The term upconversion refers to a nonlinear optical process in which two or more photons are sequentially absorbed, followed by the emission of a photon with higher energy than the original pumped photons (anti-Stokes emission). Lanthanide-doped upconversion nanoparticles are the most common one and have been recently developed as a new generation of luminescent probes, possessing considerable merits which organic dyes and quantum dots don’t have. For example, lanthanide-doped upconversion nanoparticles offer high penetration depth, low autofluorescence background, large anti-stokes shifts, sharp emission bandwidths, low toxicity, and high photostability. These advantages make them well-suited for bioimaging, therapy, biosensing, and solar cells. In addition, by rationally doping other types of lanthanide ions into nanoparticles, the upconversion nanoparticles can be further featured with other imaging modalities, such as positron emission tomography (PET), computed tomography (CT), single-photon emission tomography (SPECT), and magnetic resonance imaging (MRI).
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Upconversion mechanisms and properties
The unique optical properties of lanthanide elements originate from their electron configuration of the 4f shell, where the electrons of lanthanides can be partially filled. As a result, lanthanide ions present a great number of energy levels, enabling the occurrence of electron transitions between 4f levels. Lanthanide upconversion nanoparticles are comprised of a crystalline host and lanthanide dopants embedded in the host lattice. The dopant can be either an emitter that gives off light or a sensitizer that absorbs the excitation light and transfers the emitter. Lanthanide upconversion processes are mainly divided into three categories: excited-state absorption (ESA), energy transfer upconversion (ETU), and photon avalanche (PA).
Figure 1. Upconversion processes: (a) excited-state absorption, (b) energy transfer upconversion, and (c) photon avalanche.
The combination of Yb3+ as sensitizer and Er3+//Tm3+/Ho3+ as emitter are common upconversion nanoparticles utilizing 980 nm excitation wavelength due to the large absorption cross section of Yb3+ at 980 nm, and the highly efficient energy transfer from Yb3+ to Er3+//Tm3+/Ho3+. Until recent years, Nd3+ has been employed in the shell to realize the utilization of 800 nm excitation in core/shell upconversion nanoparticles. In aspect of their emission wavelengths, lanthanide-doped upconversion nanoparticles are able to provide abundant emission bands varying from ultraviolet, visible, to near-infrared light. For example, Yb3+/Er3+ can give off green light at 545 nm and red light at 660 nm; Yb3+/Tm3+ can produce ultraviolet emission at 360, blue emission at 450, and 475 nm, and near-infrared emission at 800 nm; Yb3+/Ho3+ can emit at 550 and 660 nm.
Compared with organic dyes and quantum dots produce higher energy emission through two-photon absorption and requires high-cost pulse laser, lanthanide-doped upconversion nanoparticles have better upconversion efficiency and only utilize inexpensive 980 or 808 nm continuous-wave diode laser as excitation source. Lanthanide-doped upconversion nanoparticles can be synthesized within the scale of nanometers and with uniform shape. Through well-designed surface modification, they are able to remain their luminescence performance and well-dispersed in aqueous solutions, and more importantly they possess extremely low cytotoxicity. Upconversion nanoparticles have been applied to image a variety of cell lines, such as breast cancer cells (MCF-7 and SK-BR-3), HeLa cells, ovarian cancer cells, KB cells, HepG2 cells, and AB12 mouse mesothelioma cells. Furthermore, the biocompatibility and potential imaging capability of upconversion nanoparticles in small animal imaging have been successfully demonstrated.
2. Detection and assay
Upconversion nanoparticles have been employed as luminescent reporters in numerous biological assays, including affinity assay, immunoassay, and DNA hybridization assay. Due to their superior signal-to-noise ratios, they significantly enhanced detection limits compared to the traditional luminescent reporters. For example, there are reports regarding a detection limit of 10 pg human chorionic gonadotropin in 100 mL sample. In another report, a detection limit of 1 ng/mL probe DNA can be successfully detected using upconversion nanoparticles, which is a fourfold improvement compared with the using of organic dye cyanine 5.
3. Drug delivery and therapy
The unique optical properties and highly tunable emissions enable the upconversion nanoparticles for drug delivery and therapy applications. There are mainly three strategies to design upconversion nanoparticles based systems for drug delivery: (1) mesoporous silica shell, (2) hydrophobic pockets, and (3) hollow spheres with mesoporous surface. The anticancer drug molecules of doxorubicin (DOX) have been conjugated with upconversion nanoparticles, and controlled release of drug can thus be realized. Upconversion nanoparticle can be easily coupled to plasmonic nanoparticles like gold nanoparticle and CuS, and such combination has the ability to convert near-infrared light into heat with a high efficiency, which has been actively used in photothermal therapy. On the other hand, when coupled to photosensitizers like chlorine 6 (Ce6), Mc540, ZnPc, and TiO2 that can produce singlet oxygen (1O2), photodynamic therapy can be applied to kill tumors or treat other diseases.