Phosphors for Drug Delivery, Medical Imaging and Magnetic Response Comparative Study

Figure 7.2 illustrates the process of active targeting. Nanoparticles can also target cancer through passive targeting. As apoptosis is stopped in cancerous cells, they continue sucking nutritious agents abnormally through the blood vessels forming wide and leaky blood vessels around the cells induced by angiogenesis. Leaky blood vessels are formed due to basement membrane abnormalities and decreased numbers of pericytes lining rapidly proliferating endothelial cells (Hobbs and Seymour 1998). Hence, the permeability of molecules to pass through the vessel wall into the interstitium surrounding tumor cells is increased. The size of the pores in leaky endothelial cells ranges from 100 to 780 nm (Hobes et al. 1998; Rubin and Casarett 1966; Shubik 1982). Thus nanoparticles below that size can easily pass through the pores (Jain and Stylianopoulos 2010; Jang et al. 2003). As a result, it facilitates to efflux the nanoparticles to cluster around the neoplastic cells. Nanoparticles can be targeted to a specific area of capillary endothelium, to concentrate the drug within a particular organ arid perforate the tumor cells by passive diffusion or convection. Lack of lymphatic drainage eases the diffusion process. The tumor interstitium is composed of a collagen network and a gel-like fluid. The fluid has high interstitial pressures which resist the inward flux of molecules. Tumors also lack well-defined lymphatic networks having leaky vasculature. Therefore, drugs that enter the interstitial area may have extended retention times in the tumor interstitium. This feature is called

Fig. 7.2. Active and passive targeting by nanoparticles. (Sutradhar and Amin 2014) Copyright Hindawi Publication House 2014.

the Enhanced Permeability and Retention (EPR) effect and facilitates tumor interstitial drug accumulation (Fig. 7.2) (Maeda 2001; Maeda et al. 2000). Ncinoparticles can easily accumulate selectively by enhanced permeability and retention effect and then diffuse into the cells (Yuan 1998).

Very recently, Hyeon and co-workers (Park et al. 2012) reported in vivo PDT effect through the systemic administration of UCNP-Ce6 followed by the 980-nm irradiation (Fig. 7.3). NaGdY4-based UCNPs after PEGylation were loaded with Ce6 molecules by both physical adsorption and chemical conjugation, yielding a UCNP-Ce6 complex with >103 Ce6 molecules per particle. The blood circulation half-life of UCNP-Ce6 was determined to be 21.6 min in BABL/C mice after intravenous injection. Nude mice bearing U87MG tumors were injected with UCNP-Ce6 through the tail vein (0.1 mg of rare earth per mouse). Obvious tumour accumulation of UCNP-Ce6 nanoparticles was revealed by dual-modal upconversion luminescence imaging and Tl-weighted MR imaging (Fig. 7.3 a and b), and could likely be attributed to the Enbumced Permeability and Retention (EPR) effect of cancerous tumors. Under the 980 run irradiation, tumor growth of UCNP- Ce6 injected mice was significantly inhibited compared with other control groups (Fig. 7.3c). These results clearly indicate the great potential of using

Fig. 7.3. In vivo imaging-guided PDT. (a) UCL images of nude mice bearing tumors after intravenous injection of UCNP-Ce6. (b) Tl-weighted MR images of a tumourbearing nude mouse before and after 1.5 hours intravenous injection of UCNP-Ce6. (c) Growth of tumors after various treatments indicated for efficient imaging guided PDT therapy. Copyright 2012 Wiley-VCH (Park et al. 2012; Wang et al. 2013).

UCNPs for multi-modal imaging guided PDT. Remarkably, this study is the first report to demonstrate UCNP-based in vivo PDT through the systemic administration of UCNP-PS complexes (Wang et al. 2013).

Recently, Zhang and co-workers (Jayakumar et al. 2012) reported the use of NIR-to-UV UCNPs for photo-controllable gene expression (Fig. 7.4). Plasmid DNA encoding Green Fluorescence Protein (GFP) and small interfering RNA (siRNA) target GFP mRNA were both caged with 4, 5-dimethoxy-2-nitrocicetophenone DMNPE to block their respective functions. After NIR light treatment, they were uncaged by the energy transferred from UCNPs, inducing controlled gene expression £md specific gene silencing, respectively. The NIR-to-UV UCNPs overcome the drawback of current photo-responsive systems in which UV light is needed to activate

Fig. 7.4. Schematic illustration of NIR triggered gene release using NIR-UV UCNPs. (a) Plasmid DNA or siRNA are caged with DMNPE and then uncaged by upconverted UV light emitted from NIR-to-UV UCNPs. Inset shows the penetration depth of UV and NIR light in the skin, (b) Photoactivation and patterned activation of caged GFP nucleic acids in cells. Copyright 2012 Highwire Press PNAS. (Jayakumar et al. 2012).

DMNPE caged nucleic acids. Besides, the upconverted UV produced by the irradiated UCNPs was also found to be relatively safe for the cells, under the applied nanoparticle dosage and duration of NIR laser irradiation. This system was then further used to

Bioluminescence imaging is a technology that allows for the non-invasive study of ongoing biological processes in small laboratory animals. Xing and co-workers (Yang et al. 2012) reported NIR light controlled uncaging of d-luciferin and bioluminescence imaging in vivo using NIR-to-UV UCNP probes. The core-shell NIR-to-UV UCNPs were coated with thiolated silane molecules and subsequently coupled to d-luciferin that was caged with a l-(2-mtrophenyl) ethyl group. UV light emitted from UCNPs under NIR irradiation could activate caged d-luciferin to release d-luciferin molecules which was an active substrate of luciferase used in bioluminescence imaging. Cell viability assays showed no obvious cytotoxicity for C6 glioma cells treated with the d-luciferin/UCNP conjugate after two hours of irradiation with NIR light. In marked contrast, UV irradiation resulted in significant cellular damage after a short exposure time. Importantly, strong bioluminescence signals were detected in the mouse injected d-luciferin/ UCNP conjugate after NIR-light induced photo uncaging. While under UV irradiation, no notable bioluminescence was detected in the mouse owing to the poor tissue penetration of UV light (Fig. 7.5).