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Nanoscience is the study of fundamental prin-ciples of molecules and structures with atleast one dimension roughly between 1-

100nm [1]. Nanotechnology is the manipulation ofmatter in dimensions <100nm, and involves buildingthings one atom at a time to eventually lead todevices with unprecedented capabilities. It is basedon the fact that the properties of matter significantlychange at these small sizes in comparison to the bulkform. These unique properties can then be utilised fora vast number of applications that would not havebeen otherwise possible. The concept of nanotech-nology was first introduced in 1959 by a PhysicsNobel Laureate Richard Feynman [2]. The termnanotechnology was first defined by Professor NorioTaniguchi in 1974 as: ‘Nanotechnology mainlyconsists of the processing of, separation, consolida-tion, and deformation of materials by one atom orone molecule [3]. It was not until the discovery of thescanning tunelling microscope (STM) in 1981 and thethe Atomic Force Microscope (AFM) in 1986 that thenanoscale world could actually be imaged andmanipulated at an atomic scale. Nanomedicine can be defined as the application of

nanotechnology to diagnose, monitor and treatdisease at a molecular and cellular level.Nanomedicine has many applications e.g. in drugdelivery, diagnostics, detection, sensing, imaging,devices and scaffolds for tissue engineering andrepair [4]. The strongest impact of nanotechnologyand nanomedicine will be in the diagnosis and treat-ment of cancer.

Classification of nanoparticlesNanomaterials are materials which have one or moredimensions in the range of 1-100nm. Nanoparticlescan be defined as aggregates of atoms bridging thecontinuum between small molecular clusters of a fewatoms and dimensions of 0.2-1nm and solidscontaining millions of atoms and having properties ofmacroscopic bulk materials [1]. They have foundapplication in many areas including advanced mate-rials, electronics as well as pharmaceuticals andbiomedicine. Nanoscience and nanotechnology lie atthe interface between physics, chemistry, engineeringand most importantly biology [5]. Nanoparticles can be broadly classified as organic

and inorganic (Figure 1). Organic nanoparticlesinclude nano-liposomes, dendrimers, amphiphilicblock copolymer micelles, carbon nanotubes (CNT)and nano-diamonds. Inorganic nanoparticles can bemetallic or composed of semiconductor material.Metallic nanoparticles include gold (Au), silver (Ag)or superparamagnetic nanoparticles of cobalt, nickelor iron (SPIO- superparamagnetic iron oxide).Semiconductor nanoparticles include quantum dots(QDs). Each type of nanoparticle has unique charac-terictics based on its composition, size and surfacechemistry that determines its stability, biocompati-bility and interaction with the surrounding environ-

ment. Of all the different types of nanoparticles, semi-conductor nanocrystals or QDs have gained signifi-cant attention due to their unique photophysicalproperties as the next generation fluorophores.

Nanotechnology and breast cancer – applica-tion of Quantum DotsAmong the many potential applications of nanotech-nology in medicine, cancer diagnosis and therapyremains the most significant and this has led to thedevelopment of a new discipline of nano-oncology[6-18]. Nanoparticles are actively being developed asprobes for in vivo tumor targeting, biomolecularprofiling of cancers, nanovectors for drug delivery aswell as probes for various theranostic applictions[7,9]. Figure 2 summarises the potential applicationsof nanoparticles in cancer diagnosis and therapy.Breast cancer is the most common cancer in

women worldwide, with an estimated 1.38 millionnew female breast cancer cases diagnosed in 2008[19]. Significant advances have been made in theapplication of nanotechnology to the diagnosis andtherapy of breast cancer [20-30].

What are Quantum Dots? Quantum Dots (QDs) are fluorescent semiconductornanocrystals, composed of materials from the

Sarwat Rizvi,Centre for Nanotechnology& Regenerative Medicine,UCL Division of Surgery &Interventional Science.

Alex Seifalian,Centre for Nanotechnology& Regenerative Medicine,UCL Division of Surgery &Interventional Science,London Centre ofNanotechnology,Royal Free Hampstead NHSTrust Hospital, London, UK.

Mo Keshtgar,Consultant SurgicalOncologist, Centre forNanotechnology &Regenerative Medicine,UCL Division of Surgery &Interventional Science,Royal Free Hampstead NHSTrust Hospital, London, UK.

Correspondence: E: m.keshtgar@ucl.ac.uk

Breast Cancer

Nanotechnology, Quantum Dots andBreast Cancer – What the Future Holds?

Figure 1: Classification of nanoparticles used in cancer diagnostics and therapeutics.

Figure 2: Outline of the applications of nanoparticles incancer diagnostics and therapeutics.

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elements in the periodic groups of II-VI, III-V or IV-VI. They range insize from 2-10 nm in diameter containing approximately 200-10000atoms [31]. Due to the effects of quantum confinement QDs arehighly photostable, with broad absorption, narrow and symmetricemission spectra, slow excited state decay rates and broad absorp-tion cross sections. Their emission colour depends on their size,chemical composition and the surface chemistry and can be tunedfrom the ultraviolet to the visible and near infrared (NIR) wave-lengths (Figure 3).

NIR wavelengths are particularly useful for deep tissue imaging asNIR light can penetrate tissues without being scattered or absorbed(Figure 4). QDs can hence be used as fluorescent probes for thebiomolecular profiling of tumors, cancer localisation, detection ofdistant micrometastatis as well as image guided surgery fordetecting the sentinal lymph node through a more sensitive andminimally invasive technique. Therapeutically they can be used forphotodynamic therapy, photothermal ablation of cancer along withcarbon nanotubes as well as probes for image guided delivery ofchemotherapeutic agents.

Cancer localisationThe biomolecular profiling of tumours determines the efficacy ofvarious targeted therapies. In breast cancer, the hormone receptorstatus correlates directly with the benefit of endocrine therapies andforms the basis on which therapeutic decisions are made. Forexample, the overexpression of HER-2 protein or gene amplificationor both determine benefit from treatment with the anti-HER2-monolonal antibody, trastuzumab [32]. The two methods commonlyapplied to the detection and quantification of the HER2 staus areimmunohistochemistry and fluorescence in situ hybridization (FISH)both of which have limitations [33].

Figure 3: Size tunable emission of QDs. QDs of the same material emit atdifferent colours or wavelengths depending on their size. Larger QDs emit atred and NIR wavelengths

Quantum dots can provide a viable alternative for determining theHER2 status and can potentially be used for in vivo localisation usingsurface bioconjugation to specific targeting molecules [34-36]. QDsmay also allow the simultaneous detection and quantification ofseveral proteins and molecular targets on small tumour samplesthrough their property of multiplexed imaging [37]. The potentialapplication of bioconjugated QDs for targeting specific receptors invivo would allow prospects of in vivo tumor imaging as well astargeted delivery of drugs and therapeutic modalities like PDT andphothermal ablation of cancer cells allowing them to be used as effec-tive theranostic agents.

Sentinel lymph node biopsySentinel Lymph Node (SLN) biopsy is a means of ultrastaging cancerand is now the standard of care in breast cancer surgery. It aims todetect the first draining lymph node from the cancer site which repre-sents the histological status of the remaining lymph nodes within thelymphatic basin. It is one of the most important prognostic indicatorsand its status also determines the need for further intervention.Presence of cancer in the SLN indicates that there may be furtherdisease in the axilla and therapeutic lymphadenectomy (axillarylymph node dissection) may be required. The current tracers for SLNBinclude radiocolloid and a vital blue dye, both of which have variouslimitations (Table 1).

To overcome the limitations of the current tracers, some centreshave explored the use of NIR fluorophores like Indocyanine Green(ICG) for localisation of the SLN through live optical imaging [38-42].NIR imaging is based on the transparency of biological tissue at wave-lengths of 650-900nm, where the absorbtion co-efficients of tissuecomponents like Hb and water are low allowing deeper penetration ofphotons [43]. However, traditional fluorophores like ICG have a short

Figure 4: Transparency of bio-logical tissues to NIR wave-lengths. NIRQDs were injectedat a depth of 1.5cm into a pieceof chicken muscle ex vivo.A) Before injection – NIRQDsin syringe B) during injection – NIRQDsvisualised in deep tissue C) Complete injection –brightly fluorescent NIRQDslocated at 1.5cm depth in thetissue.

Table 1. Limitations of the current tracers used for sentinel lymphnode localisation.

Vital Blue Dye Radiocolloid

1% risk of anaphylactic reaction Exposure of radioactively topatients and staff – cumulative effects not known

Prolonged tattooing of the skin Strict legislation requiresARSAC licence

Size < 5nm leads to rapid Expensive euipment and specialmigration and staining of measures to dispose of waste.non-sentinel LN

Bluish discolouration of body Short half life of radiocolloid (6h)secretions requires excellent co-ordination

between timing of injectionand surgery

Rapidly enters systemic Few centres have on site NMcirculation and may interfere facilities limiting the usewith pulse oximetery of this technologyintra-operatively

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half-life, low quantum yield and low photostability causing them tophotobleach rapidly on exposure to excitation light. At the sametime the size of ICG is small (1.5nm) that leads to rapid migrationacross LNs leading to detection of non-sentinel nodes. NIR emitting QDs can overcome the shortcomings of ICG through

their prolonged photostability, high molar extinction co-efficents andhigh quantum yield giving a brighter signal and a high signal tobackground ratio (SBR). The size of the QDs can be tailored withsurface coatings to fall within the critical hydrodynamic diameter (10- 100nm) for optimal retention into the SLN. The surgeon can thenlocalise the SLN prior to the surgical incision making this a highlyaccurate procedure. The enhanced photostability of QDs would alsoallow the histopathologist to identify the SLN from amongst a chainof lymph nodes several hours after the procedure. Type II NIR emitting QDs have been demonstrated for imaging the

SLN in small and large animal models [44,45]. Their considerablebrightness and high quantum yield allows depth of penetration of upto 1cm in solid tissue, and 5cm in the lung [46-48]. The main limi-

tation to the clinical application of QDs is their toxicity as most QDsare based on salts of Cadmium, Tellurium and Selenium. However,the toxicity of QDs may be positively utilised in cancer therapy asQDs can potentially be used as agents for photodynamic therapy(PDT), where light excitation of the PDT agent localised to a cancersite leads to generation of free radicals causing localised cell death.

ConclusionThe application of NIRQDs can potentially overcome current limita-tions of existing tracers for SLN localisation. Inorganic NIR probeslike QDs have a potential to replace the traditional fluorophores forlive image guided surgery. The high QY and enhanced photostabiltyof QDs along with a biofunctionalisable surface makes them idealprobes for in vitro and in vivo biomolecular and cellular imaging.While toxicity remains a limitation, it can potentially be utilised inthe application of QDs for theranostic applications like photody-namic therapy. However, a significant amount of research is stillrequired for the safe clinical translation of these novel probes. ■

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