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-mediated Imaging

Conventional fluorophores, particularly organic dyes, are highly susceptible to photobleaching. Their signals usually diminish significantly within minutes of constant excitation. This lack of long-term photostability has made it challenging to use these fluorophores as in vivo markers.[47] The required high energy excitation introduces additional complications of low light penetration depth and possible severe photodamage to living organisms.[48] As such, indocyanine green (ICG), is the sole fluorochrome that has been approved by th US FDA for clinical use.[49] Quantum dots (QDs) also have their limitations as an in vivo marker. Despite a recent report showing no obvious in vivo toxicity of II–IV group QDs to Sprague-Dawley rats over a period of approximately three months, the presence of toxic heavy metals such as cadmium (Cd) continue to raise significant concerns on the safety aspects with regards using these materials for clinical applications.[50] Conversely, as mentioned previously, lanthanide-doped UCNs showed excellent biocompatibility properties in both in vitro and in vivo settings, thus making them a safer choice for bioimaging applications. Additionally, UCNs' ability to be excited in the NIR region, where there is low autofluorescence, minimal photodamage to biological specimens and improved tissue penetration, circumvents most of the problems associated when using conventional fluorophores for bioimaging. Not to mention, UCNs are also photostable with no loss of fluorescence intensity even after hours of continuous excitation.[46] As intermittent emission/blinking (as seen in QDs) is absent from UCNs, single particle imaging is possible.[51]

As a novel class of imaging contrast agent, UCNs have been employed in multiple in vitro, ex vivo and in vivo testing models. Table 3 summarizes some of the recent studies of UCN-mediated imaging, broadly grouped into general internalization studies and targeted imaging. Exploitation in general internalization studies was performed using bare or modified UCNs. They have been used for in vitro cancer cells imaging[15,25,30,44–46,52–57] to demonstrate the possibility of using UCNs for in vivo optical imaging. Lim et al.[58] have pioneered the use of UCNs for live imaging in a model organism. 50–200 nm Y2O3:Yb,Er nanoparticles were effectively internalized into the digestive system of Caenorhabditis elegans. Chatterjee et al.[46] showed that PEI-coated NaYF4:Yb,Er nanoparticles of 50 nm in size, can be used for deep tissue imaging in Wistar rats. Upon NIR irradiation, UCNs signal can be detected up to a depth of 10 mm beneath the skin. Furthermore, for cancer cell imaging, the group have also conjugated folic acid to the PEI-coated UCNs for specific targeting of folate receptors on ovarian carcinoma cells (OVCAR3) and human colonic adenocarcinoma cells (HT29). The superiority of UCNs in terms of deep tissue penetration, low toxicity and live uptake in small animals is clearly displayed. This has certainly inspired researchers to promote UCNs as the next generation in vivo dynamic imaging tool. Idris et al.[47] have utilized these UCNs as tracking devices for transplanted cells. Migration of silica-coated NaYF4:Yb,Er nanoparticle-loaded mouse skeletal myoblasts (SkMs) can be dynamically tracked in a living C57BL/6 mouse model with cryoinjured hind limb. UCNs were applied for real time dynamic imaging to visualize in vitro events such as cell migratory activity, direction, speed and cell–cell interactions for 5 h. The labeled stem cells were identified with negligible background and at least 1.3 mm deep in a fully vascularized tissue upon intramuscular injection, even 7 days post delivery. In addition, the nanoparticles showed incredible photostability in comparison to Alexa Fluor 532 and DAPI. Fluorescence from the two dyes decreased drastically within 10 min of irradiation, where no significant reduction in intensity was observed from UCNs despite being continuously excited with 980 nm NIR for 148 min.

The development of UCNs can certainly improve biomedical detection technologies. From general internalization studies, the potential of UCNs were further explored in the next stage – targeted imaging. Wang et al.[56] have suggested that with the aid of proper cell-targeting ligands, UCNs can be used in the detection and diagnosis of cancers. The capability of antibody-modified UCNs for both in vitro and in vivo target-specific detection of cancer cells, such as HeLa cells[15,56,57] and human glioblastoma cells[25,53] has also been demonstrated. In addition, Nagarajan et al.[59] have performed labeling of gap junctions on rat-derived cardiomyoblasts with anti-Connexin43 modified UCNs. This further suggests that UCNs may contribute advantages over diagnostic pathology, highlighting their promise as a platform for in vivo cancer imaging. Other than using antibodies for targeted imaging, peptide-labeled UCNs have also been recently reported. Xiong et al.[25] performed targeted imaging of human glioblastoma tumor (U87MG) based on the high affinity of the arginine-glycine-aspartic peptide (RGD) to integrin αvβ3 receptor. Human breast cancer cells (MCF-7), which is of low integrin αvβ3 expressions, were used as a control. Athymic nude mice simultaneously bearing a U87MG tumor and MCF-7 tumor were intravenously administered with RGD-labeled UCNs over a 24 h period and subsequently imaged. No significant fluorescence signal was observed in the control tumor. An insect venom isolated from the scorpion Leiurus quengestriatus, chlorotoxin (CTX), was used to confer NaYF4:Yb,Er/Ce with tumor targeting abilities, specific to several types of cancers of neuroectodermal origin. CTX mediates this tumor-specific targeting by binding to a surface bound complex, matrix metalloproteinase (MMP)-2 endopeptidase. Balb/c nude mice bearing xenograft glioma tumor were intravenously injected with CTX-labeled UCNs for 24 h prior to imaging. These UCNs primarily localized to tumor tissue, with little macrophage uptake. In contrast, little deposition was observed in kidney, heart and liver, while some accumulation was seen in lung and spleen, at 24 h post-injection.[45] Summarizing all these promising results, they prove the versatility of UCNs in bioimaging and their potential as a successful contrast agent for in vivo diagnostics.


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