Nanotechnology: an evidence-based analysis.

OBJECTIVE: Due to continuing advances in the development of structures, devices, and systems with a length of about 1 to 100 nanometres (nm) (1 nm is one billionth of a metre), the Medical Advisory Secretariat conducted a horizon scanning appraisal of nanotechnologies as new and emerging technologies, including an assessment of the possibly disruptive impact of future nanotechnologies. The National Cancer Institute (NCI) in the United States proclaimed a 2015 challenge goal of eliminating suffering and death from cancer. To help meet this goal, the NCI is engaged in a concerted effort to introduce nanotechnology "to radically change the way we diagnose, treat and prevent cancer." It is the NCI's position that "melding nanotechnology and cancer research and development efforts will have a profound, disruptive effect on how we diagnose, treat, and prevent cancer." Thus, this appraisal sought to determine the systemic effects of nanotechnologies that target, image and deliver drugs, for example, with respect to health human resources, training, and new specialties; and to assess the current status of these nanotechnologies and their projected timeline to clinical utilization.

CLINICAL NEED: TARGET POPULATION AND CONDITION Cancer is a heterogeneous set of many malignant diseases. In each sex, 3 sites account for over one-half of all cancers. In women, these are the breast (28%), colorectum (13%) and lungs (12%). In men, these are the prostate (28%), lungs (15%), and the colorectum (13%). It is estimated that 246,000 people in Ontario (2% of the population) have been diagnosed with cancer within the past 10 years and are still alive. Most were diagnosed with cancer of the breast (21%), prostate (20%), or colon or rectum (13%). The number of new cancer cases diagnosed each year in Ontario is expected to increase from about 53,000 in 2001 to 80,000 in 2015. This represents more than a 50% increase in new cases over this period. An aging population, population growth, and rising cancer risk are thought to be the main factors that will contribute to the projected increase in the number of new cases. THE TECHNOLOGY BEING REVIEWED - MEDICAL ADVISORY SECRETARIAT DEFINITION OF NANOTECHNOLOGY: FIRST-GENERATION NANOTECHNOLOGIES: Early application of nanotechnology-enabled products involved drug reformulation to deliver some otherwise toxic drugs (e.g., antifungal and anticancer agents) in a safer and more effective manner. Examples of first-generation nanodevices include the following: liposomes;albumin bound nanoparticles;gadolinium chelate for magnetic resonance imaging (MRI);iron oxide particles for MRI;silver nanoparticles (antibacterial wound dressing); andnanoparticulate dental restoratives.First-generation nanodevices have been in use for several years; therefore, they are not the focus of this report. SECOND-GENERATION NANOTECHNOLOGIES: Second-generation nanotechnologies are more sophisticated than first- generation nanotechnologies, due to novel molecular engineering that enables the devices to target, image, deliver a therapeutic agent, and monitor therapeutic efficacy in real time. Details and examples of second-generation nanodevices are discussed in the following sections of this report.

REVIEW STRATEGY: The questions asked were as follows: What is the status of these multifunctional nanotechnologies? That is, what is the projected timeline to clinical utilization?What are the systemic effects of multifunctional nanodevices with integrated applications that target, image, and deliver drugs? That is, what are the implications of the emergence of nanotechnology on health human resources training, new specialties, etc.?The Medical Advisory Secretariat used its usual search techniques to conduct the literature review by searching relevant databases. Outcomes of interest were improved imaging, improved sensitivity or specificity, improved response rates to therapeutic agents, and decreased toxicity.

RESULTS: The search yielded 1 health technology assessment on nanotechnology by The Centre for Technology Assessment TA-Swiss and, in the grey literature, a technology review by RAND. These, in addition to data from the National Cancer Institute (United States) formed the basis for the conclusions of the review. With respect to the question as to how soon until nanotechnology is used in patient care, overall, the use of second-generation nanodevices, (e.g., quantum dots [QDs]), nanoshells, dendrimers) that can potentially target, image, and deliver drugs; and image cell response to therapy in real time are still in the preclinical benchwork stage. Table 1 summarizes the projected timelines to clinical utilization. Table 1:Summary of Timelines to Clinical Use*Organization/YearSecond-Generation NanodeviceEstimate of When Nanodevice Will be in Clinical UseNCI 2001Imaging/detection (e.g., QDs)Therapeutic (e.g., nanoshell)Combined (e.g., dendrimer)~2006-2016~2006-2016~2016-2020NCI 2004Imaging/detectionTherapeuticCombined~2009-2019~2009-2019~2019-2024RAND 2006Combinedunlikely before 2021Swiss 2003ImagingTherapeuticCombined~2005-2010~2008-2013~ 2010-2013*NCI refers to National Cancer Institute; QD, quantum dot.Medical Advisory Secretariat Estimated Timeline for Ontario Upon synthesizing the estimated timelines from the NCI, the Swiss technology assessment and the RAND reports (Figure 1), it appears that: the clinical use of separate imaging and therapeutic nanodevices is estimated to start occurring around 2010;the clinical use of combined imaging and therapeutic nanodevices is estimated to start occurring around 2020;changes in the way disease is diagnosed, treated and monitored are anticipated; andthe full (and realistic) extent of these changes within the next 10 to 20 years is uncertain.Figure 1:Medical Advisory Secretariat Estimated Timeline for the Clinical Use of Second-Generation Nanodevices in OntarioWith respect to the question on potential systemic effects of second-generation nanodevices (i.e., the implications of the emergence of these nanodevices on health human resources training, new specialties etc.), Table 2 summarizes the findings from the review. Table 2:Potential Systemic Effects Caused by Second Generation Nanodevices*ImagingTherapeuticCombined (Detect, Image, Treat, Monitor)Increased sensitivity and specificity of QDs or other nanodevices could lead to the replacement of existing technologies (e.g., PSA testing, mammogram).Sudden demand in use of MRI due to use of nanodevices that are activated in the presence of a magnetic field.Universal demand to detect cancer- how will patients be prioritized for this?Sudden demand in use of MRI due to use of nanodevices that are activated in the presence of a magnetic field.Cost: possibly more expensive than current screening modalities.Possibly more expensive than existing therapies (gold nanoshells)Many functions can be performed on one device → possibly faster, more cost-effective than individual devices.Report of results: possibly faster than existing technologies.Possibly faster determination of therapeutic efficacy (vs. existing technologies)Increase in life expectancy of population? Free-up beds in hospitals?Nanodevices may be able to pinpoint with more accuracy when cancer starts.Ethical question: when does disease start?Increased demand for imaging by people who are asymptomatic and concerned they may get cancer.Nano-radiologist or medical nano-oncologist provides treatment rather than conventional radiologists or medical oncologists.Creation of nano-nursing compared to conventional nursing.Nano-radiologist or medical nano-oncologist provides treatment, rather than conventional radiologists or medical oncologists.Creation of nano-nursing compared to conventional nursing.Uncertainty regarding how many "traditional" cancer radiologists/oncologists should be retained and trained.New branch of (nano) radiology compared to conventional radiology New/longer training in biochemistry and targeting ligands will be required by nanoradiologists.More training required for new nano-treatments Patient education - people may be concerned regarding the use of nanodevices inside their bodies.Longer time to specialize in medicine in order to use nanotechnology clinically?Insufficient number of dendrimer specialists to treat everyone with personalized dendrimersRestricted to specialized centres Possible in-house nanodevice production required to keep up with the demand for use.Will the same specialized centres that offer imaging also offer treatment?How many specialized centres will be required?Only specialized centres can perform this combined imaging/treatmentPossible nano-monitoring from patient home via wireless technology. This may free hospital beds for other patients.After imaging with nanodevices, specifically targeted therapeutic nanodevices may also be required for immediate treatment of the patient. Will both of these nanodevices be commercially available in sufficient quantities?Possible waiting time for preparation of appropriately targeted nanodevice after imaging (will a therapeutic nanodevice be immediately available?)Will a patient receive conventional treatment if there is a waiting period required to prepare the therapeutic nanodevice?Will there be a patient waiting time required for preparation of personalized dendrimers (hours, days, weeks after a patient sees a physician)?*MRI indicates magnetic resonance imaging; PSA, prostate-specific antigen; QD, quantum dot.

UNCERTAINTIES NOT ADDRESSED IN THE LITERATURE: The United States National Nanotechnology Initiative (NNI) funds a variety of research in the economic, ethical, legal, and cultural implications of the use of nanotechnology, as well as the implications for science, education and quality of life. There are many uncertainties that are sparsely or not addressed at all in the literature regarding second generation nanodevices. (ABSTRACT TRUNCATED)