Applications of Upconversion Nanoparticles in Imaging, Detection and Therapy

Lei Yin Ang; Meng Earn Lim; Li Ching Ong; Yong Zhang


Nanomedicine. 2011;6(7):1273-1288. 

In This Article

UCN-based Therapy

Researchers have started to explore the possibilities of developing UCN-based therapies utilizing them as drug carriers and active participants. These therapies are made possible due to the fact that the nanoparticles can be easily modified for specific targeting and delivery. In this method, UCNs allows synergistic treatments as they provide a common platform to combine two or more independent applications. Currently, UCNs have been applied in photodynamic therapy (PDT), drug and gene delivery.

Photodynamic Therapy

Photodynamic therapy is an oxygen-dependent treatment modality that utilizes photosensitizers, which can be activated by light of the appropriate wavelengths to generate cytotoxic reactive oxygen species (ROS). This oxygen-dependency thus distinguishes PDT from the other types of photochemotherapy.[81] The mechanism of PDT consists of three stages: excitation of photosensitizers, generation of ROS and cell death.[82] Light absorption of appropriate wavelength excites the photosensitizers to a triplet state. The excited photosensitizers can undergo either type I or type II reaction, resulting in the production of ROS.[81] These cytotoxic species damage various cellular compartments, especially plasma membrane, mitochondria and lysosomes, leading to cell death.[83,84] PDT has been predominantly used for cancer treatment by causing localized damage to tumor cells and vasculatures.[81] The use of PDT as a treatment modality is gradually gaining acceptance but it is not widely used. The approved photosensitizers absorb below 700 nm, limiting this therapy to superficial tumors.[85] Furthermore, the photosensitizers usually possess poor tumor specificity due to the multiple problems encountered when attempting to functionalize them with targeting elements.[81]

Upconversion nanoparticles, with their unique optical properties, provide a possible solution to all these limitations. First of all, the ability of these nanoparticles to convert NIR radiation to visible light can expand the use of PDT for deeper tumors due to the greater light penetration of NIR in biological tissues.[46] Moreover, UCNs can be modified accordingly to specifically deliver photosensitizers to tumors. In view of all these advantages, the development of UCN-based PDT as a potential treatment modality has attracted considerable interest. Current UCN designs for PDT of cancer can be classified into polymer-based and silica-based approaches (Table 8).

In the polymer-based approach, PEI and PEG have been used to provide capping layers in which photosensitizers become ensconced. Chatterjee et al.[86] attached zinc phthalocyanine (ZnPC) photosensitizers to the surface of PEI-coated UCNs by physical adsorption. Folic acid was further conjugated for specific targeting to the colon cancer cells. Results showed reduced cell viability upon NIR irradiation. However, the physically-adsorbed photosensitizers may be detached from the surface. Ungun et al.[87] has synthesized three-layer nanoparticles consisting of NaYF4: Yb, Er UCNs as the core, porphyrin photosensitizers as the middle layer and a PEG polymer coat as the outer layer. They have demonstrated high photosensitizer-to-UCN ratio of 1:3 but the PDT efficacy of these UCNs has not been proven.

The other design utilizes silica as a protective layer in which the photosensitizers are impregnated. Using this strategy, Zhang et al.[88] doped merocyanine-540 photosensitizers into silica-coated UCNs that were further functionalized with breast cancer-targeting antibodies. Based on the optical and fluorescence images obtained, UCN-treated cancer cells were dead or gradually dying after NIR irradiation. In this case, the release of ROS is hampered by the nonporous silica, therefore resulting in low PDT efficacy. By using mesoporous-silica-coated UCNs with a core-shell structure, release of ROS and oxygen diffusion will not be hampered. Qian et al.[54] reported such mesoporous UCNs in which the particles were first coated with a thin layer of silica followed by subsequent coating of mesoporous silica layer which was loaded with ZnPC (Figure 3). Cell viability of the treated bladder cancer cells was significantly lower compared to the controls. Additionally, production of singlet oxygen from these ZnPC-loaded nanoparticles in live cells has been proven.[89]

Figure 3.

Mesoporous-silica-coated upconversion nanoparticles for photodynamic therapy. (A) Schematic diagram showing the coating process to produce mesoporous-silica-coated upconversion nanoparticles with a core-shell structure for PDT. (B & C) TEM images of mesoporous silica-coated upconversion nanoparticles.
Reproduced with permission from [54] © Wiley-VCH Verlag GmbH & Co. KGaA.

Drug & Gene Delivery

Apart from PDT, recent efforts have begun exploring the use of UCNs in drug and gene delivery. The application of UCNs in drug delivery was demonstrated by Kong et al.[90] using a model drug, ibuprofen, which they have successfully loaded and released from the mesoporous-silica-coated UCNs. The versatility of such a UCN-based drug delivery platform was further illustrated in another study. Here, mesoporous-silica-coated nanocomposites with UC nanophosphors showed sustained drug release and the possibility of real-time monitoring of drug release kinetics via UC luminescence.[91]

Jiang et al.[92] have first examined the potential of UCN-based gene delivery by using siRNAs. In this work, silica-coated UCNs were amine-modified and further conjugated with anti-Her2 antibody, which specifically targets the surface antigens of SK-BR-3 breast cancer cells. GL3 siRNA that silences the luciferase gene was physically adsorbed onto the surface of UCNs. The results showed that luciferase gene was downregulated by approximately 50% while the gene silencing was not observed in the controls. These findings imply that UCNs can be used as bioimaging probes as well as nanocarriers for targeted gene delivery. Indeed, by using fluorescence resonance energy transfer, intracellular siRNA release profile from these nanocarriers has been determined. In this case, the method involves UCN as a donor and an intercalating dye, BOBO-3, as an acceptor (Figure 4). The siRNA–BOBO-3 complexes were physically adsorbed onto the amine-modified UCNs. Hence, as the siRNA complexes detach from the UCNs over time, fluorescence resonance energy transfer efficiency decreases.[93]

Figure 4.

Schematic drawing of the FRET-based system with upconversion nanoparticle acting as donor while BOBO-3 acts as acceptor.
FRET: Fluorescence resonance energy transfer; UCN: Upconversion nanoparticle.
Reprinted with permission from [93] © (2011) American Chemical Society.


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