cancer brochure 091609-508

8/8/2019 Cancer Brochure 091609-508

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cancer NANOTECHNOLOGY

Going Small or Big AdvancesUsing Nanotechnology to Advance

Cancer Diagnosis, Preventionand Treatment

U.S. DEPARTMENT OFHEALTH AND HUMAN SERVICESNational Institutes of HealthNational Cancer Institute

January 2004


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N aNo te ch No lo gy aN d c a N c e r

To help meet the goal o eliminating death and su eringrom cancer by 2015, the National Cancer Institute is engaged

in e orts to harness the power o nanotechnology toradically change the way we diagnose, image, and treat

cancer. Already, NCI programs have supported research

Nanotechnology will change the very

oundations o cancer diagnosis, treatment,

and prevention.

on novel nanodevices capable o one or more clinicallyimportant unctions, including detecting cancer at itsearliest stages, pinpointing its location within the body,

delivering anticancer drugs speci cally to malignant cells,and determining i these drugs are killing malignant cells.As these nanodevices are evaluated in clinical trials, researchersenvision that nanotechnology will serve as multi unctionaltools that will not only be used with any number o diagnosticand therapeutic agents, but will change the very oundationso cancer diagnosis, treatment, and prevention.

cancer Nanotechnology 1


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The advent o nanotechnology in cancer research couldnthave come at a more opportune time. The vast knowledgeo cancer genomics and proteomics emerging as a result o the Human Genome Project is providing critically important

details o how cancer develops, which, in turn, createsnew opportunities to attack the molecular underpinnings

o cancer. However, scientists lack the technological

innovations to turn promising molecular discoveries intobene ts or cancer patients. It is here that nanotechnologycan play a pivotal role, providing the technological powerand tools that will enable those developing new diagnostics,therapeutics, and preventives to keep pace with todaysexplosion in knowledge.

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To harness the potential o nanotechnology in cancer,NCI is seeking broad scienti c input to provide directionto research and engineering applications. In doing so,NCI will develop a Cancer Nanotechnology Plan. Dra ted

with input rom experts in both cancer research andnanotechnology, the Plan (see pages 4 and 5) will guide

To harness the potential o nanotechnology

in cancer, NCI is seeking broad scientifc input

to provide direction to research and

engineering applications.

NCI in supporting the interdisciplinary e orts needed toturn the promise o nanotechnology and the postgenomics

revolution in knowledge into dramatic gains in our abilityto diagnose, treat, and prevent cancer. Though this questis near its beginning, the ollowing pages highlight some o the signi cant advances that have already occurred rombridging the inter ace between modern molecular biologyand nanotechnology.



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d ev el op iN g a c a N c e rN a N o t e c h N o l o g y p l a N

NCIs Cancer Nanotechnology Plan will provide criticalsupport or the eld though extramural projects, intramuralprograms, and a new Nanotechnology StandardizationLaboratory. This latter acility will develop importantstandards or nanotechnological constructs and devices thatwill enable researchers to develop cross- unctional plat ormsthat will serve multiple purposes. The laboratory will be acentralized characterization laboratory capable o generatingtechnical data that will assist researchers in choosing whicho the many promising nanoscale devices they might wantto use or a particular clinical or research application. Inaddition, this new laboratory will acilitate the developmento data to support regulatory sciences or the translationo nanotechnology into clinical applications.

The six major challenge areas o emphasis include:

Prevention and Control o Cancer Developing nanoscale devices that can deliver cancer

prevention agents Designing multicomponent anticancer vaccines using

nanoscale delivery vehicles

Early Detection and Proteomics Creating implantable, bio ouling-indi erent molecular

sensors that can detect cancer-associated biomarkers that

can be collected or ex vivo analysis or analyzed in situ ,with the results being transmitted via wireless technologyto the physician

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Developing smart collection plat orms or

simultaneous mass spectroscopic analysis o multiplecancer-associated markers

Imaging Diagnostics Designing smart injectable, targeted contrast agents

that improve the resolution o cancer to the singlecell level

Engineering nanoscale devices capable o addressingthe biological and evolutionary diversity o the multiplecancer cells that make up a tumor within an individual

Multi unctional Therapeutics Developing nanoscale devices that integrate diagnostic

and therapeutic unctions Creating smart therapeutic devices that can control the

spatial and temporal release o therapeutic agents whilemonitoring the e ectiveness o these agents

Quality o Li e Enhancement in Cancer Care Designing nanoscale devices that can optimally deliver

medications or treating conditions that may arise overtime with chronic anticancer therapy, including pain,nausea, loss o appetite, depression, and di culty breathing

Interdisciplinary Training Coordinating e orts to provide cross-training in

molecular and systems biology to nanotechnologyengineers and in nanotechnology to cancer researchers

Creating new interdisciplinary coursework/degreeprograms to train a new generation o researchersskilled in both cancer biology and nanotechnology



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W h at i s N a N o t e c h N o l o g y ?

Nanotechnology re ers to the interactions o cellular andmolecular components and engineered materialstypicallyclusters o atoms, molecules, and molecular ragmentsatthe most elemental level o biology. Such nanoscale objectstypically, though not exclusively, with dimensions smallerthan 100 nanometerscan be use ul by themselves or aspart o larger devices containing multiple nanoscale objects.At the nanoscale, the physical, chemical, and biologicalproperties o materials di er undamentally and o ten

Noninvasive access to the interior o a living cell

a ords the opportunity or unprecedented gains

on both clinical and basic research rontiers.

unexpectedly rom those o the corresponding bulkmaterial because the quantum mechanical properties o

atomic interactions are infuenced by material variationson the nanometer scale. In act, by creating nanometer-scale structures, it is possible to control undamentalcharacteristics o a material, including its melting point,magnetic properties, and even color, without changingthe materials chemical composition.

Nanoscale devices and nanoscale components o largerdevices are o the same size as biological entities. They aresmaller than human cells (10,000 to 20,000 nanometersin diameter) and organelles and similar in size to large

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biological macromolecules such as enzymes and receptors

hemoglobin, or example, is approximately 5 nm in diameter,while the lipid bilayer surrounding cells is on the order o 6 nm thick. Nanoscale devices smaller than 50 nanometerscan easily enter most cells, while those smaller than 20nanometers can transit out o blood vessels. As a result,nanoscale devices can readily interact with biomoleculeson both the cell sur ace and within the cell, o ten in waysthat do not alter the behavior and biochemical properties

o those molecules. From a scienti c viewpoint, the actual

construction and characterization o nanoscale devices maycontribute to understanding carcinogenesis.

Noninvasive access to the interior o a living cell a ordsthe opportunity or unprecedented gains on both clinicaland basic research rontiers. The ability to simultaneouslyinteract with multiple critical proteins and nucleic acids atthe molecular scale should provide better understandingo the complex regulatory and signaling networks thatgovern the behavior o cells in their normal state and asthey undergo malignant trans ormation. Nanotechnology



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provides a plat orm or integrating e orts in proteomics

with other scienti c investigations into the molecularnature o cancer by giving researchers the opportunityto simultaneously measure gene and protein expression,recognize speci c protein structures and structural domains,and ollow protein transport among di erent cellularcompartments. Similarly, nanoscale devices are alreadyproving that they can deliver therapeutic agents thatcan act where they are likely to be most e ective, thatis, within the cell or even within speci c organelles. Yetdespite their small size, nanoscale devices can also holdtens o thousands o small molecules, such as a contrastagent or a multicomponent diagnostic system capable o assaying a cells metabolic state, creating the opportunity

or unmatched sensitivity in detecting cancer in its earlieststages. For example, current approaches may link a monoclonalantibody to a single molecule o an MRI contrast agent,requiring that many hundreds or thousands o this constructreach and bind to a targeted cancer cell in order to create astrong enough signal to be detected via MRI. Now imagine

the same cancer-homing monoclonal antibody attached toa nanoparticle that contains tens o thousands o the samecontrast agenti even one such construct reaches andbinds to a cancer cell, it would be detectable.

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N a N o t e c h N o l og y a N d d i a g N o s t i c s

Today, cancer-related nanotechnology research is proceedingon two main ronts: laboratory-based diagnostics andin vivo diagnostics and therapeutics. Nanoscale devicesdesigned or laboratory use rely on many o the methodsdeveloped to construct computer chips. For example, 12nanometer-wide wires built on a micron-scale silicon gridcan be coated with monoclonal antibodies directedagainst various tumor markers. With minimal Cancer cell

sample preparation, substrate binding to evena small number o antibodies produces ameasurable change in the devices conductivity,leading to a 100- old increase in sensitivityover current diagnostic techniques.

Nanoscale cantilevers, constructed aspart o a larger diagnostic device, canprovide rapid and sensitive detectiono cancer-related molecules.

Antibodies

Bent cantilever Antibodieswith proteins

10 -1 1 10 10 2 10 4

N a n o m e

t e r s

Water White blood Nanodevices molecule cell cantilevers



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F r om C h a d Mi r k i n ,N

or t h w e s t e r n U ni v e r s i t y

Step 2Sandwich captured target

proteins with NP probes

13 nm NPs or bio-bar-code PCR30 nm NPs or PCR-less method

Step 3MMP probe separationand bar-code DNAdehybridizationBar-code DNA

Magneticeld

Step 4Polymerasechain reaction

Step 4PCR-less detectiono bar-code DNA rom30 nm NP probes

Step 5Chip-based detectiono bar-code DNA orprotein identi cation

Target protein

Step 1Target proteincapture with

MMP probes

DNA-coated gold nanoparticles (NPs) orm the basis o a systemthat also uses larger magnetic microparticles (MMPs) to detectattomolar (10-18) concentrations o serum proteins. In this case,a monoclonal antibody to prostate speci c antigen (PSA) isattached to the MMP, creating a reagent to capture ree PSA.A second antibody to PSA, attached to the NPs, is then added,creating a sandwich o the captured protein and two particlesthat is easily separated using a magnetic eld.

Nanoscale cantilevers, microscopic, fexible beams resemblinga row o diving boards, are built using semiconductorlithographic techniques. These can be coated with moleculescapable o binding speci c substratesDNA complementaryto a speci c gene sequence, or example. Such micron-sizeddevices, comprising many nanometer-sized cantilevers, can

detect single molecules o DNA or protein.

Researchers have also been developing a wide variety o nanoscale particles to serve as diagnostic plat orm devices.For example, DNA-labeled magnetic nanobeads have thepotential to serve as a versatile oundation or detecting

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F r om S h umi n gN i e ,E m

or y U ni v e r s i t y

a n d G e or gi a T e c h

virtually any protein or nucleic acid with ar more sensitivity

than is possible with conventional methods now in use.I this proves to be a general property o such systems,nanoparticle-based diagnostics could provide the meanso turning even the rarest biomarkers into use ul diagnosticor prognostic indicators.

Quantum dots, nanoscalecrystals o a semiconductormaterial such as cadmiumselenide, are anotherpromising nanoscale tool

or laboratory diagnostics.A product o the quest to

develop new methods orharvesting solar energy,these coated nanoscale The color o a quantum dot

depends on its size. These quantumsemiconductor crystals actdots emit across the entire visible

as molecular light sources spectrum even though all arewhose color depends solely irradiated with white light.

on particle size. Whenlinked to an antibodyor other molecule capable o binding to a substanceo interest, quantum dots act like a beacon that lightsup when binding occurs.

Because o the multitude o colors with which they canemit light, quantum dots can be combined to create assayscapable o detecting multiple substances simultaneously. Inone demonstration, researchers were able to simultaneouslymeasure levels o the breast cancer marker Her-2, actin,micro bril proteins, and nuclear antigens.



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N aN ot ec hN ol og y aN dc a N c e r t h e r a p y

Nanoscale devices have the potential to radically changecancer therapy or the better and to dramatically increasethe number o highly e ective therapeutic agents. Nanoscaleconstructs, or example, should serve as customizable,targeted drug delivery vehicles capable o errying largedoses o chemotherapeutic agents or therapeutic genes intomalignant cells while sparing healthy cells, which wouldgreatly reduce or eliminate the o ten unpalatable side e ectsthat accompany many current cancer therapies. Already,research has shown that nanoscale delivery devices, suchas dendrimers (spherical, branched polymers), silica-coatedmicelles, ceramic nanoparticles, and cross-linked liposomes,can be targeted to cancer cells. This is done by attachingmonoclonal antibodies or cell-sur ace receptor ligands thatbind speci cally to molecules ound on the sur aces o cancercells, such as the high-a nity olate receptor and luteinizinghormone releasing hormone (LH-RH), or molecules uniqueto endothelial cells that become co-opted by malignant cells,such as the integrin a vb 3. Once they reach their target, thenanoparticles are rapidly taken into cells. As e orts inproteomics and genomics uncover other molecules unique tocancer cells, targeted nanoparticles could become the methodo choice or delivering anticancer drugs directly to tumorcells and their supporting endothelial cells. Eventually,it should be possible to mix and match anticancer drugs

with any one o a number o nanotechnology-based deliveryvehicles and targeting agents, giving researchers the opportunityto ne-tune therapeutic properties without needing todiscover new bioactive molecules.

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LH-RH

2050 nm

Opticalprobe

Silicashell

Magnetic coreMulti unctional nanoparticles can

be targeted to cancer cells using receptor ligands.

From Paras Prasad, State University of New York at Buffalo

On an equally unconventional ront, e orts are ocusedon constructing robust smart nanostructures that willeventually be capable o 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 e orts aremodularity and multi unctionality, i.e., creating unctionalbuilding blocks that can be snapped together and modi edto meet the particular demands o a given clinical situation.A good example rom the biological world is a virus capsule,made rom a limited set o proteins, each with a speci cchemical unctionality, that comes together to create amulti unctional nanodelivery vehicle or genetic material.

In act, at least one research group is using the empty RNAvirus capsules rom cowpea mosaic virus and fockhousevirus as potential nanodevices. The premise is that 60 copies



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o coat protein that assemble into a unctional virus capsule

o er a wide range o chemical unctionality that could beput to use to attach homing moleculessuch as monoclonalantibodies or cancer cell-speci c receptor antagonists, andreporter moleculessuch as magnetic resonance imaging(MRI) contrast agents, to the capsule sur ace, and to loadtherapeutic agents inside the capsule.

While such work with naturally existing nanostructuresis promising, chemists and engineers have already madesubstantial progress turning synthetic materials intomulti unctional nanodevices. Dendrimers, 1- to 10-nanometerspherical polymers o uni orm molecular weight made

rom branched monomers, are proving particularly adept

at providing multi unctional modularity. In one elegantdemonstration, investigators attached olatewhich targetsthe high-a nity olate receptor ound on some malignantcells, the indicator fuorescein, and either o the anticancerdrugs methotrexate or paclitaxel to a single dendrimer.Both in vitro and in vivo experiments showed that this

nanodevice delivered its therapeutic payload speci cally toolate receptor-positive cells while simultaneously labeling

these cells or fuorescent detection. Subsequent work,in which a fuorescent indicator o cell death was linkedto the dendrimer, provided evidence that the therapeuticcompound was not only delivered to its target cell but also

produced the desired e ect. Already, some dendrimer-basedconstructs are making their way toward clinical trials ortreating a variety o cancers.

Such multi unctional nanodevices, sometimes re erred toas nanoclinics, may also enable new types o therapeutic

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Contrast agent(X-ray, MRI)

Cell death sensor

TherapeuticCancer celltargeting

F r omN i c ol

a s B e e s on , U ni v e r s i t y

of Mi c h i g a n

C e n t e r f or B i ol o gi c N

a n o t e c h n ol o g y

Drug deliveryindicator

Dendrimers can serve as versatile nanoscale plat ormsor creating multi unctional devices capable o detecting

cancer and delivery drugs.

approaches or broader application o existing approachesto killing malignant cells. For example, silica-coated lipidmicelles containing LH-RH as a targeting agent have been

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

Once these so-called nanoclinics have been taken up by thetarget cell, they can not only be imaged using MRI, butcan also be turned into molecular-scale thermal scalpels:applying a rapidly oscillating magnetic eld causes theentrapped Fe 2O 3 molecules to become hot enough to kill thecell. The critical actor operating here is that nanoparticlescan entrap 10,000 or more Fe 2O 3 molecules, providing bothenhanced sensitivity or detection and enough thermalmass to destroy the cell.



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F r omR a o ul K o p e l m

a n a n d M

a r t i nP h i l b e r t , U ni v e r s i t y

of Mi c h i g a n

Smart dynamic nanoplat orms have the potential to changethe way cancer is diagnosed, treated, and prevented. Theoutside o such nanoclinics could be decorated with a tumor-homing monoclonal antibody and coated with polyethyleneglycol (PEG) to shield the device rom immune system detection.The polymer matrix o such particles could be loaded withcontrast agents, which would provide enhanced sensitivity orpinpointing tumor location within the body, and various typeso therapeutic agents, such as reactive oxygen-generatingphotodynamic sensitizers that would be activated once theparticle 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 nextstep in this work is to also entrap a light-generating system,such as the luci erin-luci erase pair, in such a way as to triggerlight production only a ter the nanoparticles have been taken

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up by a targeted cell. I success ul, such an approach would

greatly extend the use ulness o photodynamic therapyto include treatment o tumors deep within the body.

Such multi unctional nanodevices hold out the possibilityo radically changing the practice o oncology, perhapsproviding the means to survey the body or the rst signso cancer and deliver e ective therapeutics during theearliest stages o the disease. Certainly, researchers envisiona day when a smart nanodevice will be able to ngerprint aparticular cancer and dispense the correct drug at the propertime in a malignant cells li e cycle, making individualized

plat orm technologies that can be mixed and matchedwith new targeting agents that will come rom large-scale

proteomics programs already in action and therapeuticsboth old and new. Accomplishing this goal, however, willrequire that engineers and biologists work hand in handto combine the best o both o their worlds in the ght

Targeting

Therapeutic molecule(s)

Imaging agent

Multifunctional nanoplatform

Reporter

medicine a reality at the cellular level.

An important aspect o biomedicalnanotechnology research is thatmost systems are being designedas general plat orms that can beused to create a diverse set omulti unctional diagnostic andtherapeutic devices.

With the ocus on modularityand multi unctionality, one goalis to create and characterize

against cancer.

cancer Nanotechnology


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a p o We r f u l r e s e a r c h e N a b l e r

F r omMi c h a e l S i m

p s on , O a k R i d g e N

a t i on a l L a b or a t or y

Nanotechnology is providing a critical bridge betweenthe physical sciences and engineering, on the one hand,and modern molecular biology on the other. Materialsscientists, or example, are learning the principles o thenanoscale world by studying the behavior o biomolecules andbiomolecular assemblies. In return, engineers are creatinga host o nanoscale tools that are required to develop thesystems biology models o malignancy needed to betterdiagnose, treat, and ultimately prevent cancer. In particular,biomedical nanotechnology is bene ting rom the combinede orts o scientists rom a wide range o disciplines, inboth the physical and biological sciences, who togetherare producing many di erent types and sizes o nanoscaledevices, each with its own use ul characteristics.

An array o carbon nanotubes provides an addressableplat orm or probing intact, living cells.

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F r omK

a r e nW

o ol e y ,W a s h i n g t on U ni v e r s i t y

, S t .L o ui s

F r omP a ul T r om

b l e y , U ni v e r s i t y

of Mi c h i g a n

C B N

Nanotechnology research is generating a variety o constructs,giving cancer researchers great fexibility in their e orts to changethe paradigm o cancer diagnosis, treatment, and prevention.Shown here are two such structures. On the le t are highly stablenanoparticles containing a cross-linked hydrophilic shell and ahydrophobic interior. On the right are spherical dendrimers, whichare o rigorously de ned size based on the number o monomerlayers used to create a particular dendrimer. Like most o the othernanoparticles being developed, these are easily manipulated,a ording researchers the opportunity to add a variety o moleculesto the sur aces and interiors o the nanoparticles.



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N a t i oNa l N a N o t e c h N o l o g yc h a r a c t e r i z a t i o N l abo ra to ryf o r c a N c e r r e s e a r c h

As part o its cancer nanotechnology program, theNational Cancer Institute is establishing a national resourcelaboratory at its Frederick acility that will provide criticalin rastructure support to this rapidly developing eld. TheNational Nanotechnology Characterization Laboratory(NCL) will ll a major resource gap in biomedicalnanotechnology by providing nanodevice assessmentand standardization capabilities that many experts haveidenti ed as a critical requirement to rapidly integratingnanotechnology into the clinical realm.

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f o r a d d i t i o N a l i N f o r m a t i o No N N a N o t e c h N o l o g y r e s o u r c e s

NCI Unconventional Innovations Programhttp://otir.nci.nih.gov/tech/uip.html

NCI Innovative Molecular Analysis Technologies Programhttp://otir.nci.nih.gov/tech/imat.html

NCI Fundamental Technologies or Biomolecular Sensorshttp://otir.nci.nih.gov/tech/ tbs.html

National Nanotechnology Initiative

http://www.nano.gov/

Understanding nanodeviceshttp://newscenter.cancer.gov/sciencebehind/nanotech/ nano01.htm

Nanotechnology and cancerhttp://www.cancer.gov/newscenter/nanotech

The Institute o Nanotechnologyhttp://www.nano.org.uk/index.html

CRADA Opportunitieshttp://ttb.nci.nih.gov/cradaopp.html

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O ce o Technology & Industrial RelationsNational Cancer InstituteBuilding 31, Room 10A4931 Center Drive, MSC 2580

Bethesda, MD 20892-2580

Phone: (301) 496-1550Fax: (301) 496-7807

E-mail: [email protected]: http://otir.nci.nih.gov/index.html


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C ow p e a m

o s a i c v i r u s .F r omM

a r i a nn e M

a n c h e s t e r a n d M. G.F i nn , S c r i p p s R e s e a r c h I n s t i t u t e


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cancer brochure 091609-508

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