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Paper presentation: Nano-technology


                          The advent of nanotechnology in cancer research couldn’t have come at a more opportune time. The vast knowledge of cancer genomics and proteomics emerging as a result of the Human Genome Project is providing critically important details of how cancer develops, which, in turn, creates new opportunities to attack the molecular underpinnings of cancer. However, scientists lack the technological innovations to turn promising molecular discoveries into benefits for cancer patients. It is here that nanotechnology can play a pivotal role, providing the technological power and tools that will enable those developing new diagnostics, therapeutics, and preventives to keep pace with today’s explosion in knowledge.
                          Nanotechnology provides the sized materials that can be synthesized and function in the same general size range and Biologic structures. Attempts are made to develop forms of anticancer therapeutics based on nanomaterials. Dendritic polymer nanodevices serves as a means for the detection of cancer cells, the identification of cancer signatures, and the targeted delivery of anti-cancer therapeutics (cis-platin, methotrexate, and taxol) and contrast agents to tumor cells. Initial studies documented the synthesis and function of a targeting module, several drug delivery components, and two imaging/contrast agents. Analytical techniques have been developed and used to confirm the structure of the device. Progress has been made on the specifically triggered release of the therapeutic agent within a tumor using high-energy lasers. The work to date has demonstrated the feasibility of the nano-device concept in actual cancer cells in vitro.

                           Nanotechnology offers the unprecedented and paradigm-changing opportunity to study and interact with normal and cancer cells in real time, at the molecular and cellular scales, and during the earliest stages of the cancer process. Through the concerted development of nanoscale devices or devices with nanoscale materials and components, the NCI Alliance for Nanotechnology in Cancer will facilitate their integration within the existing cancer research infrastructure. The Alliance will bring enabling technologies for:
•    Imaging agents and diagnostics that will allow clinicians to detect cancer  earliest stages
•    Systems that will provide real-time assessments of therapeutic and surgical efficacy for accelerating clinical translation
•    Multifunctional, targeted devices capable of bypassing biological barriers to deliver multiple therapeutic agents directly to cancer cells and those tissues in the  microenvironment that play a critical role in the growth and metastasis of cancer .
•    Agents that can monitor predictive molecular changes and prevent precancerous cells from becoming malignant
•    Novel methods to manage the symptoms of cancer that adversely impact quality of life
•    Research tools that will enable rapid identification of new targets for clinical development and predict drug resistance.

             Nanoscale devices are somewhere from one hundred to ten thousand times smaller than human cells. They are similar in size to large biological molecules ("biomolecules") such as enzymes and receptors. As an example, hemoglobin, the molecule that carries oxygen in red blood cells, is approximately 5 nanometers in diameter. Nanoscale devices smaller than 50 nanometers can easily enter most cells, while those smaller than 20 nanometers can move out of blood vessels as they circulate through the body.
             Because of their small size, nanoscale devices can readily interact with biomolecules on both the surface of cells and inside of cells. By gaining access to so many areas of the body, they have the potential to detect disease and deliver treatment in ways unimagined before now. And since biological processes, including events that lead to cancer, occur at the nanoscale at and inside cells, nanotechnology offers a wealth of tools that are providing cancer researchers with new and innovative ways to diagnose and treat cancer.

                Nanoscale devices have the potential to radically change cancer therapy for the better and to dramatically increase the number of highly effective therapeutic agents. Nanoscale constructs can serve as customizable, targeted drug delivery vehicles capable of ferrying large doses of chemotherapeutic agents or therapeutic genes into malignant cells while sparing healthy cells,greatly reducing or eliminating the often unpalatable side effects that accompany many current  cancer therapies.
                 On an equally unconventional front, efforts are focused on constructing robust “smart” nanostructures that Will eventually be capable of detecting malignant cells in vivo, pinpointing their location  in the body, killing the cells, and reporting back that their payload has done its job. The operative principles driving these current efforts are modularity and multifunctionality, i.e., creating functional building blocks that can be snapped together and modified to meet the particular demands of a given clinical situation.

                In this diagram, nano sized sensing wires are laid down across a microfluidic channel. These nanowires by nature have incredible properties of selectivity and specificity. As particles flow through the microfluidic channel, the nanowire sensors pick up the molecular signatures of these particles and can immediately relay this information through a connection of electrodes to the outside world.

                These nanodevices are man-made constructs made with carbon, silicon and other materials that have the capability to monitor the complexity of biological phenomenon and relay the information, as it is monitored, to the medical care provider.
                They can detect the presence of altered genes associated with cancer and may help researchers pinpoint the exact location of those changes


            Nanoscale cantilevers – microscopic, flexible beams resembling a row of diving boards – are built using semiconductor lithographic techniques. These can be coated with molecules capable of binding specific substrates—DNA complementary to a specific gene sequence, for example. Such micron-sized devices, comprising many nanometer-sized cantilevers, can detect single molecules of DNA or protein.

             As a cancer cell secretes its molecular products, the antibodies coated on the cantilever fingers selectively bind to these secreted proteins. These antibodies have been designed to pick up one or more different, specific molecular expressions from a cancer cell. The physical properties of the cantilevers change as a result of the binding event. Researcherscan read this change in real time and provide not only information about the presence and the absence but also the concentration of different molecular expressions.
             Nanoscale cantilevers, constructed as part of a larger diagnostic device, can provide rapid and sensitive detection of cancer-related molecules.

             Nanoshells have a core of silica and a metallic outer layer. These nanoshells can be injected safely, as demonstrated in animal models.Because of their size, nanoshells will preferentially concentrate in cancer lesion sites. This physical selectivity occurs through a phenomenon called enhanced permeation retention (EPR).Scientists can further decorate the nanoshells to carry molecular conjugates to the antigens that are expressed on the cancer cells themselves or in the tumor microenvironment. This second degree of specificity preferentially links the nanoshells to the tumor and not to neighboring healthy cells.  As shown in this example, scientists can then externally supply energy to these cells. The specific properties associated with nanoshells allow for the absorption of this directed energy, creating an intense heat that selectively kills the tumor cells. The external energy can be mechanical, radio frequency, optical – the therapeutic action is the same.The result is greater efficacy of the therapeutic treatment and a significantly reduced set of side effects.

               Nanoscale devices have the potential to radically change cancer therapy for the better and to dramatically increase the number of highly effective therapeutic agents.In this example, nanoparticles are targeted to cancer cells for use in the molecular imaging of a malignant lesion. Large numbers of nanoparticles are safely injected into the body and preferentially bind to the cancer cell, defining the anatomical contour of the lesion and making it visible.

            These nanoparticles give us the ability to see cells and molecules that we otherwise cannot detect through conventional imaging. The ability to pick up what happens in the cell — to monitor therapeutic intervention and to see when a cancer cell is mortally wounded or is actually activated — is critical to the successful diagnosis and treatment of the disease.
            Nanoparticulate technology can prove to be very useful in cancer therapy allowing for effective and targeted drug delivery by overcoming the many biological, biophysical and biomedical barriers that the body stages against a standard intervention such as the administration of drugs or contrast agents.


The six major challenge areas of emphasis include:
   9.1 Prevention and Control of Cancer:
•    Developing nanoscale devices that can deliver cancer prevention agents
•    Designing multicomponent anticancer vaccines using  nanoscale delivery vehicles
   9.2 Early Detection and Proteomics:
•    Creating implantable, biofouling-indifferent molecular sensors that can detect cancer-associated biomarkers that can be collected for ex vivo analysis or analyzed in situ, with the results being  transmitted via wireless technology to the physician
•    Developing “smart” collection platforms for simultaneous mass spectroscopic analysis of multiple cancer-associated markers. 
   9.3 Imaging Diagnostics:
•    Designing “smart” injectable, targeted contrast agents that improve the resolution of cancer to the single cell level
•    Engineering nanoscale devices capable of addressing the biological and evolutionary diversity of the multiple cancer cells that make up a tumor within an individual.
  9.4 Multifunctional Therapeutics:
•    Developing nanoscale devices that integrate diagnostic and therapeutic functions
•    Creating “smart” therapeutic devices that can control the spatial and temporal release of therapeutic agents while monitoring the effectiveness of these agents
  9.5 Quality of Life Enhancement in Cancer:
•    Designing nanoscale devices that can optimally deliver medications for treating conditions that may arise over time with chronic anticancer therapy, including pain, nausea, loss of appetite, depression, and difficulty breathing.
  9.6 Interdisciplinary Training:
•    Coordinating efforts to provide cross-training in molecular and systems biology to nanotechnology engineers and in nanotechnology to cancer researchers.
•    Creating new interdisciplinary coursework/degree programs to train a new generation of researchers skilled in both cancer biology and nanotechnology.

                 Work is currently being done to find ways to safely move these new research tools into clinical practice. Today, cancer-related nanotechnology is proceeding on two main fronts: laboratory-based diagnostics and in vivo diagnostics and therapeutics.
 Nanodevices can provide rapid and sensitive detection of cancer-related molecules byenabling scientists to detect molecular changes even when they occur only in a small percentage of cells.        Nanotechnology is providing a critical bridge between the physical sciences and engineering, on the one hand, and modern molecular biology on the other. Materials scientists, for example, are learning the principles of the nanoscale world by studying the behavior of biomolecules and biomolecular assemblies. In return, engineers are creating a host of nanoscale tools that are required to develop the systems biology models of malignancy needed to better diagnose, treat, and ultimately prevent cancer.  In particular, biomedical nanotechnology is benefiting from the combined efforts of scientists from a wide range of disciplines, in both the physical and biological sciences, who together are producing many different types and sizes of nanoscale devices, each with its own useful characteristics.

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