Quantum Dots for Cancer Diagnosis and Therapy: Biological and Clinical Perspectives

Hua Zhang; Douglas Yee; Chun Wang

Disclosures

Nanomedicine. 2008;3(1):83-91. 

In This Article

Quantum Dots

QDs are semiconductor nanocrystals with a quantum-confinement property that enables them to emit fluorescence from visible to infrared wavelengths on excitation.[5,7,8] Typically, a single QD contains a total of approximately 100-100,000 atoms in its crystal core. The size of QDs ranges within the nanometer scale, normally 2-10 nm in diameter.

The majority of QDs are binary semiconductor crystals, which are composed of two types of atoms from the II/VI[9,10] or III/V[11] group elements in the periodic table. Cadmium selenide (Cd/Se) QDs are the most well studied and widely used. A Cd/Se QD consists of a Cd/Se core, capped with a ZnS shell that significantly increases the quantum yield of Cd/Se nanocrystals to approximately 30-50% at room temperature.[10] The outmost surface of these nanocrystals is passivated with a monolayer of tri-n-octylphosphine oxide (TOPO), a high-temperature coordinating solvent. The emission wavelength of Cd/Se QDs lies in the range of 470-655 nm.

Recently, the so-called type II QDs, which consist of Cd/Te core with Cd/Se (or ZnS) shell, has made new progress in biological applications.[12,13] Increased thickness of the Cd/Se shell correlates with higher emission wavelength in the far-red and near-infrared (NIR) range, which is ideal for in vivo imaging because tissue autofluorescence in the visible wavelength can be avoided.

Compared with the traditional small-molecule fluorophores, QDs have the following distinct features. First, QDs have extremely high brightness when excited, owing to their high quantum yield and high molar-extinction coefficient values. Second, QDs are highly resistant to photobleaching, which is crucial for long-term real-time image tracking. Third, the emission spectra of QDs can be tuned by the size and composition of their cores and shells. Finally, QDs have broad excitation and narrow and symmetric emission spectra, which make it feasible to perform 'multiplexing' (simultaneous detection of multiple signals) imaging using a single excitation source (reviewed in).[14]

TOPO-passivated binary QDs are highly hydrophobic and, therefore, only soluble in organic solvents. To achieve solubility in aqueous media, these QDs are often encapsulated by amphiphilic molecules. The hydrophobic segment of these molecules interacts with the hydrophobic TOPO molecules on the QD surface, whereas the hydrophilic segment interacts with the aqueous medium, solublizing the QDs. Several types of amphiphilic polymers, including polyethylene glycol (PEG)-derived phospholipids,[15] triblock copolymers,[16] octylamine-modified polyacrylic acid,[17] oligomeric phosphine[13] and copolymers of alkyl monomers and anhydrides,[18] have been reported to serve this encapsulation function. After encapsulation, the hydrodynamic radius of QDs increases to approximately 10-20 nm.[8,16,19,20]

To functionalize QDs with biomolecules, amphiphilic polymers are engineered to carry chemically reactive groups, such as amines and carboxylic acids. Biomolecules, such as peptides, antibodies, DNA or siRNA, can react with these functional groups to form covalent linkages mediated by various coupling reagents. In addition, biomolecules can be conjugated with QDs through noncovalent affinity binding, such as the interactions of biotin/avidin,[21] or nickel nitrilotriacetic acid (Ni-NTA)/histidine-tagged peptides.[22] By controlling the molar ratio of the reactive groups and reaction time, the average number of biomolecules conjugated to each QD can be controlled to a certain extent (reviewed in).[23] Furthermore, because the hydrodynamic sizes of QDs are relatively larger than the conjugated biomolecules, averages of two or a few biomolecules are typically conjugated to one QD. In addition, the pharmacokinetics of biomolecule-conjugated QDs tends to be similar to that of encapsulated QDs but not that of the biomolecules. Encapsulation and bioconjugation do not usually alter the optical property of QDs significantly.

Recently, QDs based on silicon have drawn much attention because of their potential lower toxicity than heavy metal QDs, such as Cd/Se dots. Silicon QDs are typically 2-8 nm in size, with a silicon-crystal core surrounded by a layer of amorphous silicon oxide.[24] Despite that, the silicon QDs are much safer, their use has been hampered for several technical reasons. Common methods of silicon QD synthesis, such as gas-phase decomposition of silanes,[25] laser-vaporization controlled condensation[26] or solution synthesis,[27] often result in low yield of approximately a few milligrams per day. Recently, Mangolini et al. have developed a novel silicon QD synthesis methodology using low-pressure nonthermal plasma.[24] Compared with the dots synthesized in liquid phase or regular gas phase, these QDs have a high yield, up to 50 mg/h, and emit fluorescence right after synthesis without acid etching used in other gas-phase synthetic processes. In addition, the surface of QDs can be passivated with organic ligands, such as octadecene and dodecene, resulting in QDs that are more stable during storage with dramatically increased quantum yield and solubility in organic solvents.[28,29] Some silicon QDs can emit fluorescence at red and infrared range, which is ideal for in vivo imaging. However, their excitation wavelength normally lies in the ultraviolet region, which penetrates poorly into tissues and might be damaging to cells. In addition, there are few reports on how to make silicon QDs water soluble[30] and amenable to bioconjugation, which is another major hurdle towards the application of these QDs in biomedicine. There is, however, a large body of literature on the chemical functionalization of silica particles and surfaces, which can be applied to silicon QDs.[31,32,33]

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