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Sandwich-structured upconversion nanoprobes coated with thin silica layer for mitochondria-targeted cooperative photodynamic therapy for solid malignant tumors Xin-Yue Song, Zihong Yue, Tongtong Hong, Zonghua Wang, and Shusheng Zhang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b01805 • Publication Date (Web): 06 Jun 2019 Downloaded from http://pubs.acs.org on June 6, 2019
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Analytical Chemistry
Sandwich-structured upconversion nanoprobes coated with thin silica layer for mitochondria-targeted cooperative photodynamic therapy for solid malignant tumors Xinyue Song,a Zihong Yue,ab Tongtong Hong,ab Zonghua Wangb and Shusheng Zhanga* Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Provincial Key Laboratory of Detection Technology for Tumor Markers, College of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, P. R. China. b Shandong Sino-Japanese Center for Collaborative Research of Carbon Nanomaterials, College of Chemistry and Chemical Engineering, Qingdao University, Shandong 266071, P. R. China a
ABSTRACT: Upconversion nanoparticles-based photodynamic nanotheranostic agents (UCNPs-PDT) have obtained great interest due to the improved tissue penetration, weak autofluorescence and low biotoxicity. However, conventional UCNPs-PDT is often limited by the low energy transfer efficiency from UCNPs to photosensitizer (PS) molecules, insufficient generation and limited diffusion distance of reactive oxygen species (ROSs). Herein, an “all in one” nanotheranostic agent has been developed which has multi-color sandwich-structured UCNPs (SWUCNPs) as the core, a thin silica layer with mitochondria-targeted group for loading dual PS as the medium layer, and polyethylene glycol-folic acid (PEG-FA) chains as the outer layer. Multi-color SWUCNPs simultaneously achieve the two-photon fluorescence imaging and energy donor for dual PS molecules. The thin luminescence layer and silica layer control most UCNPs activators and PS molecules in the effective energy transfer distance to guarantee a high energy transfer efficiency. Via the FA-mediated endocytosis, the nanotheranostic agent is selectively endocytosed by cancer cells, escapes from endosome/lysosome, targets to the mitochondria and in-situ produces ROSs under the excitation of NIR, leading to significant mitochondria-mediated cell apoptosis. Furthermore, the established nanotheranostic agent shows tumor targetability, increased generation of ROSs, high PDT efficacy, significant cell apoptosis, minimal systemic cytotoxicity and efficacious in vivo tumor inhibition.
Over the past few decades, photodynamic therapy (PDT) has considered as an effective cancer therapy modality which involves the excitation of photosensitizers (PS) by the focused light to form the PS at the excited triplet state and then interacts directly with molecular oxygen to produce reactive oxygen species (ROSs). The produced ROSs could induce cancer cell apoptosis and further destroy tumor section.1,2 Compared with other treatment models, PDT could minimize the collateral damage to normal tissues by localized delivery of the PS and light irradiation which could precisely treat the tumor with facile, flexible, and spatiotemporal control.3,4 Thus, PDT could act as “magic bullets” to selectively destroy malignant tumors.5 Therefore, the development of PDT may bring novel opportunities to future precise cancer diagnosis. However, most clinically-approved PS molecules have absorption in the ultraviolet-visible (UV-Vis) range, suffering from the limited tissue penetration depth and ineffective therapeutic response for deep-seated tumors.6 The nearinfrared (NIR) light is located within the biological transparency window, allowing greater tissue penetration depth and negligible background autofluorescence, thus the NIR light would act as a perfect alternative to the excitation light for PDT.7 Via the two-photon or multi-photon
mechanism, upconversion nanoparticles (UCNPs) could convert continuous NIR excitation light to tunable UV-Vis emissions. Based on the luminescence resonance energy transfer (LRET) strategy, UCNPs as the energy donor could excite PS molecules (energy acceptor) to achieve UCNPsbased PDT which could achieve deep PDT for malignant tumors at deep locations.8,9 However, conventional UCNPsPDT is often limited by the low energy transfer efficiency from UCNPs to PS, the insufficient ROSs generation, short lifespan and limited diffusion distance of ROSs. To increase the ROSs production, the dual-PS structure was introduced into the UCNPs-PDT nanoplatform which dual PS molecules10,11 and the combination of nano-PS (TiO2)12-14 and PS molecules15 were co-loaded into UCNPs. The in vitro and in vivo experiments indicated that dual PS-doped system could produce increased amount of ROSs and induce higher cancer cell apoptosis than single PS-doped system. However, upconversion fluorescence was quenched by PS molecules to produce ROSs, thus an extra fluorescence dye or PS molecules were indispensable for tracking UCNPs,10,15 which weakened the superiorities of upconversion luminescence imaging such as deep penetration, weak autofluorescence, minimal photobleaching and low phototoxicity. TiO2 as the nano-PS
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would face with several limitations including poor water solubility, easy aggregation in physiological environment, possible biomolecular damage due to the requirement of the UV excitation.16,17 Compared with nano-PS, organic PS molecules such as methylene blue (MB) and rose bengal (RB) have been widely used in PDT nanoplatform. MB has advantageous characteristics for application in PDT such as high light absorbance in the therapeutic window and induction of both photosensitization mechanism type I and type II to produce ROSs.18 RB has been confirmed as a very promising PS as it ensures a long-lasting cytotoxic effects by induction of relevant percentage of apoptosis and autophagy in a timerelated manner after PDT.19 Thus, MB and RB involved nanotheranostic agents have promising PDT efficacy. Furthermore, the established dual-PS involved UCNPs-PDT nanoplatforms were lack of the special targetability to cancer cells and organelles involved in cell apoptosis,10,11 would leading to the possible biotoxicity to normal cells and low cytotoxicity to cancer cells. Limited by the short half-life (
