| Cancer is a leading cause of deaths. More than 10 million people are diagnosed with cancer every year. It is estimated that there will be 15 million new cases every year by 2020. Cancer causes 6 million deaths every year or 12% of deaths worldwide. In the United States, about 16 million new cancer cases have been diagnosed since 1990, where there were 553,768 cancer deaths and the overall costs for cancer treatment were estimated as high as $156.7 billion in 2001, and about 1.3 million new cases were diagnosed and more than half a million deaths were caused by cancer, i.e., one in every four deaths, in 2002. The Cancer Challenge Facing Nanotechnology Researchers Although we have been facing such a serious situation, there has been no substantial progress in the past 50 years in fighting against cancer. ‘The cancer death rate in US was 1.939‰ in 1950 and still 1.940‰ in 2001. These two statistics mean that for every one thousand people in the population of USA, there would be an average of 1.939 (in 1950) and 1.940 (in 2001) people who would die in that year of cancer.' It is clear, therefore, that the progress in cancer treatment has been slow and inefficient and we are in crisis in fighting against cancer. Significant increment in cure rate would be unlikely achieved unless more profound knowledge of cancer pathophysiology can be pursued, new anticancer agents can be discovered and new biomedical technologies can be developed. The emerging nanotechnology brings new hope for significant breakthroughs to be achieved in the near future. How Molecular Imaging and Molecular Labeling Might Improve Cancer Diagnosis Although there is no thorough cure for cancer at late stage, early stage cancer is treatable in general and the prognosis could be great. Cancer diagnosis is thus an important and practical way to improve the cure rate. The current diagnosis techniques are usually in tissue level, which has low efficiency and fails to detect invisible cancer cells. Molecular imaging has become a high area in cancer diagnosis. Molecular labeling is a key. The existing ways of labeling and visualizing DNA and protein molecules rely on the light-emitting properties of a limited group of radioactive elements, chemical dyes, and protein molecules. What are the Problems with Labeling Methods? These labeling techniques have several drawbacks: radioactive markers have short life spans, while organic dyes come with a limited number of colors and may quickly lose their glow. There have been great demands for more reliable and more robust labeling fluorophores, to enable real-time imaging and quantitative determination of multiple-molecule types present in cells. Benefits of Using Quantum Dots in Medical Imaging and Labeling Highly luminescent quantum dots can overcome the functional limitations encountered with chemical and organic dyes. They are highly stable against photo-bleaching and have narrow, symmetric emission spectra. In particular, the emission wavelength of quantum dots can be continuously tuned by changing the particle size or composition, and a single light source can be used for simultaneous excitation of all different-colored dots. The Aims of this Nanobiotechnology Cancer Research Project This synergistic program will develop robust biological nanoprobes using optically active quantum dots for multi-parameter and quantitative analysis of genes and proteins in tissues. This research will include synthesis of high quality luminescent quantum dots, a reasonable understanding of the surface chemistry for bioconjugation, and the preparation of water-soluble and biocompatible nanocrystals for real-time monitoring, simultaneous screening and quantitative bio-imaging of multiple biochemical contents in cancerous organisms by using confocal micro-spectrophotometer. The research will be focused more on cancer diagnosis (Project Co-ordinators: Dr Han Ming-Yong and Dr Zhang Yong). Using Nanosensors for Cancer Detection Another technology which will be developed in this synergistic program is nanosensors. Sensors constructed at the molecular scale are promising and have achieved to be extremely sensitive, selective and responsive, which can be used to replace more costly and tedious laboratory methods for monitoring a patient's blood for proteins, chemicals and pathogens. This FG has utilized high-density well-aligned carbon nanotubes, which are multi-walled and vertically aligned on a large area of substrates. We have a unique expertise in developing electrochemical multiwalled nanotubes, ordered nanotube arrays, chemically functionalized nanotubes, and conjugated polymers as nanosensors. We will build a team for further development of the nanosensor technology for cancer diagnosis (Project Co-ordinators: Prof Sheu Fwu-Shan and A/P Lim Chwee Teck). Developing Lab-on-a-Chip Devices This synergistic program will develop two fully integrated laboratory-on-a-chip devices for cancer diagnosis. The first contains numerous functional features such as indicators for physical parameters and reaction chambers for cell growth and separation at micro- and nano-scale to rapid identify cancer cells. Potential cancer cells can be delivered into the microfluidic device and possibly cultivated in-vitro followed by detection using various optical-based detection methods. Building Beads-Based Lab-on-a-Chip Devices The second is a beads-based lab-on-chip device to rapidly identify metabolites, genes and singlenucleotide-polymorphism (SNP) sites associated with specific cancers. The two lab-on-chip devices have several distinct advantages over the current cell culturing and detection methods, which include ease of use for cell culture and reaction, rapid hybridization and sensitive detection, and low cost for commercial interest (Project Co-ordinators: Prof Liu Wen-Tso and A/P Sheu Fwu-Shan). Methods Currently Used for Treating Cancer and Associated Problems The standard treatment for cancer has been surgery plus radiotherapy in the past decades. If cancer patients fail such a treatment, he/she has only less than 10% to be cured by other treatment such as chemotherapy, immunotherapy, and molecular therapy. Chemotherapy is one of the most effective treatments available for cancer and other diseases such as cardiovascular diseases and AIDS. The present status of chemotherapy, however, is far from being satisfactory. Its efficacy is limited and patients have to suffer from severe side effects. How Nanobiotechnology Might Help to Solve Problems Associated with Chemotherapy Treatments Nanobiotechnology may provide an ideal solution for the problems in the current regime of chemotherapy and promote a new concept of chemotherapy, which may include sustained, controlled and targeted chemotherapy; personalized chemotherapy; chemotherapy across various physiological drug barriers such the gastrointestinal (GI) barrier for oral chemotherapy and the blood-brain barrier (BBB) for treatment of brain tumors and other central nerve system (CNS) diseases; and eventually, chemotherapy at home. How Nanobiotechnology Will Change the Way That Drugs are Made Indeed nanobiotechnology, especially nanoparticle technology, will change the way we make drugs and the way we take drugs. Paclitaxel, one of the best antineoplastic drugs found from nature in the past decades, will be used as a prototype drug in this synergistic program due to its excellent therapeutic efficacy against a wide spectrum of cancers, and its great commercial success as one of the best sellers among various antineoplastic agents. Our preliminary results have shown by fluorescence microscopy and cell mortality experiment with HT-29 cells that paclitaxel formulated by Vitamin E TPGS-emulsified PLGA nanoparticles can be at least 18 times more effective than the free drug Taxol® after 24 hours of cell culture, and oral chemotherapy by nanoparticles seems feasible. Other Cancer Research Areas that this Project Will Explore We shall continue to be focused on our established strength which includes synthesis of co-polymers more friendly to anti-cancer drugs and molecular drugs (proteins and peptides), characterization and application of natural emulsifiers such as phospholipids, cholesterols and molecularly modified vitamins, surface medication techniques, enhanced molecular conjugation techniques and nanoparticle techniques. Our research will speed up to animal test and clinical trials (Project Co-ordinators: A/P Feng Si-Shen and Dr Zhang Yong). Gene Therapy, Targeted Gene Delivery and Gene Transfer Gene therapy will also be a focus of this synergistic program. Targeted gene delivery to selected cell types provides a means for highly specific gene expression. Improved efficiency of gene transfer could be achieved through enhancing the entry of gene vectors into the desired cells and reducing the uptake of the vectors by non-target cells. Developing Materials for Research into the Targeting of Cancer Gene Therapy We are developing chimeric peptides, containing a nucleic acid binding domain linked to a receptor-binding domain of neurotrophins, to target gene delivery vectors to tumor cells. These and other functional peptides are also tried to be conjugated to cationic polymer-based DNA vectors. The developed materials would hopefully form stable nanoparticles with DNA that are suitable for in vivo targeting of cancer gene therapy (Project Co-ordinators: A/P Wang Shu and A/P Feng Si-Shen). What is a Cell-Specific Promoter and How Does It Work? The second approach is to use a cell-specific promoter in a viral vector, which allows the control of specific gene expression in a selected cell type. Because of their cellular authentic sequences, the cell-specific promoter may reduce the chance of activating host cell defense machinery and are usually less sensitive to cytokine-induced promoter inactivation than viral promoters, thus improving the stability of gene expression. What is Small Interfering RNA (siRNA) Technology? The third approach involves small interfering RNA (siRNA) technology, which is currently emerging as a potentially useful method to develop highly specific double stranded RNA-based gene silencing therapeutic. The aim is to develop efficient and effective siRNA delivery systems for tumors in the central nervous system (Project Co-ordinators: A/P Wang Shu and A/P Sheu Fwu-Shan). The Role of Cellular and Molecular Biomechanics in Cancer Diagnosis Cellular and molecular biomechanics of cancer cells can be a fascinating area, which characterizes the rheological properties of mutant cancer cells and relates the measurable mechanical properties to their molecular basis. Changes in the rheological properties may provide useful information for cancer diagnosis and physical evidence to understand therapeutic mechanisms of various anti-cancer agents. Recent advances in experimental biomechanics have enabled direct and real-time mechanical probing and manipulation of single cells and molecules. Such methods are now capable of imposing and sensing forces and displacements with nano and picoscale resolutions. Experimental Methods and Tools that Will Be Used in this Research Project Our experimental techniques to probe single cells include micropipette aspiration, optical/laser traps and atomic force microscopy. Focus will be made on the original biochemical conditions of the cancerous cells, as well as drug treatment for which the mechanical properties of these cells can either increase or decrease, as compared to the healthy cell. Such changes in mechanical response with the underlying changes in molecular architecture as a consequence of disease development, and how that changes cell shape and mobility, can also be observed. Research Aims of the Nano Biomechanics Laboratory at the National University of Singapore Our Nano Biomechanics Laboratory has been well established in the area of nanomechanics of biological cells and molecules. It will focus its effort on investigating biomechanical responses to the progression of the disease state of cancer cells as well as the effects arising from treatment using anti-cancer agents/molecular drugs. (Project Co-ordinators: A/P Lim Chwee Teck and Dr Han Min-Yong) Research Grants Allocated and Partnership Working with Pharmaceutical Companies and Academic Institutions We have successfully obtained a few research grants from the Singapore Cancer Syndicate (SCS) and BMRC, A*STAR. We shall file more grant applications based on this synergistic program. We shall also contact pharmaceutical companies for industrial investment on this synergistic program. International collaboration with top universities and in the world will be widened and strengthened. |