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UCNP-based drug delivery systems commonly rely on stimuli-sensitive auxiliaries, lacking a straightforward manipulation strategy. Here we designed Yb3+-enhanced upconversion/mesoporous silica nanocomposites (UCNP@SiO2) for consecutive cell imaging, photothermal drug delivery and cancer therapy. Core UCNPs (NaYbF4: 2% Er3+) were synthesized and coated with mesoporous silica, whose high-efficiency photothermal properties were verified in vitro. Then doxorubicin hydrochloride (DOX) was loaded on the UCNP@SiO2 and successfully triggered to release by a 975 nm laser of 150 mW or 300 mW. Before the therapy, we used a much lower laser power of 15 mW (which would cause little DOX release) for UCNP-probed fluorescence imaging of Hela cells and affirmed a favorable cell uptake of nanocomposites. Subsequently, cell viability assay and PI stain have demonstrated that the 300 mW laser could manipulate drug delivery of UCNP@SiO2-DOX and cause a severe loss of cell viability. The Yb3+-enhanced UCNP@SiO2 shows a great potential in simultaneous biomedical imaging and photothermal-triggered on-site drug delivery for chemotherapy of cancer.
© 2016 Optical Society of America
1. Introduction
In recent years, stimuli-responsive nanoparticles have emerged as vital carriers for anticancer drug delivery systems, as they have many unique advantages, such as easy synthesis, morphology and size controllability; a large surface area for drug loading; and a high stability in vivo [1]. Typically, these drug carriers can be conveniently manipulated by a wide variety of external stimuli, such as pH, salts, light, magnetic fields and temperature [2]. To date, a variety of nanoparticles have been designed and applied to anticancer drug delivery, such as gold nanoparticles [3,4 ], magnetic nanoparticles [5,6 ], carbon nanotubes [7,8 ], mesoporous silica nanoparticles [9–11 ], upconversion nanoparticles (UCNPs) [12,13 ], etc. In particular, core–shell multifunctional nanocomposites composed of upconversion nanoparticles and mesoporous silica are becoming a research hots topic [14,15 ].
UCNPs can sequentially absorb two or more low-energy near-infrared (NIR) photons and emit anti-Stoke shifted light, which endow the materials with high spatial resolution, high signal-to-noise ratio (autofluorescence-free), and superior deep biological tissue penetration without causing harm [16]. In addition, UCNPs possess attractive merits including sharp emission lines, exceptional photostability, and low toxicity [17]. With unique properties for biological applications, UCNPs have been widely used in imaging, therapy, and, particularly, drug delivery systems [18]. UCNPs applied in drug delivery systems were generally coated with a pH-sensitive polymer to trigger drug delivery. Lin et al. coated the upconversion/mesoporous silica nanocomposites with poly[(Nisopropylacrylamide)-co-(methacrylic acid)] to trigger drug delivery by pH [15]. Poly(ethylene glycol) (PEG) was also frequently used to act as a pH-sensitive controller modified on the nanocomposites in the UCNP-based drug delivery process [19,20 ]. However, because of the flexibility of light as a controller in vivo, UCNPs with a caged anticancer drug and phototrigger organic molecule could be used to develop a drug delivery system, which could be manipulated by a laser. Shi J. et al. synthesized a Tm-doped core-shell UCNP coated with mesoporous silica as well as loaded with azobenzene groups to emit UV and visible light simultaneously, which could be manipulated to change the isomer and propel loaded drug delivery by the emission light [21]. Li F. et al. used two octanyl groups to make the phototrigger of amino-coumarin hydrophobic, forming an amino-coumarin-caged drug, with multilayer yolk-shell nanoparticles loaded inside, which can be photodegraded to release the anticancer drug [22]. Furthermore, because the high-efficiency photothermal effect could offer a method to trigger drug delivery, gold nanocrystals were integrated with UCNP-based nanocomposites utilizing the superficial amino group [23].In conclusion, it seems that it is difficult to shake off stimuli-sensitive auxiliaries for a UCNP-based drug delivery system, and a simple and straightforward strategy manipulated by light still not exists.
In this work, we designed and synthesized Yb3+-enhanced upconversion/mesoporous silica nanocomposites (UCNP@SiO2) without any stimuli-sensitive auxiliary for consecutive imaging, photothermal-controlled on-site drug delivery and chemotherapy of cancer cells. Prepared UCNPs (NaYbF4: 2% Er3+) were coated with a mesoporous silica shell to load doxorubicin hydrochloride (DOX, anticancer drug). The high Yb3+ concentration doping in UCNPs features high-efficiency photothermal effects for dexterously manipulating drug delivery by laser as well as intense upconversion luminescence signals for imaging. We found that the DOX could be easily loaded in UCNP@SiO2, which has obvious photothermal properties within a few minutes and effectively triggers the DOX to deliver when exposed to a 975 nm laser of 150 mW or 300 mW in vitro. Before chemotherapy, a laser with a much lower power of 15 mW, which has little effect on the drug release, was opportunely used for UCNP-probed fluorescence imaging of Hela cells and a good biocompatibility of the DOX-loaded UCNP@SiO2 (UCNP@SiO2-DOX) was confirmed. The UCNP@SiO2-DOX is steady in cells without causing excrescent mortality but dexterously responds to 975 nm lasers and delivers DOX to kill the Hela cells, which cause acute loss of cell viability. The Yb3+-enhanced UCNP@SiO2 provide great potential applications in imaging-guided cancer therapy.
2. Methods
2.1 Materials
Lanthanide chlorides (YbCl3•6H2O and ErCl3•6H2O, ≥99.9%), Oleic acid (AR), 1-octadecene (ODE) (≥90%), NH4F and sodium oleate was purchased from Aladdin Co., Ltd. NaOH (99%), N-Cetyltrimethylammonium bromide (CTAB, 99%), ethyl alcohol (AR), chloroform (AR), and methanol (AR) were purchased from Sinopharm Chemical Reagent Co., Ltd. Etraethyl orthosilicate (TEOS, AR), and PI (94%) was purchased from Sigma-Aldrich Co., LLC. Doxorubicin hydrochloride (DOX) was purchased from Beijing Huafeng United Technology CO., Ltd. Cell Counting Kit-8 (CCK-8) was purchased from Beyotime Biotechnology. All of these reagents were used without further purified. Deionized (DI) water was used in all the experimental procedures.
2.2 Synthesis of Core UCNPs (NaYbF4: 2% Er3+)
The NaYbF4: 2% Er3+ UCNPs were synthesized according to the protocol in our previous work [24]. Briefly, YbCl3•6H2O (0.98 mmoL) and ErCl3•6H2O (0.02 mmoL) were heated to 120 °C in oleic acid (6 mL) and ODE (15 mL) for 40 min. The solution was cooled down to room temperature, after which NH4F (4 mmoL) and sodium oleate (2.5 mmoL) were added. The solution was then heated to 320 °C for 60 min under the protection of argon air, then cooled rapidly, and 10 mL ethanol was added when the solution reached <75 °C. Nanoparticles were precipitated by ethanol and collected by centrifugation at 7400 rpm for 4 min. Then the UCNPs were cleaned by ethanol several times and stored in 5 mL chloroform.
2.3 Preparation of UCNP@SiO2
This process was carried out through a modified method based on Gorelikov’s and Matsuura’s protocol [25]. As-synthesized UCNPs capped with a mixture of oleic acid were transferred to water using CTAB. The UCNPs (1 mL) were added to 10 mL of 0.1 M CTAB under vigorous stirring. While stirring, the mixture was slowly heated up to 70 °C (within 15-20 minutes) to evaporate the chloroform, which resulted in a transparent mixture. Then the solution was cooled down to 40 °C for another 2 hours. The UCNPs were collected by centrifugation at 7400 rpm for 4 min. Then the UCNPs were cleaned by DI water several times to remove the excess CTAB and stored in 3 mL 0.003 mM CTAB.
After the hydrophilic process, 1 mL of the UCNP-CTAB solution was mixed with 14 mL of 0.003 M CTAB. Upon stirring, 0.1 M NaOH (100 µL-200 μL) was added to keep the pH value within 10-11. Then, 50 µL of 20% TEOS in methanol was added under gentle stirring three times at 30 minutes intervals. The mixture was allowed to react for 2 days at 37 °C. Nanoparticles were collected by centrifugation and washed with methanol to remove some of the residual CTAB and re-dispersed in water.
2.4 DOX loading and in vitro release
The UCNP@SiO2 were mixed with a DOX solution (0.4mg/mL) and stirred at room temperature for 4 days to reach the equilibrium state. Then the UCNP@SiO2-DOX particles were collected and washed with PBS to remove the free DOX. The absorption spectra of UCNP@SiO2-DOX were measured by a UV-Vis-NIR spectrophotometer. The concentrations of DOX loaded on UCNP@SiO2 were determined by the DOX characteristic peak at 480 nm after subtracting the absorbance of UCNP@SiO2, similar to some previous works [20,26 ]. The loading efficiency was calculated by: Loading efficiency = (weight of drug in UCNP@SiO2) / (total weight of drug).
In the in vitro drug release experiment, 1mL of UCNP@SiO2-DOX solution in various pH (5, 6.0, 7.4) PBS-buffer were quiescent at room temperature. The solution was irradiated by a continuous wave (CW) 975 nm laser. At two hours intervals, the mixture was centrifuged and the supernate was collected. The same volume of PBS was added back to the precipitate. A similar procedure was used to measure the drug delivery.
2.5 Cell uptake and scanning microscopy images
Hela cells were seeded onto a confocal dish and grew in 1.5 mL of a complete medium containing DMEM medium, 10% fetal bovine serum (FBS), 100U/mL penicillin, and 100 µg/mL streptomycin at 37 °C. After 24 h, cells were incubated with 150 μL UCNP@SiO2 and UCNP@SiO2-DOX solution of 212 µM for 12 h. Then, the excess nanocomposites were washed by PBS twice. The signal intensity of red emission band (645 nm - 675 nm) were observed by a scanning microscope with a 60 × oil immersion objective lens with excitation at 975 nm (15 mW).
2.6 Cell viability evaluation of using CCK-8 assay and PI
HeLa cells (6 × 103) in 100 μL of medium were seeded onto 96-well plates for 24 h. Then the cells were incubated with a 10 μL UCNP@SiO2 and UCNP@SiO2-DOX solution of 212 µM. After 12 h of incubation, the cells were washed by PBS twice and exposed to a 975 nm laser of different power for 8 min (diameter: 4 mm). A double-layer shelf was used to place the 96-well plate (on the hollow upstair) and laser beam expanders (on the downstair), which allows the laser go through the bottom up. After irradiating, the medium was changed into a fresh one to culture for another 24 h. Then 10 μL of the CCK-8 solution were added to each well, followed by incubation for another 1 hour. Cell viability was determined by measuring the absorbance at the wavelength of 450 nm with a microplate reader. All the measurements were conducted in triplicate.
In the PI stain experiment, cells were incubated with the nanocomposites and washed as described. The cells were stained with PI (50 μM) for 10min and washed by PBS twice to obtain fluorescence microscopy images.
2.7 Characterization methods
The size of the nanoparticles were characterized by transmission electron microscopy (TEM) using a JEM-2100HR microscope at an acceleration voltage of 100-200 kV. The emission spectra of UCNPs were recorded by a fiber spectrograph (QE65000, Ocean Optics) in the microscope system. The temperature was measure by a thermocouple. The absorption spectra were measured by a UV-Vis-NIR Spectrophotometer (Lambda 950, PerkinElmer). Zeta potential measurements were performed by a NanoPlus instrument (Micromeritics, USA) at room temperature. A CW diode laser (LEO Photonics,China) working at a 975 nm wavelength was utilized in this experiment. The scanning microscopy imaging experiment was implemented in the multiphoton laser scanning microscopy system (IX81-MPE1000, Olympus) with a 975 nm laser. Cell viability was determined by a microplate reader (iMark, Bio-rad). The PI-stained cells were imaged by fluorescence microscopy (IX71, Olympus).
3. Results and discussion
The schematic illustration of Yb3+-enhanced UCNP-SiO2 for consecutive Imaging, photothermal-controlled drug delivery and chemotherapy of cancer cells is shown in Fig. 1 . The UCNPs (NaYbF4: 2% Er3+ cores) were synthesized through a solvothermal procedure stated in the methods. Then, CTAB was adopted to transfer the OA-coated core UCNPs into an aqueous medium. In this process, CTAB could not only act as a phase transfer reagent but also an organic template for the subsequent formation of mesoporous silica [19]. The mesopore in the silica shell could provide an immense surface area to carry the anticancer drug. DOX was loaded on the nanocomposites through strong hydrogen bonds and electrostatic interactions for the surface silanol groups [27]. The increased Yb3+ concentration in UCNPs leads to a reduced average distance between the adjacent ions which tend to nonradiatively relaxate (for thermal energy), as well as a great absorption cross section [28]. When irradiated by a 975 nm laser, the drastically improved local photothermal effect of UCNP cores accumulates and transfers to the silica surrounding, which would weaken the intermolecular forces between DOX and silica and cause a fast release [4]. The UCNP-SiO2-DOX could serve as a fluorescence probe for cell imaging with a laser of 15 mW, as well as a photothermal drug delivery system for cancer therapy with a laser of 300 mW.
Fig. 1 Schematic illustration of Yb3+-enhanced UCNP@SiO2 nanocomposites for consecutive Imaging, photothermal-controlled drug delivery and chemotherapy of cancer cells.
3.1 Characterization of UCNPs and UCNP@SiO2
The NaYbF4: 2% Er3+ core UCNPs were synthesized through a solvothermal procedure, which is stated in the experiment. Characterized by TEM, the core UCNPs exhibit a uniform shape with an average diameter of 76.32 nm (Fig. 2(a) ). Afterwards, the synthesized core UCNPs coated with OA were transferred into a water medium by CTAB. After the hydrophilic process, the CTAB surfactants were capped on the nanoparticles, which was beneficial for the formation of a silica shell embedded with a single UCNP (Fig. 2(b)-2(c)). The silica layer shows a ~19.01 nm thickness and obvious mesopore structure (Fig. 2(c)). The incompact mesopore structure was endowed with a large surface area and volume for high-efficiency drug loading. In addition, the emission spectra of UCNPs and UCNP@SiO2 were detected under 975 nm laser excitation (Fig. 2(d)), exhibiting a sharp emission peak at ~656 nm. This shows that the mesoporous silica layer has no influence on the emission and that the UCNP@SiO2 is applicable for microscopy imaging. Besides, the signal intensity of red emission band (645 nm - 675 nm) were collected to affirm the power dependence by the photomultiplier tube (PMT) (Fig. 2(e)). The experimental dependence of the red emission band versus the incident excitation power. And the slopes of red emission bands were 1.62 and 1.56 for UCNP and UCNP@SiO2 respectively, which indicates that the red emission processes of two nanoparticles were two-photon processes. In addition, there is no remarkable difference of the signal intensity in the two nanoparticles. Figures 2(f)-2(g) shows a solution fluorescence photograph and fluorescence imaging of UCNP@SiO2 under excitation of 15 mW, which reveal adequate fluorescence signal of the prepared nanocomposites for imaging.
Fig. 2 (a) TEM images of NaYbF4: 2% Er3+ core UCNPs and a histogram of its size distribution. TEM of (b) UCNP@SiO2 and (c) amplification of the mesoporous silica shell. (d) The emission spectra of UCNPs and UCNP@SiO2. (e) The power dependence of UCNP and UCNP@SiO2. (f) The bright field photograph and fluorescence photograph of UCNP@SiO2 solution. (g) fluorescence imaging of UCNP@SiO2. All the optical characterization measured by 975 nm laser of 15 mW.
3.2 Photothermal effects of UCNP@SiO2
In the NaYbF4: 2% Er3+ core UCNPs, the energy absorbed by the Yb3+ sensitizer was mainly dedicated to radiatively relaxate (for luminescence) and nonradiatively relaxate (for thermal energy). However, the quantum yield of upconversion luminescence was generally below 10−2, despite the excitation intensity [29–31 ], while down-conversion luminescence suffers quenching with superabundant Yb3+ doping. The concentration-enhanced Yb3+ doping in UCNPs would lead to a great absorption cross section as well as concentration quenching with very high non-radiative transition, which greatly contributes to the photothermal effect.
The local photothermal effects of nanoconposites would accumulate and cause a measurable temperature rise of solution. Here, distinct photothermal effects of UCNP@SiO2 solution were measured by a thermocouple. To avoid the heating effect of the water solution irradiated by the 975 nm laser, DMSO was used as the solvent of the nanocomposites. The DMSO and UCNP@SiO2 solution of different concentrations were added in the cuvette and irradiated by laser. When using the unified power of 800 mW, the UCNP@SiO2 solution shows a temperature rise of 6.4-10.6 °C in a concentration dependent manner, compared with DMSO (Fig. 3(a) ). Conversely, when the UCNP@SiO2 solution of a unified concentration (1.06 mM) was detected, the temperature shows an apparent increase with a high power intensity (Fig. 3(b)). The difference value between the UCNP@SiO2 solution and DMSO also increased with the power. This indicates that the irradiation successfully gave rise to the photothermal effect of UCNP@SiO2 and caused a detectable temperature rise in the nanocomposite solution at high concentration. In addition, when the irradiation power was reduced to 300 mW, the temperature of the UCNP@SiO2 solution (1.06 mM) only rose by 3.8 °C, compared with DMSO. There is no distinguishable temperature difference between the UCNP@SiO2 solution and DMSO when nanocomposites of lower concentration with a laser of 300 mW were tested.
Fig. 3 (a) Photothermal effects of (a) different concentrations of UCNP@SiO2 with a 975 nm laser of 800 mW and (b) UCNP@SiO2 (1.06 mM) with laser of different power. The initial temperatures of the solution were unified at ~20 °C and the subsequent temperature change was measured at room temperature. Each data point is represented as mean ± standard deviation (SD) of three independent experiments.
3.3 Drug loading and in vitro release
The UCNP@SiO2 was stirred with DOX for 4 days and collected by centrifugation. The nanocomposite precipitate was washed three times to remove the redundant DOX and finally show a distinct reddish color, indicating that the DOX was clinging to the UCNP@SiO2. The absorption spectra of UCNP@SiO2, DOX and UCNP@SiO2-DOX also reconfirm the result. As illustrated in Fig. 4(a) , the absorption spectra of UCNP@SiO2 is smooth, while the UCNP@SiO2-DOX solution reveals an absorption peak of 480 nm, which is analogous to that of DOX. The loading efficiency reached 45.4%, which was calculated with the equation stated in the methods. Furthermore, the surface zeta potential of the DOX and nanoparticles were measured by a Zeta-Plus (Table 1 ). With CTAB capped, the hydrophilic UCNPs in DI water exhibited a strong positive potential of 148.87 mV. When coated with mesoporous silica, the nanocomposites became negatively charged, and this allowed for positively-charged DOX to be attracted next. The potential sharply increases when the DOX were loaded on the UCNPs. The result indicates that DOX was indeed loaded on UCNP@SiO2 instead of escaping to the solution. It is noteworthy that the positive potential of nanocomposites could be conducive to cell uptake, as cell membranes are negatively charged.
Fig. 4 (a) Absorption spectra of UCNP@SiO2, DOX and UCNP@SiO2-DOX. (b) DOX release profile of UCNP@SiO2-DOX in different pH and irradiation power. Each data point is represented as mean ± standard deviation (SD) of three independent experiments.
Table 1. Zeta potential of nanoparticles.
The chemotherapy molecule DOX strongly clung to the surface of silica mesopores, which led to a minor DOX release in aqueous environments. The cumulative DOX release of UCNP@SiO2-DOX solution was monitored in PBS at different pH values, as shown in Fig. 4(b). The UCNP@SiO2-DOX precipitate redispersed in PBS had to undergo a rebalancing process to reach an equilibrium state, causing a cumulative DOX release rate of ~8.9%. The mesoporous silica shell acceptably minimized the drug release during the circulation. The cumulative release remains stable after 12 h. There’s not significant difference in the release rate between different pH values. For the photothermal drug release process in vitro, we used a 975 nm laser of 300 mW or 150 mW (since a higher power laser could cause cell damage in vivo). With a laser of 300 mW, the cumulative DOX release rate sharply increased within 6 h and soon got stabilized at around 40.7%. When the power decreased to 150 mW, the cumulative DOX release rate revealed a similar trend but got stabilized at about 20.6%. The result strongly demonstrates that the laser of 150 mW or 300 mW could effectively trigger the DOX in the nanocomposites to release into the solution. The drug release went to a steady state because the irregular silica mesoporous structure, the thickness of silica layer and the intermolecular forces of drug and silica surface could engender resistance. On the other hand, we also found that a laser of 15 mW cause little extra DOX release. Thus the 15 mW laser could be opportunely applied for UCNP-probed fluorescence imaging of cancer cells and the inspection of cell uptake, providing guidance to the subsequent manipulations of drug release.
3.4 Cell uptake and scanning microscopy imaging
Hela cells were imaged by scanning microscopy to observe the cell uptake of the nanocomposites after 12 hours of incubation with the UCNP@SiO2 and UCNP@SiO2-DOX. Herein, excitation light of ~15 mW could produce an adequate fluorescence signal for imaging, as shown in Fig. 5 . The fluorescence of both UCNP-based nanocomposites generally overlap for the Hela cells, ignoring the DOX loading, which suggests a favorable cell uptake. In the partially enlarged detail, the signal of upconversion fluorescence was mainly found in the cytoplasm, leaving a blank space in the nucleus. This reveals that the nanocomposites have biocompatibility and adequate fluorescence intensity to serve as fluorescence probes for cell imaging.
Fig. 5 Scanning microscopy images of Hela cell incubated with (a) UCNP@SiO2 and (b) UCNP@SiO2-DOX for 12 h.
3.5 Cell viability assay
To explore the chemotherapeutic potential of the drug delivery system, cell viability was measured by the CCK-8 assay and PI stain. Hela cells were incubated with the UCNP@SiO2 and UCNP@SiO2-DOX for 12 h and partially treated with a 975 nm laser of 15 mW and 300 mW for 8 min subsequently. Cells treated with pure DOX of equal concentration was set as a positive group. It could be found in Fig. 6(a) that cells treated with the two nanocomposites and no laser still have a high viability, suggesting that the materials have low toxicity and a slightly premature drug release. The 15mW laser shows no distinct effect on the cell viability for all the experimental groups. This demonstrates once again that the 15-mW laser light could be opportunely applied for imaging guidance of the subsequent manipulations of drug release. The laser of 300 mW could slightly decrease cell viability for the untreated and UCNP@SiO2-treated cells, but cause acute loss of cell viability for the UCNP@SiO2-DOX-treated cells. The 975 nm laser of 300 mW was shown to be capable of manipulating drug delivery of UCNP@SiO2-DOX and achieve satisfactory therapeutic effects.
Fig. 6 (a) Differences in the viability of nanocomposites-treated cells irradiated with the 975 nm laser of 15mW and 300 mW for 8min, determined by a CCK-8 assay. *P < 0.05; **P < 0.01. Fluorescence microscopy images of Hela cell (b) incubated with UCNP@SiO2-DOX and (c) incubated with UCNP@SiO2-DOX + 300 mW laser. Dead cells were stained red with PI.
The PI stain of the UCNP@SiO2-DOX-treated cell also testifies consistent results. As shown in Fig. 6(b), a small amount of cells were dead and stained with PI after treated with UCNP@SiO2-DOX, while acute cell death was found with an extra 8 min of irradiation. The results exhibit a favorable chemotherapy effect of UCNP@SiO2-DOX managed by the laser.
4. Conclusion
We have synthesized Yb3+-enhanced upconversion (NaYbF4: 2% Er3+)/ mesoporous silica nanocomposites, which feature a high-efficiency photothermal effect when irradiated by a 975 nm laser. The anticancer drug DOX was loaded onto the nanocomposites and effectively triggered to release in vitro by a laser of 150 mW or 300 mW. The cumulative DOX release with a laser of 300 mW could reach up to 40.7% within 12 h. Furthermore, a 15 mW laser was applied for the scanning microscopy imaging to verify a favorable uptake in the nanocomposites-incubated cells, which cause little drug release. The 300 mW laser manipulated drug delivery of UCNP@SiO2-DOX and caused an acute loss of cell viability, which was measured by the CCK-8 assay and PI stain.
In this study, the Yb3+-enhanced UCNP@SiO2 were successfully applied to consecutive imaging, photothermal-controlled drug delivery for cancer therapy, which reveal many distinct advantages. Firstly, the Yb3+-enhanced UCNP@SiO2 nanocomposites provide a simple and straightforward drug delivery strategy manipulated by light, without other stimuli-sensitive auxiliaries. Secondly, the design of mesoporous silica shell acceptably minimized drug release during the circulation and bring a high DOX release rate. Thirdly, the Yb3+-enhanced UCNP@SiO2 possesses great potential applications in simultaneous biomedical imaging and photothermal-triggered on-site delivery systems for cancer therapy (low power laser for imaging and subsequently high power for drug delivery). For pursuing better therapeutic effect, the nanocomposites could be equiped with functional group (such as carboxyl) to improve the loading efficiency and ligand (such as folic acid) to obtain cancer targeting. Besides, different rare earth iron species and concentration should be tried to get better luminous efficiency and thermal energy. More efforts should be done to develop the potential applications in imaging-guided cancer therapy of the Yb3+-enhanced UCNP@SiO2 drug delivery system.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (61405062, 91233208), the Guangdong Innovative Research Team Program (201001D104799318), the Guangdong Natural Science Foundation of Guangdong province (2014A030313445), the China Postdoctoral Science Foundation (2013M530368, 2014T70818), and the Discipline and Specialty Construction Foundation of Colleges and Universities of Guangdong Province (2013LYM_0017).
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