Areas of Focus

Targeted Discovery

On the basis of discussions with a wide range of clinicians, cancer researchers, and technologists, it is clear that nanotechnology is ready today to solve mission-critical problems in cancer research. Indeed, one of the goals of the NCI Alliance for Nanotechnology in Cancer is to increase the visibility and availability of nanomaterials and nanoscale devices technology within the cancer research and development community to allow investigators the opportunity to do what they do best—discover and invent using new tools, just as they are doing with other disruptive technologies such as DNA microarrays and proteomic analysis.

But the NCI’s major goal in implementing the components of the Alliance is to catalyze targeted discovery and development efforts that offer the greatest opportunity for advances in the near and medium terms and to lower the barriers for those advances to be handed off to the private sector for commercial development. The Alliance focuses on translational research and development work in the following six major challenge areas, where nanotechnology can have the biggest and fastest impact.

Molecular Imaging and Early Detection
In Vivo Nanotechnology Imaging Systems
Reporters of Efficacy
Multifunctional Therapeutics
Prevention and Control
Research Enablers

Molecular Imaging and Early Detection

Nanotechnology can have an early, paradigm-changing impact on how clinicians will detect cancer in its earliest stages. Exquisitely sensitive devices constructed of nanoscale components-such as nanocantilevers, nanowires, and nanochannels-offer the potential for detecting even the rarest molecular signals associated with malignancy. Collecting those signals for analysis could fall to nanoscale harvesters, already under development, that selectively isolate cancer-related molecules such as proteins and peptides present in minute amounts from the bloodstream or lymphatic system. Investigators have already demonstrated the feasibility of this approach using the serum protein albumin (a naturally existing nanoparticle), which happens to collect proteins that can signal the presence of malignant ovarian tissue.

Another area with near-term potential is detecting mutations and genome instability in situ. Already, investigators have developed novel nanoscale in vitro techniques that can analyze genomic variations across different tumor types and distinguish normal from malignant cells. Nanopores are finding use as real-time DNA sequencers, and nanotubes are showing promise in detecting mutations using a scanning electron microscope. Further work could result in a nanoscale system capable of differentiating among different types of tumors accurately and quickly, information that would be invaluable to clinicians and researchers alike. Along similar lines, other investigators have developed nanoscale technologies capable of determining protein expression patterns directly from tissue using mass spectroscopy. This technique has already shown that it can identify different types of cancer and provide data that correlate with clinical prognosis.

In addition, nanoscale devices can enable new approaches for real-time monitoring of exposures to environmental and lifestyle cancer risk factors. Such information would be important not only for identifying individuals who may be at risk for developing cancer, but also for opening the door to complex studies of gene-environment interactions as they relate to the development of or resistance to cancer.

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In Vivo Imaging

One of the most pressing needs in clinical oncology is for imaging agents that can identify tumors that are far smaller than is possible with today's technology, at a scale of 100,000 cells rather than 1,000,000,000 cells. Achieving this level of sensitivity requires better targeting of imaging agents and generation of a bigger imaging signal, both of which nanoscale devices are capable of accomplishing. When attached to a dendrimer, for example, the MRI contrast agent gadolinium generates a 50-fold stronger signal than in its usual form, and given that nanoscale particles can host multiple gadolinium ions, affords an opportunity to create a powerful contrast agent. When linked to one of the increasing number of targeting agents, such a construct would have the potential of meeting the 100,000 cell detection level.

First-generation nanoscale imaging contrast agents are already pointing the way to new methods for spotting tumors and metastatic lesions much earlier in their development, before they are even visible to the eye. In the future, implantable nanoscale biomolecular sensors may enable clinicians to more carefully monitor the disease-free status of patients who have undergone treatment or individuals susceptible to cancer because of various risk factors.

Imaging agents should also be targeted to changes that occur in the environment surrounding a tumor, such as angiogenesis, that are now beyond our capability to detect in the human body. Already, various nanoparticles are being targeted to integrins expressed by growing capillaries. Given that angiogenesis occurs in distinct stages and that antiangiogenic therapies will need to be specific for a given angiogenic state, angiogenesis imaging agents that can distinguish among these stages will be invaluable to obtain optimal benefit from therapeutics that target angiogenesis.

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Reporters of Efficacy

Today, clinicians and patients must often wait months for signs that a given therapy is working. In many instances, this delay means that should the initial therapy fail, subsequent treatments may have a reduced chance of success. This lag also adversely impacts how new therapies undergo clinical testing, since it leaves regulatory agencies reluctant to allow new cancer therapies to be tested on anyone but those patients who have exhausted all other therapeutic possibilities. Unfortunately, this set of patients is far less likely to respond to any therapy, particularly to those molecularly targeted therapies that aim to stop cancer early in its progression, an approach that virtually all of our knowledge says is the best approach for treating cancer.

Nanotechnology offers the potential to develop highly sensitive imaging agents and ex vivo diagnostics that can determine whether a therapeutic agent is reaching its intended target and whether that agent is killing malignant or support cells, such as growing blood vessels. Targeted nanoscale devices may also enable surgeons to more readily detect the margins of a tumor prior to resection or to detect micrometastases in lymph nodes or tissues distant from the primary tumor, information that would inform therapeutic decisions and have a positive impact on patient quality-of-life issues.

The greatest potential for immediate results in this area would focus on detecting apoptosis following cancer therapy. Such systems could be constructed using nanoparticles containing an imaging contrast agent and a targeting molecule that recognizes a biochemical signal only seen when cells undergo apoptosis. Using the molecule annexin V as the targeting ligand attached to nanoscale iron oxide particles, which act as a powerful MRI contrast agent, investigators have shown that they can detect apoptosis in isolated cells and in tumor-bearing mice undergoing successful chemotherapy. Further development of this type of system could provide clinicians with a way of determining therapeutic efficacy in a matter of days after treatment. Other systems could be designed to detect when the p53 system is reactivated or when a therapeutic agent turns on or off the biochemical system that it targets in a cancer cell, such as angiogenesis.

Another approach may be to use targeted nanoparticles that would bind avidly, or perhaps even irreversibly, to a tumor and then be released back into the bloodstream as cells in the tumor under apoptosis following therapy. If labeled with a fluorescent probe, these particles could be easily detected in a patient's urine. If also labeled with an imaging contrast agent, such a construct could double as a diagnostic imaging probe.

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Multifunctional Therapeutics

Because of their multifunctional capabilities, nanoscale devices can contain both targeting agents and therapeutic payloads at levels that can produce high local levels of a given anticancer drug, particularly in areas of the body that are difficult to access because of a variety of biological barriers, including those developed by tumors. Multifunctional nanoscale devices also offer the opportunity to utilize new approaches to therapy, such as localized heating or reactive oxygen generation, and to combine a diagnostic or imaging agent with a therapeutic and even a reporter of therapeutic efficacy in the same package. "Smart" nanotherapeutics may provide clinicians with the ability to time the release of an anticancer drug or deliver multiple drugs sequentially in a timed manner or at several locations in the body. Smart nanotherapeutics may also usher in an era of sustained therapy for those cancers that must be treated chronically or to control the quality-of-life symptoms resulting from cancers that cannot be treated successfully. "Smart" nanotherapeutics could also be used to house engineered cellular "factories" that would make and secrete multiple proteins and other antigrowth factors that would impact both a tumor and its immediate environment.

The list of potential multifunctional nanoscale therapeutics grows with each new targeting ligand discovered through the use of tools such as proteomics. Nanoscale devices containing a given therapeutic agent would be "decorated" with a targeting agent, be it a monoclonal antibody or Fv fragment to a tumor surface molecule, a ligand for a tumor-associated receptor, or other tumor-specific marker. In most cases, such nanotherapeutics could double as imaging agents.

Many nanoparticles will respond to an externally applied field, be it magnetic, focused heat, or light, in ways that might make them ideal therapeutics or therapeutic delivery vehicles. For example, nanoparticulate hydrogels can be targeted to sites of angiogenesis, and once they have bound to vessels undergoing angiogenesis it should be possible to apply localized heat to "melt" the hydrogel and release an antiangiogenic drug. Similarly, iron oxide nanoparticles, which can serve as the foundation for targeted MRI contrast agents, can be heated to temperatures lethal to a cancer cell merely by increasing the magnetic field at the very location where these nanoparticles are bound to tumor cells.

In some instances, nanoscale particles will target certain tissue strictly because of their size. Nanoscale dendrimers and iron oxide particles of a specific size will target lymph nodes without any molecular targeting. Nanoscale particles can also be designed to be taken up by cells of the reticuloendothelial system, which raises the possibility of delivering potent chemotherapeutics to the liver, for example.

Nanoscale devices should also find use in creating immunoprotected cellular factories capable of synthesizing and secreting multiple therapeutic compounds. Early-stage research has already demonstrated the value of such cellular factories, and a concerted effort could turn this research into a powerful multivalent therapeutic capable of responding to local conditions in a physiologically relevant manner.

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Prevention and Control

Many of the advances that nanotechnology will enable in each of the four preceding challenge areas will also find widespread applicability in efforts to prevent and control cancer. Advances driven by the NCI's initiatives in proteomics and bioinformatics will enable researchers to identify markers of cancer susceptibility and precancerous lesions, and nanotechnology will then be used to develop devices capable of signaling when those markers appear in the body and deliver agents that would reverse premalignant changes or kill those cells that have the potential to become malignant. Nanoscale devices may also prove valuable for delivering polyepitope cancer vaccines that would engage the body's immune system or for delivering cancer-preventing nutraceuticals or other chemopreventive agents in a sustained, time-release and targeted manner.

One intriguing idea for preventing breast cancer comes from work suggesting that breast malignancies may derive from a limited population of pluripotent stem cells in breast tissue. Should this prove true, it may be possible to develop a nanoscale device that could be injected into the ductal system of the breast, bind only to those stem cells, and deliver an agent capable of killing those cells. Such an agent could then be administered to women who are at an increased risk of breast cancer as a preventive therapy.

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Research Enablers

Nanotechnology offers a wide range of tools, from chip-based nanolabs capable of monitoring and manipulating individual cells to nanoscale probes that can track the movements of cells, and even individual molecules, as they move about in their environment. Using such tools will enable cancer biologists to study, monitor, and alter the multiple systems that go awry in the cancer process and identify key biochemical and genetic "choke points" at which the coming wave of molecular therapies might best be directed. As such, nanotechnology can serve as the perfect complement to other technology platforms, such as proteomics and bioinformatics, that the NCI is emphasizing in its research initiatives as critical components of the discovery and development engine that will power both near-term and long-term advances in cancer diagnosis, treatment, and prevention.

The discussion above has already highlighted the potential for nanoscale devices to act as molecular harvesting agents. Such a tool would be invaluable to proteomics efforts aimed at identifying tumor-specific indicators. Similarly, nanoscale devices that can detect the biological changes associated with therapeutic efficacy should also find widespread use as a tool for understanding how cells respond to a variety of perturbations. One of the most powerful near-term uses of nanotechnology to accelerate basic research will come from using molecular-size nanoparticles with a wide range of optical properties, such as quantum dots, to track individual molecules as they move through a cell or individual cells as they move through the body. In combination with the new generation of mouse models that more accurately reproduce the genetic, biochemical, and physiological properties of human cancers, these nanolabels will prove invaluable for systems-scale research. Increased focus on the development of nanoscale devices for making simultaneous biochemical measurements on multiple cells, particularly those grown in such a way as to mimic tissue development in vivo, will also have a significant impact on basic cancer research.

Nanoscale devices should also enable direct analysis of single nucleotide polymorphisms (SNPs) and large-scale mutational screening for cancer susceptibility genes. Real-time methylation analysis should also benefit from various nanoscale tools and devices. Indeed, nanotechnology should prove to be a valuable technology platform for the burgeoning field of cancer molecular epidemiology.

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