NIR-triggered anticancer drug delivery by upconverting nanoparticles with integrated azobenzene-modified mesoporous silica.

Cancer is one of the most common causes of death in the world, and chemotherapy remains to be one of the most frequent treatments for many cancers. However, its success has been greatly limited because of systemic toxicity due to the toxic effects by the nonspecific distribution of anti-cancer drugs. The drug delivery systems with the features of sustained drug release have attracted much attention owing to their enhanced therapeutic efficacy and reduced side effect. For example, mesoporous silica nanoparticles (MSNs) with interesting properties, such as thermal and photostability, tunable sizes, high loading capacity, and the ease of functionalization according to currently available results, have made the MSNs one of the most promising carriers for drug delivery. Although MSNs-based drug delivery systems have been proven effective, however, the use of cytotoxic drugs that are only released in the target area is much more preferred in clinical application. One way to prevent any premature release of anticancer drugs before they reach the target cells is to develop stimuli-responsive systems with controlled release features. Over the past decade, researches on MSNs-based light-controlled drug delivery systems have been carried out extensively because light as an external stimulus offers controllable drug release both spatially and temporally and thus exhibits great potentials for further biomedical applications. However, most of them have achieved limited success in applications in vitro and in vivo mainly because of the easy damages to both biological samples and living tissues by UV light used to excite the photosensitizer and extremely quick attenuation of UV light in tissues. To tackle this issue, it is highly desirable to develop NIR remote-controllable MSNs-based system which can be used both in vitro and in vivo, which, however, has not been well addressed and remains a great challenge. Compared to UV light, near-infrared (NIR) light is much less damaging to biological specimens and living tissues involved and has remarkably deeper tissue penetration. For example, Parak and co-workers reported that polyelectrolyte multilayer capsules loaded with cargo and plasmonic (Au or Ag) NPs can be used to release the cargo by NIR-photothermal heating. The cargo can be easily released with high efficiency under NIR exposure in one second. However, the size of these capsules can be as large as several microns, which will inevitably suffer from phagocytosis by reticuloendothelial systems (RES) when these systems are intravenously injected. Recently, upconverting nanoparticles (UCNPs) have emerged as an appealing candidate for the application of NIR light. Because of the unique ladder-like energy level structures of lanthanide ions (such as Tm, Er, and Ho), UCNPs are able to absorb NIR light and convert it into highenergy photons in a very broad range from the UV to the NIR region. Such a unique and fascinating photoluminescence property enables UCNPs to function as a NIR-induced mediator by coating caged compounds on the nanoparticle surface, and as a NIR-controlled photoswitch for reversible ring-closing and ring-opening transformation of a dithienylethene compound. Very recently, Branda and co-workers successfully used the NIR laser to dissociate block copolymer micelles by encapsulating UCNPs inside micelles. Since the copolymer micelles will inevitably suffer from self-degradation in biological environment, a combination between UCNPs and micelles may find few opportunities in practical bio-applications for remote-controlled drug delivery using a NIR laser in vitro and in vivo. In more recent studies, our group successfully demonstrated UCNP/methylene bluebased photodynamic therapy (PDT) through controlled singlet oxygen release triggered by NIR light. However, in spite of all the above efforts, reports on the direct NIRlight-controlled anticancer drug release for cancer therapy from a UCNPs-containing structure has not been found in the literature to date, which remains a great challenge in lightcontrolled drug delivery studies. Herein, we report a novel and general strategy for NIR light-triggered anticancer drug release based on amesoporous silica-coated UCNPs structure, designated as UCNP@mSiO2. Figure 1a shows the synthetic procedure for UCNP@mSiO2. The strategy consists of preparing NaYF4: TmYb@NaYF4 core–shell nanoparticles and subsequently coating the Tmdoped core–shell UCNPs with mesoporous silica. After [*] J. N. Liu, Prof. W. B. Bu, L. M. Pan, Prof. J. L. Shi State Key Laboratory of High Performance Ceramics and Superfine Microstructure Shanghai Institute of Ceramics, Chinese Academy of Sciences 1295 Ding-Xi Road, Shanghai 200050 (China) E-mail: wbbu@mail.sic. ac.cn jlshi@sunm.shcnc. ac.cn