cancer NANOTECHNOLOGY 

Going Small for Big Advances 

Using Nanotechnology to Advance 

Cancer Diagnosis, Prevention 

and Treatment 

U.S. DEPARTMENT OF 

HEALTH AND HUMAN SERVICES 

National Institutes of Health 

National Cancer Institute 

January 2004 

 

 

NaNotechNology aNd caNcer
 

To help meet the goal of eliminating death and suffering 

from cancer by 2015, the National Cancer Institute is engaged 

in efforts to harness the power of nanotechnology to 

radically change the way we diagnose, image, and treat 

cancer. Already, NCI programs have supported research 

Nanotechnology will change the very 

foundations of cancer diagnosis, treatment, 

and prevention. 

on novel nanodevices capable of one or more clinically 

important functions, including detecting cancer at its 

earliest stages, pinpointing its location within the body, 

delivering anticancer drugs specifically to malignant cells, 

and determining if these drugs are killing malignant cells. 

As these nanodevices are evaluated in clinical trials, researchers 

envision that nanotechnology will serve as multifunctional 

tools that will not only be used with any number of diagnostic 

and therapeutic agents, but will change the very foundations 

of cancer diagnosis, treatment, and prevention. 

cancer Nanotechnology 1 
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. 

2 
 

To harness the potential of nanotechnology in cancer, 

NCI is seeking broad scientific input to provide direction 

to research and engineering applications. In doing so, 

NCI will develop a Cancer Nanotechnology Plan. Drafted 

with input from experts in both cancer research and 

nanotechnology, the Plan (see pages 4 and 5) will guide 

To harness the potential of nanotechnology 

in cancer, NCI is seeking broad scientific input 

to provide direction to research and 

engineering applications. 

NCI in supporting the interdisciplinary efforts needed to 

turn the promise of nanotechnology and the postgenomics 

revolution in knowledge into dramatic gains in our ability 

to diagnose, treat, and prevent cancer. Though this quest 

is near its beginning, the following pages highlight some of 

the significant advances that have already occurred from 

bridging the interface between modern molecular biology 

and nanotechnology. 

cancer Nanotechnology 3 
 

 

developiNg a caNcer
 

NaNotechNology plaN
 

NCI’s Cancer Nanotechnology Plan will provide critical 

support for the field though extramural projects, intramural 

programs, and a new Nanotechnology Standardization 

Laboratory. This latter facility will develop important 

standards for nanotechnological constructs and devices that 

will enable researchers to develop cross-functional platforms 

that will serve multiple purposes. The laboratory will be a 

centralized characterization laboratory capable of generating 

technical data that will assist researchers in choosing which 

of the many promising nanoscale devices they might want 

to use for a particular clinical or research application. In 

addition, this new laboratory will facilitate the development 

of data to support regulatory sciences for the translation 

of nanotechnology into clinical applications. 

The six major challenge areas of emphasis include: 

Prevention and Control of Cancer 

•	 Developing nanoscale devices that can deliver cancer 

prevention agents 

•	 Designing multicomponent anticancer vaccines using 

nanoscale delivery vehicles 

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 

4 
 

 

•	 Developing “smart” collection platforms for 

simultaneous mass spectroscopic analysis of multiple 

cancer-associated markers 

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 

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 

Quality of Life Enhancement in Cancer Care 

•	 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 

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 

cancer Nanotechnology 5 
What is NaNotechNology?
 

Nanotechnology refers to the interactions of cellular and 

molecular components and engineered materials—typically 

clusters of atoms, molecules, and molecular fragments—at 

the most elemental level of biology. Such nanoscale objects— 

typically, though not exclusively, with dimensions smaller 

than 100 nanometers—can be useful by themselves or as 

part of larger devices containing multiple nanoscale objects. 

At the nanoscale, the physical, chemical, and biological 

properties of materials differ fundamentally and often 

Noninvasive access to the interior of a living cell 

affords the opportunity for unprecedented gains 

on both clinical and basic research frontiers. 

unexpectedly from those of the corresponding bulk 

material because the quantum mechanical properties of 

atomic interactions are influenced by material variations 

on the nanometer scale. In fact, by creating nanometerscale structures, it is possible to control fundamental 

characteristics of a material, including its melting point, 

magnetic properties, and even color, without changing 

the material’s chemical composition. 

Nanoscale devices and nanoscale components of larger 

devices are of the same size as biological entities. They are 

smaller than human cells (10,000 to 20,000 nanometers 

in diameter) and organelles and similar in size to large 

6 
biological macromolecules such as enzymes and receptors— 

hemoglobin, for example, is approximately 5 nm in diameter, 

while the lipid bilayer surrounding cells is on the order of 

6 nm thick. Nanoscale devices smaller than 50 nanometers 

can easily enter most cells, while those smaller than 20 

nanometers can transit out of blood vessels. As a result, 

nanoscale devices can readily interact with biomolecules 

on both the cell surface and within the cell, often in ways 

that do not alter the behavior and biochemical properties 

of those molecules. From a scientific viewpoint, the actual 

construction and characterization of nanoscale devices may 

contribute to understanding carcinogenesis. 

Noninvasive access to the interior of a living cell affords 

the opportunity for unprecedented gains on both clinical 

and basic research frontiers. The ability to simultaneously 

interact with multiple critical proteins and nucleic acids at 

the molecular scale should provide better understanding 

of the complex regulatory and signaling networks that 

govern the behavior of cells in their normal state and as 

they undergo malignant transformation. Nanotechnology 

cancer Nanotechnology 7 
 

 

provides a platform for integrating efforts in proteomics 

with other scientific investigations into the molecular 

nature of cancer by giving researchers the opportunity 

to simultaneously measure gene and protein expression, 

recognize specific protein structures and structural domains, 

and follow protein transport among different cellular 

compartments. Similarly, nanoscale devices are already 

proving that they can deliver therapeutic agents that 

can act where they are likely to be most effective, that 

is, within the cell or even within specific organelles. Yet 

despite their small size, nanoscale devices can also hold 

tens of thousands of small molecules, such as a contrast 

agent or a multicomponent diagnostic system capable of 

assaying a cell’s metabolic state, creating the opportunity 

for unmatched sensitivity in detecting cancer in its earliest 

stages. For example, current approaches may link a monoclonal 

antibody to a single molecule of an MRI contrast agent, 

requiring that many hundreds or thousands of this construct 

reach and bind to a targeted cancer cell in order to create a 

strong enough signal to be detected via MRI. Now imagine 

the same cancer-homing monoclonal antibody attached to 

a nanoparticle that contains tens of thousands of the same 

contrast agent—if even one such construct reaches and 

binds to a cancer cell, it would be detectable. 

8 
NaNotechNology aNd diagNostics 

Today, cancer-related nanotechnology research is proceeding 

on two main fronts: laboratory-based diagnostics and 

in vivo diagnostics and therapeutics. Nanoscale devices 

designed for laboratory use rely on many of the methods 

developed to construct computer chips. For example, 1–2 

nanometer-wide wires built on a micron-scale silicon grid 

can be coated with monoclonal antibodies directed 

against various tumor markers. With minimal Cancer cell 

sample preparation, substrate binding to even 

a small number of antibodies produces a 

measurable change in the device’s conductivity, 

leading to a 100-fold increase in sensitivity 

over current diagnostic techniques. 

Nanoscale cantilevers, constructed as 

part of a larger diagnostic device, can 

provide rapid and sensitive detection 

of cancer-related molecules. 

Antibodies 

Bent cantilever	 Antibodies 

with proteins 

10-1 1 10 102 104

Nanometers 

Water White blood Nanodevices

molecule cell cantilevers 

cancer Nanotechnology 9 
 

 

 

 

From Chad Mirkin, Northwestern University 

Step 2 

Sandwich captured target 

proteins with NP probes 

13 nm NPs for bio-bar-code PCR 

30 nm NPs for PCR-less method 

Step 3 

MMP probe separation 

and bar-code DNA 

dehybridization Bar-code DNA 

Magnetic 

field 

Step 4 

Polymerase 

chain reaction 

Step 4 

PCR-less detection 

of bar-code DNA from 

30 nm NP probes 

Step 5 

Chip-based detection 

of bar-code DNA for 

protein identification 

Target protein 

Step 1 

Target protein 

capture with 

MMP probes 

DNA-coated gold nanoparticles (NPs) form the basis of a system 

that also uses larger magnetic microparticles (MMPs) to detect 

attomolar (10-18) concentrations of serum proteins. In this case, 

a monoclonal antibody to prostate specific antigen (PSA) is 

attached to the MMP, creating a reagent to capture free PSA. 

A second antibody to PSA, attached to the NPs, is then added, 

creating a “sandwich” of the captured protein and two particles 

that is easily separated using a magnetic field. 

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. 

Researchers have also been developing a wide variety of 

nanoscale particles to serve as diagnostic platform devices. 

For example, DNA-labeled magnetic nanobeads have the 

potential to serve as a versatile foundation for detecting 

10 
From Shuming Nie, Emory University and Georgia Tech 

virtually any protein or nucleic acid with far more sensitivity 

than is possible with conventional methods now in use. 

If this proves to be a general property of such systems, 

nanoparticle-based diagnostics could provide the means 

of turning even the rarest biomarkers into useful diagnostic 

or prognostic indicators. 

Quantum dots, nanoscale 

crystals of a semiconductor 

material such as cadmium 

selenide, are another 

promising nanoscale tool 

for laboratory diagnostics. 

A product of the quest to 

develop new methods for 

harvesting solar energy, 

these coated nanoscale The color of a quantum dot 

depends on its size. These quantum semiconductor crystals act dots emit across the entire visible 

as molecular light sources spectrum even though all are 

whose color depends solely irradiated with white light. 

on particle size. When 

linked to an antibody 

or other molecule capable of binding to a substance 

of interest, quantum dots act like a beacon that lights 

up when binding occurs. 

Because of the multitude of colors with which they can 

emit light, quantum dots can be combined to create assays 

capable of detecting multiple substances simultaneously. In 

one demonstration, researchers were able to simultaneously 

measure levels of the breast cancer marker Her-2, actin, 

microfibril proteins, and nuclear antigens. 

cancer Nanotechnology 11 
 

 

 

 

 

NaNotechNology aNd caNcer therapy 

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, for example, should 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, which would 

greatly reduce or eliminate the often unpalatable side effects 

that accompany many current cancer therapies. Already, 

research has shown that nanoscale delivery devices, such 

as dendrimers (spherical, branched polymers), silica-coated 

micelles, ceramic nanoparticles, and cross-linked liposomes, 

can be targeted to cancer cells. This is done by attaching 

monoclonal antibodies or cell-surface receptor ligands that 

bind specifically to molecules found on the surfaces of cancer 

cells, such as the high-affinity folate receptor and luteinizing 

hormone releasing hormone (LH-RH), or molecules unique 

to endothelial cells that become co-opted by malignant cells, 

such as the integrin avb3. Once they reach their target, the 

nanoparticles are rapidly taken into cells. As efforts in 

proteomics and genomics uncover other molecules unique to 

cancer cells, targeted nanoparticles could become the method 

of choice for delivering anticancer drugs directly to tumor 

cells and their supporting endothelial cells. Eventually, 

it should be possible to mix and match anticancer drugs 

with any one of a number of nanotechnology-based delivery 

vehicles and targeting agents, giving researchers the opportunity 

to fine-tune therapeutic properties without needing to 

discover new bioactive molecules. 

12 
 

LH-RH 

20–50 nm 

Optical 

probe 

Silica 

shell 

Magnetic core 

Multifunctional 


nanoparticles can 


be targeted to 


cancer cells using 


receptor ligands. 


From Paras Prasad, State University of New York at Buffalo 

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. 

A good example from the biological world is a virus capsule, 

made from a limited set of proteins, each with a specific 

chemical functionality, that comes together to create a 

multifunctional nanodelivery vehicle for genetic material. 

In fact, at least one research group is using the empty RNA 

virus capsules from cowpea mosaic virus and flockhouse 

virus as potential nanodevices. The premise is that 60 copies 

cancer Nanotechnology 13 
of coat protein that assemble into a functional virus capsule 

offer a wide range of chemical functionality that could be 

put to use to attach homing molecules—such as monoclonal 

antibodies or cancer cell-specific receptor antagonists, and 

reporter molecules—such as magnetic resonance imaging 

(MRI) contrast agents, to the capsule surface, and to load 

therapeutic agents inside the capsule. 

While such work with naturally existing nanostructures 

is promising, chemists and engineers have already made 

substantial progress turning synthetic materials into 

multifunctional nanodevices. Dendrimers, 1- to 10-nanometer 

spherical polymers of uniform molecular weight made 

from branched monomers, are proving particularly adept 

at providing multifunctional modularity. In one elegant 

demonstration, investigators attached folate—which targets 

the high-affinity folate receptor found on some malignant 

cells, the indicator fluorescein, and either of the anticancer 

drugs methotrexate or paclitaxel to a single dendrimer. 

Both in vitro and in vivo experiments showed that this 

nanodevice delivered its therapeutic payload specifically to 

folate receptor-positive cells while simultaneously labeling 

these cells for fluorescent detection. Subsequent work, 

in which a fluorescent indicator of cell death was linked 

to the dendrimer, provided evidence that the therapeutic 

compound was not only delivered to its target cell but also 

produced the desired effect. Already, some dendrimer-based 

constructs are making their way toward clinical trials for 

treating a variety of cancers. 

Such multifunctional nanodevices, sometimes referred to 

as nanoclinics, may also enable new types of therapeutic 

14 
 

 

 

Contrast agent 

(X-ray, MRI) 

Cell death sensor 

Therapeutic 

Cancer cell 

targeting

From Nicolas Beeson, University of Michigan Center for Biologic Nanotechnology

Drug delivery 

indicator 

Dendrimers can serve as versatile nanoscale platforms 

for creating multifunctional devices capable of detecting 

cancer and delivery drugs. 

approaches or broader application of existing approaches 

to killing malignant cells. For example, silica-coated lipid 

micelles containing LH-RH as a targeting agent have been 

used to deliver iron oxide particles to LH-RH receptorpositive cancer cells. 

Once these so-called nanoclinics have been taken up by the 

target cell, they can not only be imaged using MRI, but 

can also be turned into molecular-scale thermal scalpels: 

applying a rapidly oscillating magnetic field causes the 

entrapped Fe2O3 molecules to become hot enough to kill the 

cell. The critical factor operating here is that nanoparticles 

can entrap 10,000 or more Fe2O3 molecules, providing both 

enhanced sensitivity for detection and enough thermal 

mass to destroy the cell. 

cancer Nanotechnology 15 
 

 From Raoul Kopelman and Martin Philbert, University of Michigan 

“Smart” dynamic nanoplatforms have the potential to change 

the way cancer is diagnosed, treated, and prevented. The 

outside of such “nanoclinics” could be decorated with a tumorhoming monoclonal antibody and coated with polyethylene 

glycol (PEG) to shield the device from immune system detection. 

The polymer matrix of such particles could be loaded with 

contrast agents, which would provide enhanced sensitivity for 

pinpointing tumor location within the body, and various types 

of therapeutic agents, such as reactive oxygen-generating 

photodynamic sensitizers that would be activated once the 

particle detected a malignant cell. 

Photosensitizers used in photodynamic therapy, in which 

light is used to generate reactive oxygen locally within tumors, 

have also been entrapped in targeted nanodevices. The next 

step in this work is to also entrap a light-generating system, 

such as the luciferin-luciferase pair, in such a way as to trigger 

light production only after the nanoparticles have been taken 

16 
17 

up by a targeted cell. If successful, such an approach would 

greatly extend the usefulness of photodynamic therapy 

to include treatment of tumors deep within the body. 

Such multifunctional nanodevices hold out the possibility 

of radically changing the practice of oncology, perhaps 

providing the means to survey the body for the first signs 

of cancer and deliver effective therapeutics during the 

earliest stages of the disease. Certainly, researchers envision 

a day when a smart nanodevice will be able to fingerprint a 

particular cancer and dispense the correct drug at the proper 

time in a malignant cell’s life cycle, making individualized 

platform technologies that can be mixed and matched 

with new targeting agents that will come from large-scale 

proteomics programs already in action and therapeutics 

both old and new. Accomplishing this goal, however, will 

require that engineers and biologists work hand in hand 

to combine the best of both of their worlds in the fight 

Targeting

Therapeutic

molecule(s)

Imaging

agent

Multifunctional

nanoplatform

Reporter

medicine a reality at the cellular level. 

An important aspect of biomedical 

nanotechnology research is that 

most systems are being designed 

as general platforms that can be 

used to create a diverse set of 

multifunctional diagnostic and 

therapeutic devices. 

With the focus on modularity 

and multifunctionality, one goal 

is to create and characterize 

against cancer. 

cancer Nanotechnology 
 

 

 

 

a p oWerful research eNabler
 From Michael Simpson, Oak Ridge National Laboratory 

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. 

An array of carbon nanotubes provides an addressable 

platform for probing intact, living cells. 

18 
From Karen Wooley, Washington University, St. Louis 

From Paul Trombley, University of Michigan CBN 

Nanotechnology research is generating a variety of constructs, 

giving cancer researchers great flexibility in their efforts to change 

the paradigm of cancer diagnosis, treatment, and prevention. 

Shown here are two such structures. On the left are highly stable 

nanoparticles containing a cross-linked hydrophilic shell and a 

hydrophobic interior. On the right are spherical dendrimers, which 

are of rigorously defined size based on the number of monomer 

layers used to create a particular dendrimer. Like most of the other 

nanoparticles being developed, these are easily manipulated, 

affording researchers the opportunity to add a variety of molecules 

to the surfaces and interiors of the nanoparticles. 

cancer Nanotechnology 19 
 

 

 

 

NatioNal NaNotechNology 

characterizatioN laboratory 

for caNcer research 

As part of its cancer nanotechnology program, the 

National Cancer Institute is establishing a national resource 

laboratory at its Frederick facility that will provide critical 

infrastructure support to this rapidly developing field. The 

National Nanotechnology Characterization Laboratory 

(NCL) will fill a major resource gap in biomedical 

nanotechnology by providing nanodevice assessment 

and standardization capabilities that many experts have 

identified as a critical requirement to rapidly integrating 

nanotechnology into the clinical realm. 

20 
In creating the NCL, NCI will provide a stable and standardized 

environment for intramural and extramural researchers to 

bring their nanodevices and nanomaterials for assessment 

and development. The laboratory will also serve as an 

incubator in which private and public sector research efforts 

could be coordinated, yielding new partnerships that would 

accelerate the translation of basic research into clinical advances.

 The basic functions carried out by the NCL will include: 

•	 GMP	synthesis	of	sizable	quantities	of	a	variety	

of nanoparticles and nanodevices; 

•	 Characterization	of	nanoparticles	and	devices;	

•	 Functionalization	of	nanoparticles;

•	 Development	of	tools	and	methods	for	characterizing	

both native and functionalized nanoparticles; 

•	 Creation	of	reference	standards	and	release	

specifications; and 

•	 Facilitation	of	testing	and	analysis	protocol	development	

that will speed the regulatory review of novel diagnostics, 


therapeutics, and prevention strategies that use 


nanoscale devices.
 

In addition, the laboratory will have the capability of 

performing preclinical toxicology, pharmacology, and efficacy 

testing of nanodevices created both by NCI intramural and 

extramural efforts as well as by the private sector. 

cancer Nanotechnology 21 
for additioNal iNformatioN oN NaNotechNology resources 

NCI Unconventional Innovations Program— 

http://otir.nci.nih.gov/tech/uip.html 

NCI Innovative Molecular Analysis Technologies Program— 

http://otir.nci.nih.gov/tech/imat.html 

NCI Fundamental Technologies for Biomolecular Sensors— 

http://otir.nci.nih.gov/tech/ftbs.html 

National Nanotechnology Initiative— 

http://www.nano.gov/ 

Understanding nanodevices— 

http://newscenter.cancer.gov/sciencebehind/nanotech/ 

nano01.htm 

Nanotechnology and cancer— 

http://www.cancer.gov/newscenter/nanotech 

The Institute of Nanotechnology— 

http://www.nano.org.uk/index.html 

CRADA Opportunities— 

http://ttb.nci.nih.gov/cradaopp.html 

22 

Office of Technology & Industrial Relations 

National Cancer Institute 

Building 31, Room 10A49 

31 Center Drive, MSC 2580 

Bethesda, MD 20892-2580 

Phone: (301) 496-1550 

Fax: (301) 496-7807 

E-mail: otir@mail.nih.gov 

Website: http://otir.nci.nih.gov/index.html 
Cowpea mosaic virus. From Marianne Manchester and M.G. Finn, Scripps Research Institute 
NIH Publication No 04-5489
 

Printed January 2004