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Maksym V Yezhelyev, Xiaohu Gao, Yun Xing, Ahmad Al-Hajj, Shuming Nie and Ruth M O’Regan- Emerging use of nanoparticles in diagnosis and treatment of breast cancer

Maksym V Yezhelyev, Xiaohu Gao, Yun Xing, Ahmad Al-Hajj, Shuming Nie and Ruth M O’Regan- Emerging use of nanoparticles in diagnosis and treatment of breast cancer

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http://oncology.thelancet.com
Vol 7 August 2006
657
ReviewEmerging use of nanoparticles in diagnosis and treatmentof breast cancer
Maksym V Yezhelyev, Xiaohu Gao, Yun Xing, Ahmad Al-Hajj, Shuming Nie, Ruth M O’Regan
The biological application of nanoparticles is a rapidly developing area of nanotechnology that raises newpossibilities in the diagnosis and treatment of human cancers. In cancer diagnostics, fluorescent nanoparticlescan be used for multiplex simultaneous profiling of tumour biomarkers and for detection of multiple genes andmatrix RNA with fluorescent in-situ hybridisation. In breast cancer, three crucial biomarkers can be detected andaccurately quantified in single tumour sections by use of nanoparticles conjugated to antibodies. In the nearfuture, the use of conjugated nanoparticles will allow at least ten cancer-related proteins to be detected on tinytumour sections, providing a new method of analysing the proteome of an individual tumour. Supermagneticnanoparticles have exciting possibilities as contrast agents for cancer detection in vivo, and for monitoring theresponse to treatment. Several chemotherapy agents are available as nanoparticle formulations, and have at leastequivalent effi cacy and fewer toxic effects compared with conventional formulations. Ultimately, the use of nanoparticles will allow simultaneous tumour targeting and drug delivery in a unique manner. In this review, wegive an overview of the use of clinically applicable nanoparticles in oncology, with particular focus on the diagnosisand treatment of breast cancer.
Introduction
Nanobiotechnology, defined as biomedical applicationsof nano-sized systems, is a rapidly developing areawithin nanotechnology. Nanomaterials, which measure1–1000 nm, allow unique interaction with biologicalsystems at the molecular level. They can also facilitateimportant advances in detection, diagnosis, andtreatment of human cancers and have led to a newdiscipline of nano-oncology.
1,2
Nanoparticles are beingactively developed for tumour imaging
 
in vivo, bio-molecular profiling of cancer biomarkers, and targeteddrug delivery. These nanotechnology-based techniquescan be applied widely in the management of differentmalignant diseases.Some breast cancers express protein biomarkers (eg,oestrogen receptor, progesterone receptor, and ERBB2)on which therapeutic decisions are made. Semiconductorfluorescent nanocrystals, such as quantum dots, havebeen conjugated to antibodies, allowing for simultaneouslabelling and accurate quantification of these targetproteins in one breast tumour section (figure 1).
3
Theuse of nanoparticles—not only quantum dots of differentsizes and emission spectra, but also gold-containingnanoparticles (ie, Raman probes)—will allow thesimultaneous detection and quantification of severalproteins on small tumour samples, which will ultimatelyallow the tailoring of specific anticancer treatment to anindividual patient’s specific tumour protein profile.
Theability to detect molecular targets simultaneously onindividual tumour samples could allow correlationbetween gene products and proteins in real time.
5
Inaddition, the effects of an individual treatment onexpression of the target protein can be monitored beforeand after treatment, and provide a rapid method tomeasure the effi cacy of a targeted therapy.Nanotechnological approaches (eg, nanocantileversand nanoprobes) are being actively investigated incancer imaging.
6
Nanoparticles coupled with cancer-specific targeting ligands can be used to image tumoursand detect peripheral metastases.
7
Supermagneticnanoparticles that have a metal core and arebioconjugated with antibodies against ERBB2 haveshown promising results for simultaneous imagingand targeting of breast cancers therapeutically in vivo.
8
 Moreover, nanoparticles conjugated to cancer-specificligands could be used in early identification of tumours,allowing early intervention with a chemopreventiveagent.Several nanotechnological approaches have been usedto improve delivery of chemotherapeutic agents tocancer cells with the goal of minimising toxic effects onhealthy tissues while maintaining antitumour effi cacy.
Lancet Oncol
2006; 7: 657–67Winship Cancer Institute,
(M V Yezhelyev MD,A Al-Hajj MD, R M O’Regan MD)
 and Department of BiomedicalEngineering
(Y Xing PhD,S Nie PhD)
,
 
Emory University,Atlanta, GA, USA; Departmentof Bioengineering, Universityof Washington, Seattle, WA,USA
(X Gao PhD)
; and GeorgiaInstitute of Technology,Atlanta, GS, USA
(S Nie)Correspondence to: DrRuth M O’Regan,Translational Breast CancerProgram, Winship CancerInstitute, 1701 Upper Gate Drive,Emory University, Atlanta,GA 30322, USA
roregan@emory.edu
OligonucleotideProtein adapterQuantumlotsRamanprobesMagneticnanoparticlesCadmium selenide fluorescent coreProtective Zinc sulphide layerCovering polymerOrganic layerAffinity peptideLinker moduleMagnetic coreGold or silver coreAntibodyDirect covalentbondReporter agentSilica coating
Figure 1:
Basic structure of inorganic nanoparticles
 
658
http://oncology.thelancet.com
Vol 7 August 2006
Review
Doxorubicin has been formulated with a liposomedelivery system into nanoparticle size (figure 2), whichmaintains the effi cacy of the drug and decreases cardiactoxic effects.
9,10
One of these delivery systems, pegylatedliposomal doxorubicin, is approved for treatment of refractory ovarian cancer and Kaposi’s sarcoma in theUSA. Nanoparticle albumin-bound (NAB) paclitaxelalso has greater effi cacy than conventional castor-oil-based paclitaxel with an improved safety profile,
11,12
andis approved in the USA for treatment of metastaticbreast cancer.The use of nanotechnology in cancer encompassesmany nanotechnological approaches, and it would beimpossible to cover these in a single review. We havetherefore focused this review on the emerging use of nanoparticles in breast cancer.
Types of biomedical nanoparticles
Although the number of different types of nanoparticlesis increasing rapidly, most can be classified into twomajor types: particles that contain organic molecules asa major building material (figure 1) and those that useinorganic elements, usually metals, as a core (figure 2).Liposomes, dendrimers, carbon nanotubes, emulsions,and other polymers are a large and well-establishedgroup of organic particles. Use of these organicnanoparticles has already produced exciting results.
13–19
 Liposomes are being used as vehicles for drug deliveryin different human tumours, including breast cancer.
13,14 
 Dendrimers, used in MRI as contrast agents, have aidedvisualisation of various pathological processes.
15,16
 Conjugated with pharmacological agents and targetingmolecules, organic nanovectors are potent vehicles fordrug delivery and selective imaging of different humancancers.
15–19
The structure, function, and biomedicalapplications of these organic nanoparticles have beenreviewed (table).
13–19
 Most inorganic nanoparticles share the same basicstructure—a central core that defines the fluorescence,optical, magnetic, and electronic properties of theparticle, with a protective organic coating on the surface(figure 1). This outside layer protects the core fromdegradation in a physiologically aggressive environmentand can form electrostatic or covalent bonds, or both,with positively charged agents and biomolecules thathave basic functional groups such as amines and thiols.Several research groups have successfully linkedfluorescent nanoparticles to peptides, proteins, andoligonucleotides (figure 1).
5,7,8,20,21
Quantum dots are fluorescent nanoparticles withsizes of 2–10 nm that contain a core of hundreds tothousands of atoms of group II and VI elements (eg,cadmium, technetium, zinc, and selenide) or group III(eg, tantalum) and V elements (eg, indium).
22,23
 Quantum dots containing a cadmium selenide core anda zinc sulphide shell, surrounded by a coating of acoordinating ligand and an amphiphilic polymer, aremost commonly used for biological application (figure1).
7,23
This structure enables quantum dots to emitpowerful fluorescence that differs in nature fromorganic dyes. Quantum dots can be tuned to emit atbetween 450 nm and 850 nm (ie, from ultraviolet tonear infrared) by changing the size or chemicalcomposition of the nanoparticle. This so-called quantumconfinement effect produces many quantum-dotcolours, which can be visualised simultaneously withone light source. Quantum dots emit narrowsymmetrical emission peaks with minimum overlapbetween spectra, allowing unique resolution of theirspectra and measurement of fluorescent intensity fromseveral multicolour fluorophores by real-timequantitative spectroscopy. These key advantages makeit possible to label multiple molecular targetssimultaneously by use of quantum dots both in vitroand in vivo.
3,7,23–25
However, use of quantum dots inimaging and therapeutics in vivo is limited by the toxiceffects of the heavy-metal core.
26
Surface-enhanced Raman scattering is anothersensitive method for spectroscopic detection of multipletargets.
27
Modern surface-enhanced Raman scatteringprobes typically contain a metal core of silver or gold foroptical enhancement, a reporter molecule for
Figure 2:
Basic structure of organic nanoparticlesStructureApplicationsRe
LiposomesSelf-assembled closed colloidstructures composed of lipid layersDrug delivery: anthracyclines, taxanes,vinca alkaloids, platinums, camphothecins;immunoliposomes: antiERBB2 conjugates13,14DendrimersGlobular macromolecules for which allbonds emerge radially from a centralfocal point with regular branchingpattern and repeated unitsDrug delivery: fluorouracil, methotrexate,doxorubicin, oestrogen; MRI; gene delivery15,16CarbonnanoparticlesCarbon-containing nanotubes Drug delivery; sentinel-node visualisation17,18
Table:
Clinical applications of organic nanoparticles in breast cancer
Polyethylene glycolDoxorubicinLipid membranePaclitaxelHuman albumin
 
http://oncology.thelancet.com
Vol 7 August 2006
659
Review
spectroscopic signature, and a silica shell for proteinconjugation (figure 1). When illuminated with a laserbeam, the reporter dye molecule produces a uniqueshift in the electromagnetic spectrum, which manifestsas several sharp peaks and give the characteristicfingerprint of the reporter.
28
Colloidal gold nanoparticleswith a size range of 55–60 nm can be optimised forsurface enhancement at 632–647 nm excitation. Thebenefit of using surface-enhanced Raman scatteringand nanoparticles in terms of selectivity and sensitivityhas previously been shown by the detection of ultra-lowconcentrations (ie, 10
⁴ mol/m³) of amfetamine sulfatein colloidal suspension.
29
 Supermagnetic nanoparticles contain a metal core(eg, iron, cobalt, or nickel) that is magnetically active,and are used as contrast enhancement agents toimprove the sensitivity of MRI. Magnetic particles,when coated with an organic outer layer, can also beconjugated to biomolecules and used as site-specificdrug-delivery agents for cancer treatment (figure 2).Iron-oxide-based magnetic materials have been usedwidely in clinical practice as magnetic resonance agentsand in studies of gene expression, angiogenesisimaging, and cellular traffi cking.
30,31
Metal nanoparticlesin combination with fluorescent active molecules canbe used for combined optical and magnetic imaging.
32
Diagnosis and imaging of breast cancer
Profiling of biomarkers
With the increasing use of targeted therapies in oncology,it is imperative that methods of molecular profiling areoptimised. The success of many targeted treatmentsdepends on the expression of specific proteins or genespresent in cancer cells. For example, in breast cancers,the level of hormone-receptor expression correlatesdirectly with the benefit of endocrine treatments, and thepresence of HER2 protein overexpression or geneamplification, or both, is a prerequisite for benefit fromthe monoclonal antibody, trastuzumab.
33–36
Immuno-histochemistry is the standard method of determiningthe expression of hormone receptors or HER2. Althoughimmunohistochemical methods combined with auto-mated image analysis can quantify precisely theexpression of these biomarkers in clinical breast-cancerspecimens, these systems are not widely available.
37
 Furthermore, the use of immunohistochemistry to detectproteins simultaneously on single tumour specimenscan be dicult for several reasons, including the need touse antibodies needing different antigen retrievalmethods. An assay that could accurately quantify severalcancer-related proteins simultaneously on single tumoursections or small tumour specimens could offer clearadvantages over standard immunohistochemicalmethods.Although several, even colocalised, targets can bevisualised by use of immunofluorescent stainingmethods with spectra-separation systems, the use of organic dye molecules such as fluorescent tags forantibodies has important limitations.
38
Quantum dotshave unique optical properties that can overcome somedrawbacks associated with conventional methods of biomolecular labelling. They have exceptionalphotostability, allowing the emission of fluorescent lightover a long time without a rapid decline in emission (ie,photobleaching).
7,20,39
The unique fluorescent emissionpeaks of quantum dots can be easily detected andquantified with spectrometry. Since their emissionspectrum depends on size, the peak wavelength of everycolour is known. Individual quantum dots can be linkedto different antibodies targeted to specific proteins,allowing spectra from multiple quantum dots conjugatedto different proteins to be detected simultaneously byspectroscopy.The level of fluorescent emission from theseconjugated nanoparticles correlates with expression of the protein.
3
The bright fluorescence of quantum dotsenables identification of targets in low levels in cancercells, resulting in increased sensitivity.
24,25
In addition,several studies
7,20,40
have shown exceptional specificity of quantum dots for labelling of molecular targets.Giepmans and colleagues
41
used multiple quantum dotsto detect molecular targets with high sensitivity andspecificity. They showed that quantum dots targeted tomicrotubules in fibroblasts suggested colocalisationwith the cytoskeleton, which was confirmed by electronmicroscopy. Because quantum dots have fluorescentproperties and are electron dense, they can bediscriminated optically by their emission wavelengthand physically by size during electron microscopy.These findings will allow quantum dots to be used asprobes for light microscopy and simultaneous
COOHAntibodyEDACSMCCAntibody fragments
    C     O     O    H
C   O   O   H   
      C     O     O      H
 C   O  O 
    C    O    O    H
   C  O  O   H
  C  O  O   H
NH
2
NH
2
H
2
N
AB
     N    H
    2
C   O   O   H   
      C     O     O      H
 N
2  
    N    H
    2
   C  O  O   H
  C  O  O   H
++
SHHSHSSH
N   H   
2   
    N    H
2
QuantumdotQuantumdotQuantumdotQuantumdot
Figure 3:
Methods for conjugating quantum dots to biomolecules
EDAC=ethyl-3-dimethyl-amino-propyl-carbodiimide. SMCC=succinimidyl-4-N-maleimidomethyl-cyclohexanecarboxylate. COOH=carboxyl group. NH2= amine group. SH=sulydryl group. (A) Traditional covalent crosslinkingchemistry with EDAC as catalyst. (B) Conjugation of antibody fragments to quantum dots via reduced sulphhydryl-amine coupling. Reproduced with permission from ref 22.

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