Nanotechnology offers the potential for new approaches to detecting, treating, and preventing cancer. To determine the current status of the cancer nanotechnology field and the optimal path forward, the National Cancer Institute's Alliance for Nanotechnology in Cancer held three strategic workshops, covering the areas of in vitro diagnostics and prevention, therapy and post-treatment, and in vivo diagnosis and imaging. At each of these meetings, a wide range of experts from academia, industry, the nonprofit sector, and the U.S. government discussed opportunities in the field of cancer nanotechnology and barriers to its implementation. Cancer Res; 70(11); 4265–8. ©2010 AACR.
Cancer is one of the most pressing public health concerns of the 21st century. The statistics are daunting; it was projected that 550,000 people would die of cancer and that another 1.4 million would be diagnosed with the disease in 2009 in the United States alone. Five years ago, the National Cancer Institute (NCI) initiated the NCI Alliance for Nanotechnology (1), in hopes of fostering revolutionary new ways to approach cancer research and care. Nanomaterials have the potential to deliver drugs directly to cancerous tissues and to open up entirely new modalities of cancer therapy. Nanotechnology-enhanced microfluidic devices can increase sensitivity and multiplexing capability for cancer-marker identification and detection.
The first nanotechnology-based constructs for cancer care are already on the market, including liposomal doxorubicin (DOXIL, Centocor Ortho Biotech Products L.P.) and albumin-bound paclitaxel (Abraxane, Abraxis Bioscience). Similarly, diagnostic and therapeutic monitoring techniques are benefiting from nanotechnology. New assays using microfluidic-based microarrays are being used for genomic and proteomic analysis of cancerous samples, whereas novel nanoparticle-based contrast agents and molecular imaging approaches are entering clinical trials. Most nanotechnology tools currently in development aim to improve diagnostic sensitivity and specificity, or to increase the therapeutic index for established chemotherapeutic drugs via selective delivery to cancerous tissue. These tools are advancing cancer research and gradually moving toward the clinic, but are still more evolutionary than revolutionary. The identification of new areas of impact and development of novel nanotherapeutics could make the field of cancer nanotechnology more significant and powerful.
To assess the status of the field and provide guidance for future development, the NCI convened three one-day strategic workshops around the following topics:
Workshop I: In vitro Diagnostics and Prevention, February 20, 2008
Workshop II: Therapy and Post-Treatment, March 6, 2008
Workshop III: In vivo Diagnosis and Imaging, March 28, 2008
Participants were asked to consider what the most important goals for cancer research should be for the next 5 or 10 years, how nanotechnology can address these goals, and what barriers exist to the integration of nanotechnology and oncology. A summary of discussions from the workshops is presented here.
In vitro Diagnostics and Prevention Workshop
This workshop hosted presentations by Steven Rosen, MD (Northwestern University, Evanston, IL) and Gregg Shipp, MD, PhD (Nanosphere, Inc., Northbrook, IL) on clinical needs in oncology and David Walt, PhD (Yale University, New Haven, CT) and Paul Yager, PhD (University of Washington, Seattle, WA) on technological opportunities and challenges. The speakers discussed the limitations of current cancer-screening technologies: insufficient sensitivity and specificity to detect precancerous conditions or early-stage cancer with a low rate of false positives; inability to determine tumor stage or type; and high cost. They suggested alternative cancer indicators, including constitutive or stimulated proteins, peptides, anomalous cells in fluids or tissues, cell surface markers, genomic or proteomic signatures, and inflammation markers. Ideally, these indicators would distinguish between cancer types and stages and characterize immune response. Technical challenges to the development of these markers include protein heterogeneity, nonspecific binding, lack of good capture agents for cells and molecules, and the expense and difficulty of genomic sequencing.
It was agreed that single molecule or cell measurements are stochastic and potentially unrepresentative, making measurement of multiple markers necessary for reliable diagnosis at early stages. Nanotechnology-based sensors using quantum dots of multiple colors, Raman probes with distinct spectra, nanoparticle arrays, and nanoscale cantilevers are capable of the high-throughput, multiplexed screening these measurements would require. Improvements in genomic sequencing due to nanotechnology were also predicted (2), enabling recognition of cancer-specific genes, rapid sequencing of large and heterogeneous samples, and in depth profiling of single cells. Enhanced biomarker detection should also result in the discovery and validation of new cancer signatures.
A lively discussion resulted from a suggestion by Dr. Walt that the detection of very early-stage disease may be undesirable and lead to unnecessary treatment of lesions that would otherwise be destroyed by the innate immune system. The participants reached a clear consensus in favor of detection at the earliest possible stage.
The speakers also expressed a need for technologies that monitor tumor progression and recurrence, as well as delivery and bioavailability of administered chemotherapeutics and therapeutic efficacy. Dr. Shipp discussed early results from trials of a biobarcode assay that uses oligonucleotide-labeled gold nanoparticles to monitor PSA levels in patients following radical prostatectomy; the nanoparticle labeling results in inherent signal amplification. The new assay allows recognition of rising PSA levels as much as 2 years earlier than standard enzyme-linked immunosorbent assay (3), so that postsurgical disease management can be guided by knowledge of a patient's low or high risk of recurrence.
During working group discussions, participants proposed that highly sensitive and specific multiplexed nano-enabled detection technology would enable speedier marker validation; development of new marker types (e.g., cellular metabolic signatures, anoxia, and necrosis); and better characterization of tumor heterogeneity (e.g., tumor cell subset and immune cell and cancer stem cell recognition). The working groups also made recommendations for technology development, including the following:
Devices for single-cell analysis of circulating tumor cells
Microfluidics or nanopore-based technologies to produce a $1,000 genome
New diagnostics using unprocessed bodily fluids, (e.g., blood, serum)
Synthetic antibodies with superior affinity, specificity, and stability (4)
Participants also raised several technical issues affecting the development of reliable in vitro diagnostics: variability in biospecimen collection and preparation procedures, which complicate marker and device validation; poor understanding of molecular recognition processes; and uncertainty about how to best characterize disease states using biomarkers, such as static measurement versus dynamic tracking of markers, marker concentration versus absolute number versus binding affinity measurement, and marker multivalency. Binding to inert surfaces and nonspecific binding were considered of particular concern with nanoscale materials, which have large, high energy surfaces.
Therapy and Post-Treatment Workshop
In this workshop, David Parkinson, MD (Nodality, Inc., San Francisco, CA); James J. Baker, MD (University of Michigan, Ann Arbor, MI) presented clinical needs in oncology; Naomi Halas, PhD (Rice University, Houston, TX) and Joseph DeSimone, PhD (University of North Carolina, Chapel Hill, NC) presented clinical applications of nanotechnology.
Currently, most new anticancer drugs fail in clinical trials, or offer only marginal improvements to the standard of care. Dr. Parkinson suggested that in many of these trials, some patients experienced a strong benefit from the tested drugs, but the trials failed because most patients experienced no effect. This result is due to our poor comprehension of the complexity of cancer and interpatient heterogeneity, including variations in cell-signaling pathways, tumor microenvironment, and patient metabolism. The key question to be answered is what level of biological characterization is sufficient to handle this heterogeneity and match therapy to patient. There also needs to be a better understanding of the time progression of cancer, if it is to be managed as a chronic disease. Many other drugs fail in trials owing to unacceptable toxicity; nanoformulations that enable targeted tumor delivery with a corresponding decrease in side effects could rehabilitate these drugs.
Dr. Halas spoke of the intrinsic therapeutic potential of nanomaterials. Gold nanoshells can convert infrared light into heat at tumor sites, killing cancerous cells, as demonstrated by preclinical studies by Lal and colleagues (5). The FDA has approved clinical trials of this system in head and neck cancers. Plasmonic nanoparticles can also function as contrast agents, raising the possibility of a multifunctional nanoparticle platform combining therapy and monitoring.
However, issues of poor biodistribution and unknown toxicity must be addressed before nanomaterials can be clinically translated. Studies using highly uniform particle replication in nonwetting templates (PRINT) nanoparticles invented at the University of North Carolina indicate that biodistribution and cellular uptake of nanoparticles depend on the nanoparticle size, shape, deformability, and surface chemistry, but the reasons are poorly understood (6). There is also little understanding of how nanoparticles access the cell interior, complicating efforts to target drugs to intracellular compartments. The role and importance of targeting agents, (e.g., peptides, oligonucleotides, and antibodies) in delivering nanoparticles to cells and tissue must also be understood and compared with mechanistic effects, (e.g., enhanced retention and permeability of nanomaterials in leaky tumor vasculature).
In discussions following the presentations, participants identified several additional areas in which nanotechnology could affect clinical cancer practices in the next 5 to 10 years. Successful development of the rapid, multiplexed biomarker detection systems discussed in the previous section would lead to more rational and effective tumor stratification and therefore treatment choice. The ability to inexpensively collect large data sets of cancer markers across individuals and disease stages should also promote a better understanding of basic cancer biology and heterogeneity, resulting in more predictive models of cancer growth and patient response, including dormancy and metastasis. Personalized treatment regimes could then be constructed by combining the enhanced data collection and cancer models garnered through these detection systems. Highly tumor-specific targeting ligands could enhance diagnostic imaging, drug delivery, and in vivo monitoring of treatment response. Specific areas recommended for development included the following:
Cell surface-targeting ligands
In situ drug release from nanocarriers, triggered externally (e.g., plasmonic heating) or chemically (e.g., proteolytic peptide cleavage)
Combination therapies, (e.g., nanoparticle hyperthermia and drug delivery)
Multifunctional nanoplatforms, (e.g., liposomes encapsulating imaging agents and drugs or small interfering RNA [siRNA])
Another serious barrier to clinical development discussed is the lack of animal models that simulate human cancers. Most nanotherapeutic delivery exploits tumor structure, making appropriate models indispensible to evaluation of therapeutic efficacy. Unfavorable host immune and cellular response to nanomaterials, the mechanisms of which are poorly understood, must also be resolved before nanomaterials can be clinically useful.
In vivo Diagnosis and Imaging Workshop
In this workshop, James Olson, MD, PhD (Fred Hutchinson Cancer Research Center, Seattle, WA), Shimon Weiss, PhD (University of California, Los Angeles, CA), and Renata Pasqualini, PhD (University of Texas M.D. Anderson Cancer Center, Houston, TX) presented wish lists of desired cancer-imaging capabilities, surveyed promising nanotechnologies for imaging applications, and outlined the gaps between technology development and clinical application. Oncologists wish they had sufficient spatial resolution and molecular recognition abilities to detect very early-stage tumors, diagnose tumor type, and define metastases without surgery or pathology. This detailed imaging information could then be used to guide tumor and lymph node removal using intra-operative imaging or to track drug delivery and response in disease sites. This information could also be used to identify emerging resistance to chemotherapy. Dr. Olson suggested that amplification of signal from rare events, such as mitosis and anaplasia, could be used to differentiate diseased from healthy tissue, and that recognition of cellular differences, such as open versus closed chromatin, could be used to distinguish tumor types. Other diagnostically useful measures suggested were differences in the ratio of the nucleus to the cytoplasm in suspected tumors, differences in oxygen tension, pH differences, heterogeneity, and specific tumor markers.
Participants recognized the opportunity afforded by nanotechnology to do rapid, multiplexed molecular imaging in multiple modalities. If nanoprobes targeted to multiple markers could accumulate at the tumor and be detected using MRI, PET, and/or near-infrared imaging, the information could be combined to noninvasively diagnose tumor type and stage. Additional targeting to recognize multiple cell types (e.g., healthy, tumor, stem) or activities could give a complex picture of tumor microenvironment and metabolism and track tumor growth and therapeutic response. Nanoparticles coated with enzymatically or pH-sensitive peptides that experience aggregation, fluorescent quenching, or some other measureable signal change in response to peptide activation by tumor cells are already being explored for this type of imaging. Dr. Weiss suggested combining these probes with implantable devices, themselves recognizable by MRI, that conduct detailed molecular analyses of tumor tissue before, during, and after therapy (7). Deep-tissue imaging can also be achieved using fiber optics to access and illuminate targets that have previously been targeted with optically active nanomaterials, (e.g., quantum dots or Raman spectroscopy tags).
One promising avenue of research discussed by Dr. Pasqualini is the development of organ-specific and angiogenesis-related vascular ZIP codes (8) that enable region- or activity-based targeting strategies. This technique can be used to map molecular diversity and target accessible tumor receptors that can internalize and accumulate nanoparticles, increasing image signal. As an example, Dr. Pasqualini described a bioinorganic nanoparticle that binds to a lung vascular endothelial receptor and that may provide a predictive tool for drug response on the basis of imaging data (9).
To attain these ambitious goals, workshop participants identified several necessary developments. Existing imaging strategies must be quantified so that findings across centers can be compared and the effects of nanotechnology on imaging capabilities measured. A reasonable number of targets for imaging must be determined for development, as well as measures of therapeutic efficacy in addition to apoptosis, and automated image analysis software will be necessary to make meaningful sense of the data collected. There is also a pressing need for a battery of in vitro and in vivo tests to develop “go–no go” criteria for nanoparticles for in vivo use. Toxicity and targeting efficacy standards must be established. During discussions, participants also identified several specific technologies as being ready for development, including the following:
Automated, microfluidics-based imaging probe synthesis (10)
Carbon nanotube-based X-ray imaging CT scanners
Nanomaterials with increased relaxivities for magnetic resonance–based imaging
Nanoparticle contrast agents with external activation of therapeutic effect
Substitution of a PET-suitable isotope into an approved nanoparticle-based therapeutic for biodistribution studies
A national facility representing good manufacturing practice for scaling up nanoparticle production
These applications require development of suitable cancer biomarkers and targeting ligands, as well as tools to monitor and evaluate nanomaterial pharmacokinetics and cellular interactions in vivo. Studies are also required to determine the lower limits of tumor size that are detectable using in vivo imaging.
Workshop participants believed that nanotechnology applied to clinical oncology practice has the potential to better monitor therapeutic efficacy, provide novel methods for detecting and profiling early-stage cancers, and enable surgeons to delineate tumor margins and sentinel lymph nodes. The field is well positioned to provide improved methods for imaging and staging cancers and to more effectively deliver therapeutics in a targeted manner to tumors. However, nanotechnology-based cancer therapies and diagnostics need to pass several critical tests before the future of the field is assured. These tests include successful in vivo delivery of a targeted therapeutic, establishing viability of both targeting chemistry and nanomaterial pharmacokinetics, and deployment of a multiplexed in vitro diagnostic for cancer, establishing biomarker and capture agent validity and device design integrity.
Ultimately, if nanotechnology researchers can establish methods to detect tumors at a very early stage, prior to vascularization and metastasis, cancer will become a disease amenable to complete cure via surgical resection. The impact on the disease survival rates and disease management expenditures could be exceedingly high.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
We thank Capital Consulting Corporation, especially Amy S. Rabin and Jennifer Kostiuk, for organizing these strategic workshops.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Grant Support: This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E.