Research Article Cite This: ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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Multifunctional Two-Photon AIE Luminogens for Highly Mitochondria-Specific Bioimaging and Efficient Photodynamic Therapy Weihua Zhuang,†,§ Li Yang,†,§ Boxuan Ma,† Qunshou Kong,† Gaocan Li,*,† Yunbing Wang,*,† and Ben Zhong Tang‡ †
National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Institute for Advanced Study, Department of Chemical and Biological Engineering and Division of Life Science, The Hong Kong University of Science and Technology (HKUST), Clear Water Bay, Kowloon, Hong Kong, China
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S Supporting Information *
ABSTRACT: In recent years, photodynamic therapy (PDT) has drawn much attention as a noninvasive and safe cancer therapy method due to its fine controllability, good selectivity, low systemic toxicity, and minimal drug resistance in contrast to the conventional methods (for example, chemotherapy, radiotherapy, and surgery). However, some drawbacks still remain for the current organic photosensitizers such as low singlet oxygen (1O2) quantum yield, poor photostability, inability of absorption in the near-infrared (NIR) region, short excitation wavelength, and limited action radius of singlet oxygen, which will strongly limit the PDT treatment efficiency. As a consequence, the development of efficient photosensitizers with high singlet oxygen quantum yield, strong fluorescent emission in the aggregated state, excellent photostability, NIR excitation wavelength ranging in the biological transparency window, and highly specific targeting to mitochondria is still in great demand for the enhancement of PDT treatment efficiency. In this study, two new two-photon AIEgens TPPM and TTPM based on a rigid D−π−A skeleton have been designed and synthesized. Both AIEgens TPPM and TTPM show strong aggregation-induced emission (AIE) with the emission enhancement up to 290-folds, large two-photon absorption with the two-photon absorption cross section up to 477 MG, and highly specific targeting to mitochondria in living cells with good biocompatibility. They can serve as two-photon bioprobes for the cell and deep tissue bioimaging with a penetration depth up to 150 μm. Furthermore, high 1O2 generation efficiency with high 1O2 quantum yield under white light irradiation has been found for both TPPM and TTPM and high PDT efficiency to HeLa cells under white light irradiation has also been proven. To the best of our knowledge, AIEgens in this work constitute one of the strongest emission enhancements and one of the highest 1 O2 generation efficiencies in the reported organic AIEgens so far. The great AIE feature, large two-photon absorption, high specificity to mitochondria in living cells, and high PDT efficiency to living cells as well as excellent photostability and biocompatibility of these novel AIEgens TPPM and TTPM reveal great potential in clinical applications of two-photon cell and tissue bioimaging and image-guided and mitochondria-targeted photodynamic cancer therapy. KEYWORDS: aggregation-induced emission, two-photon, mitochondria imaging, photosensitizer, photodynamic therapy
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reactive oxygen species such as 1O2 to kill the cancer cells.4−6 Different kinds of photosensitizers such as bacteriochlorin, phthalocyanines, and porphyrin derivatives have been developed with simultaneous capabilities of tumor bioimaging and therapy, and some porphyrin derivatives such as chlorin e6 (Ce6) have been approved for clinical applications.7 However, some drawbacks still remain for the current organic photosensitizers such as low singlet oxygen quantum yield, poor
INTRODUCTION Malignant tumors have been one of the most serious health threats with high mortality rate, and much effort has been devoted to develop effective treatments to enhance treatment effect and reduce side effects over past decades. In recent years, photodynamic therapy (PDT) has attracted much attention as a noninvasive and safe cancer therapy method due to its precise controllability, good selectivity, low systemic toxicity, and minimal drug resistance in contrast to the conventional methods (for example, chemotherapy, radiotherapy, and surgery).1−3 In the presence of oxygen and light irradiation, photosensitizers (PSs) play an important role that produce © XXXX American Chemical Society
Received: March 19, 2019 Accepted: May 21, 2019
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DOI: 10.1021/acsami.9b04813 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
Research Article
ACS Applied Materials & Interfaces Scheme 1. Synthesis of Two-Photon AIEgens TPPM and TTPM
can only be excited by one-photon absorption and can only absorb a narrow range of white light compared to these PSs with two-photon absorption that can be excited by both onephoton absorption and two-photon absorption. Until now, several examples of two-photon mitochondria-targeted PSs with AIE-active emission have been reported by Tang and coworkers.24,26,27 However, most of these reported two-photon PSs are limited by a relatively low efficiency of 1O2 generation, which would limit their further application in PDT.24,26 Moreover, the synthesis of some PSs through a special cyclization reaction may limit the further regulation of their molecular electron effect and the further expansion of new kinds of PSs.27 Therefore, the development of new kinds of two-photon mitochondria-targeting PSs with concise synthetic routes, significantly enhanced 1O2 generation, and bright fluorescent emission in aggregated state is highly desirable. In this contribution, two new two-photon AIEgens TPPM and TTPM based on a D−π−A skeleton have been designed and synthesized (Scheme 1). Both TPPM and TTPM show dramatic AIE features, efficient 1O2 generation with high 1O2 quantum yield. Furthermore, high specificity to mitochondria in living cells, deep tissue imaging, and high PDT effect to living cells under white light irradiation have also been observed for both TPPM and TTPM with excellent photostability and good biocompatibility, which would be promising candidates for the clinic application in two-photon cell and tissue bioimaging and mitochondria-targeted PDT.
photostability, inability of absorption in the near-infrared (NIR) region (>700 nm), short singlet oxygen lifetime (
