the very core of the canonical definition of cancer: “tissue invasion and metastasis.” A malignant disease is one that invades the surrounding tissue, and metastasis—the process of disseminating cancer deposits distant from the site of origin—is the threshold that makes cancer such a tragedy. While surgery is effective in curing most localized cancers, medicine has no general answer for metastatic disease. Both tissue invasion and metastasis are mechanical aspects of the disease, as they pertain to the motion and transport of organized mass units, the biological cells that comprise the cancer. The second hallmark is the process of angiogenesis, or the generation of new blood vessels. The growth of cities requires expanded systems for the supply of water, food, utilities, and waste disposal; the same is true for cancers. The vasculature is the key component of the expanded system of biological facilities and services. Thus, without angiogenesis, there cannot be cancer growth. In turn, without the profound change of the dynamics of mass transport at the tissue level generated by angiogenesis, cancer would be largely a localized disease, and therefore generally curable. The four remaining hallmarks Hanahan and Weinberg identified—insensitivity to anti-growth signals, the ability of cancer cells to excite their own population growth, resistance to preprogrammed cell death (apoptosis), and limitless cell replication potential—all depend on the ways signals are transported in biology, within cells, and between cells. We tend to think of signals as going in a specific direction, from one point to another, since that's how most human communication works. But biological signals are most often carried by molecules that are released in the environment, inside or outside of the originating cell, or shed in the blood stream. They have no directional transport, but they “know” when they get to their intended location, since they have molecular components that dock with high lock-and-key specificity to their target molecular counterparts. This docking in itself is the message transmission, and may encode a request to enhance cell proliferation, or resist preprogrammed death, or some other activity. In the exquisitely biological view, the over- or under-transmission of these molecular signals has historically been linked to hyper- or hypo-production of the messenger molecules through over- or under-expression of the respective genes. Given that molecular signaling is really a mass transport phenomenon, the mechanical, diverging view is that perhaps it is not the number of letters that counts, but rather what happened to the metaphorical postman on the way to the cellular or subcellular mailbox. The actual determinants of mass transport in the body are the so-called biological barriers, including the walls of the blood vessels, the filtering organs of the body, the membranes that envelop cells and subcellular organelles such as the tightly protected nucleus that contains the genetic material that is the blueprint of individual life. The fundamental contention is that these biological barriers change essentially in the process of development of cancer. In other words, cancer is emerging as a disease of mass transport dysregulation, from the molecular to the cellular, to the tissue, organ, and organism levels. To use an expression that is familiar to this distinguished readership, we might view cancer as a multi-scale mechanics problem in mass transport. Multi-Stage Vectors are intended to attach to the blood vessel walls in a tumor (above left). Nanoparticles released by the MSVs (above right) then seek out cancerous cells and inject them with material designed to kill that particular cancer (below). A NEW GENERATION OF NANOTECH-BASED THERAPEUTIC AGENTS HAVE ENTERED THE FIGHT AGAINST CANCER. Lipid-based nanoparticles, or liposomes, have been used in cancer clinics for over a decade, following FDA approval in the mid-1990s of liposomal formulations of drugs such as doxorubicin and antifungal agents. In 2005 a class of albumin-based nanoparticles was approved for delivery of taxanes for breast cancer, and then later for ovarian cancer. Therapeutic and imaging contrast nanoparticles now have a market size exceeding5 billion per year, and many higher functionality nanodrugs are awaiting approval in the regulatory pipeline.

Generally, nanoparticle formulations of drugs tend to concentrate in tumor lesions, thus reducing dispersion in healthy parts of the body and yielding lower adverse side effects for a given therapeutic efficacy. The concentration at tumor sites of the current, clinically available nanoparticles takes place because the angiogenic blood vessels supplying tumors are “leaky” and permeable to nanoparticles, while normal vasculature is not. That is another powerful illustration of the notion of cancer as a disease of transport dysregulation through pathological variations in its biological barriers. And it motivates the search for a deeper understanding of the characteristics of bio-barrier transport.

Researchers have developed prototype MSVs (green). In laboratory tests, the devices have been able to target ovarian cancer cells and inject them with therapeutic chemicals. They can also be used to aid imaging of cancers.

A second, essential role of nanoparticles in cancer mechanics is in the building of the necessary tools for experimental studies of transport. The research carried out so far on cancer transport differentials has employed nanoparticles (mostly liposomes and quantum dots) as test probes. A new field is now emerging, termed “transport oncophysics,” that focuses on understanding the mass transport properties and time dynamics of evolution of all biological barriers in neoplastic pathologies.

Biological barriers are many, and they are sequential in nature. Any drug—nano or conventional—that is injected in the general circulation of a cancer patient must overcome all barriers to be able to discharge its therapeutic effect on the target cancer lesions. This is true regardless of the biological recognition capabilities of the drug molecule, which actually often come at the expense of its biobarrier-crossing abilities.

To overcome the multitude of biological barriers we have introduced a system of nanoparticles, designed to address the barriers in their time sequence of presentation. Called “Multi-Stage Vectors,” or MSVs, they consist of nested particles that release consecutively. The first stage is designed to localize on the target blood vessel walls; once there, the carriers release the nested, second-and-higher stages.

The design of the first stage is an exquisite problem in mechanical design, where the design parameters are the size, shape, modulus, degradation rate, and surface properties of the carrier vector. Those parameters must be determined so as to optimize important properties. For instance, the first stage must avoid “trapping” cells in the blood stream and in filtering organs. It must move toward the margin of the blood vessel walls in target vasculature and adhere firmly to the cells that make up those walls. And the first stage must penetrate across the blood vessel walls, into the target cancer tissue and cells.

Paolo Decuzzi of the University of Texas Health Science Center in Houston has led our way in the solution of this problem, resulting in a series of publications on the component parts of the optimization problem, and the establishment of veritable mechanical engineering “design maps” for intravascular vectors. The MSVs have demonstrated superior performance in the delivery of exquisitely targeted therapeutic molecules in animal models of ovarian cancer, and 50-fold enhanced radiological imaging capabilities.

WE ARE ON THE BRINK OF A NEW ERA IN CANCER TREATMENT, ONE IN WHICH TREATMENT IS INDIVIDUALIZED. In view of the extraordinary diversity of malignant presentations, such individualization is a necessity if we are ever going to end the death and suffering caused by cancer.

One insight that opens some exciting possibilities in this direction is the recognition that the parameters of the vector design optimization problem can be largely identified through conventional imaging. In a not-too-distant future, for instance, one can envision that an individual cancer lesion in a patient will be radiologically imaged to ascertain the properties of its vasculature and microenvironmental biological barriers. The imaging results will be used as input for the computer-based optimization problem, yielding the vector design parameters that give the greatest likelihood of reaching the target lesion. Think of it as individualization of cancer treatment at the single lesion level.

The level of specificity that can be achieved through the use of the conceptual model of cancer as a mechanical disease—and through the power of the mechanical engineering design process—will result in greater therapeutic efficacy with reduced side effects. The tools the mechanical engineer has at his or her command are the ones best suited for understanding and defeating this insidious foe.

Topics: Cancer , Diseases
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