Full length articleNear-infrared light-activated red-emitting upconverting nanoplatform for T1-weighted magnetic resonance imaging and photodynamic therapy
Graphical abstract
Introduction
In cancer treatment, chemotherapy is a major approach that has severe toxic side effects and a tendency to lead to drug resistance that limits the efficiency of chemotherapy drugs for cancer treatment [1], [2], [3], [4]. By contrast, as a clinically approved therapeutic modality, photodynamic therapy (PDT) has been proved as a more favorable cancer treatment with a minimally invasive nature, fewer side effects, and less damage to normal tissues [5], [6], [7]. In PDT, light, photosensitizer molecules, and reactive oxygen species (ROS) are the three key components [8]. Under irradiation of a specific light, photosensitizers produce cytotoxic ROS (cytotoxic singlet oxygen (1O2) or free radicals) through an energy transfer process [9], and cancer cells are killed by ROS-mediated DNA breakage [10], [11], [12], [13]. To efficiently avoid injuring the normal tissue in PDT, many investigators are trying to improve ROS generation and sufficiently enhance the accumulation of photosensitizer agents at tumor sites [14], [15]. It is known that red light is often preferentially used with second-generation photosensitizers in clinical practice [16] because the longer wavelength increases the tissue penetration of light, thereby improving ROS generation. Improving the tissue penetration of irradiated light remains a major challenge in PDT therapy [17], [18]. However, the optical transparency window (600–1000 nm) of a biological tissue has been revealed to be in the near-infrared (NIR) region, which has less scattering and increased tissue penetration of light [19], [20]. At present, with the development of nanotechnology, lanthanide-doped upconverting nanoparticles (UCNPs) have been developed; UCNPs can be excited by tissue-penetrating NIR light (980 nm), and they emit in the ultraviolet and visible ranges [21], [22], [23], [24], [25]. UCNPs have been proved to have the ability to efficiently produce ROS by fluorescence resonance energy transfer (FRET) from the surface of UCNPs to photosensitizer molecules [26], [27], [28], [29], [30], [31]. NIR light-activated UCNPs potentially open new doors to the next generation of PDT. The current UCNP-based NIR light-activated PDT systems mainly focus on designing photosensitizers to efficiently utilize the upconverted light for the green and red emissions of Yb/Er-codoped UCNPs [32], [33], [34]. In general, traditional Yb/Er systems have much higher emissions in the green region than those in the red region under 980-nm excitation [35], [36], [37]; this limits the further application of UCNPs in cancer treatment. Although Mn2+ doping in NaLnF4: Yb, Er systems has been proposed to enhance red emission, its application is hindered by the particle size of Mn2+ doped-UCNPs and its toxicity, which makes it difficult to use for applications in drug delivery systems.
In this investigation, we developed a glioma-targeted multifunctional nanoplatform based on NIR light-activated rUCNPs for PDT. The novel rUCNPs were synthesized by thermal decomposition and a seed-mediated process, and this was followed by modification with human serum albumin (HSA) protein molecules that were used as a vehicle for the Ce6-Mn photosensitizer. The cRGDyK peptide, which targets αvβ3-integrin that is overexpressed in the tumor vasculature endothelium, was covalently linked to the rUCNPs@HSA surface to increase its specific binding to glioma. We designed and synthesized this nanoplatform for the following reasons: (1) HSA, the most abundant plasma protein, is a good biocompatible molecule and often used to load various hydrophobic drugs owing to the hydrophobic domains inside its tertiary structure [38]. (2) Enhanced red emission of the novel rUCNPs under 980-nm light excitation was obtained by doping 40% Yb, and the optimally red-emitting rUCNPs caused the Ce6-Mn complex inside HSA to produce ROS and induce cancer cell apoptosis. (3) Ce6 molecules, a second-generation photosensitizer, have a long-lived photoexcited triplet state and can be complexed with Mn2+. This chelate complex that is distributed around the rUCNPs enabled our nanoplatform to be used for tumor diagnosis with T1-weighted magnetic resonance imaging (MRI) functionality and provided a probe with a whole-body distribution for fluorescence imaging. Furthermore, in vivo experiments showed that the PDT based on our nanoplatform had efficient antitumor ability for glioma treatment.
Section snippets
Materials
ScCl3·6H2O, YbCl3·6H2O, ErCl3·6H2O, oleic acid (OA, 90%), 1-octadecene (ODE, 90%), poly(acrylic acid) (PAA, MW = 1800), diethylene glycol (DEG), sodium oleate, and dimethyl sulfoxide (DMSO, 99%) were purchased from Aladdin. 1-Ethyl-3-(3-(dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) were purchased from Sinopharm Chemical Reagent Co., Ltd. Chlorin e6 (Ce6) was purchased from J&K Chemical Reagent Co., Ltd. HSA was bought from Beijing Biosynthesis Biotechnology Co., Ltd.
Synthesis and characterization of the rUCNPs@HSA(Ce6-Mn)-RGD nanoplatform
The synthetic procedure for the rUCNPs@HSA(Ce6-Mn)-RGD nanoplatform is illustrated in Fig. 1a. Monodisperse NaScF4: 40% Yb, 2% Er NPs were first synthesized by a modified high-temperature protocol and were then coated with a CaF2 shell through a seed-mediated process to obtain the NaScF4: 40% Yb, 2% Er@CaF2 (rUCNPs) core/shell structure. To decorate rUCNPs with a carboxyl group, PAA was used for ligand exchange. Given that biostability and biocompatibility are prerequisites for clinical use,
Conclusion
In summary, we have successfully developed an efficient NIR light-activated glioma tumor-targeting nanoplatform for PDT treatment based on a novel, enhanced red-emitting rUCNP core/shell structure. The R/G ratio of the rUCNPs almost reached 6. By loading the Ce6-Mn complex into the rUCNPs@HSA-RGD system, the nanoplatform could be used for T1-weighted MRI diagnosis and PDT treatment of glioma tumors. The nanoplatform has shown excellent ROS generation under NIR irradiation and good PDT antitumor
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (81471183), the Clinical Medical Special Program of Science and Technology Project of Jiangsu Province (BL2014074), the Industry Program of Science and Technology Support Project of Jiangsu Province (BE2014128), the Major Program of Natural Science Fund in Colleges and Universities of Jiangsu Province (15KJA430005), the Prospective Joint Research Program of Jiangsu Province (BY201500501), the Program for
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