Discovery of Imaging and Therapeutic Integration Bifunctional Molecules Based on Bio-Orthogonal Reaction and Releasable Disulfide Bond

Abstract

The application of conventional fluorescent probes in living cells has been limited by excess fluorescence interference, reduced selectivity, and poor permeability. Herein, we describe a convenient solution for overcoming the above limitations based on bio-orthogonal reactions and releasable linkers that provide bifunctional molecules for imaging and therapeutic integration. To reduce the interference of excess fluorescent moieties, a bioorthogonal reaction was applied to activate the fluorescence of the active parent drugs without fluorophores. Moreover, disulfide bonds were incorporated as releasable linkers. After imaging the target protein, the newly yielded fluorophore could be released from the active drugs based on the highly reducing conditions of the tumor. Thus, these bifunctional molecules are comparable in therapeutic activity to the parent drug. These novel imaging and therapeutic integration molecules could be used to realize imagingaided diagnosis and perform efficient real-time monitoring of cancer cells. Our findings are expected to enable efficient and specific imaging and real-time in vivo prognostic monitoring in the clinic.

Dual-Functional AIE Fluorescent Probe for Visualization of Lipid Droplets and Photodynamic Therapy of Cancer

“…As depicted in Scheme 1., the dithiophene ethylene group of TDTI acted as an extended π-bridge to connect TPA (electron donor) and the 1,3indandione (electron acceptor) group, which could not only distinctly extend the emission wavelength and decrease the autofluorescence interference for precise bioimaging but also form a strong D−π−A structure to separate the highest occupied molecular orbital (HOMO)−the lowest unoccupied molecular orbital (LUMO) distribution, thus facilitating reducing the energy gap between the excited singlet state and the excited triplet state (ΔE ST ) for efficient ROS generation. To validate our hypothesis, TDTI was synthesized from 4-(diphenylamino)phenylboronic acid in two steps (Scheme 1) and verified by 1 H NMR, 13 C NMR, and highresolution mass spectrometry, as shown in the Supporting Information (Figures S12−S15).…”

“…4−13 Most of these assays were developed based on the platform designed to realize the simultaneous detection of cancer biomarkers and delivery of antitumor drugs, 7−11 and concerns remained including drug immunity, bone marrow suppression, and so on. 8,10,12,13 Fluorescence imaging provided a powerful tool for early disease diagnosis by monitoring the variation of biomarkers at the cellular level because of its noninvasive nature, easy operation, excellent sensitivity, and prominent resolution. 14−16 On the other hand, photodynamic therapy (PDT) with noninvasive, slight drug immunity and few adverse effects, 17,18 when compared with traditional cancer therapy (drug therapy or radiotherapy), has emerged as a prospective solution for cancers.…”

“…4-(Diphenylamino)phenylboronic acid and 5-bromo-2,2-dithiophene formaldehyde were manufactured by Macklin Reagent Factory, and 4-(triphenylphosphine) palladium was obtained from Jiuding Chemical Factory. 1 H and 13 C NMR spectra were detected on a 600 MHz spectrometer (Bruker Avancez III). A mass spectrometer (Bruker Autoflex) was utilized to measure the high-resolution mass spectrum.…”

“…The high fatality rate of cancer is always associated with diagnosis at an advanced period, and prompt diagnosis of cancer is therefore crucial to ensure efficient treatment at an early stage without local metastasis or further progression of the disease. − Compared with the traditional separation of cancer diagnosis and therapy, the integration of diagnosis and therapy permits real-time diagnosis and parallel therapy, which possibly seizes the golden age of treatment, simplifies the process of therapy, and avoids the unsatisfactory biological distribution and bioactivity of diagnostic or therapeutic reagents . In recent years, a series of literature regarding the integration of cancer diagnosis and treatment has been reported. − Most of these assays were developed based on the platform designed to realize the simultaneous detection of cancer biomarkers and delivery of antitumor drugs, − and concerns remained including drug immunity, bone marrow suppression, and so on. ,,, Fluorescence imaging provided a powerful tool for early disease diagnosis by monitoring the variation of biomarkers at the cellular level because of its noninvasive nature, easy operation, excellent sensitivity, and prominent resolution. − On the other hand, photodynamic therapy (PDT) with noninvasive, slight drug immunity and few adverse effects, , when compared with traditional cancer therapy (drug therapy or radiotherapy), has emerged as a prospective solution for cancers. − PDT generally utilizes prime photosensitizers (PSs) to spatiotemporally generate reactive oxygen species (ROS) under irradiation to induce apoptosis of cancer cells. , Currently, many PSs such as BODIPY derivatives, metal–organic frameworks (MOFs), chlorine E6, and Rose Bengal have thus been developed for PDT. − However, the aggregation-caused quenching (ACQ) effects of these conventional PSs incurred low PDT efficiency. − Conversely, luminogens with aggregation-induced emission (AIE) performance could effectively produce ROS even in the aggregated status and circumvent the ACQ effect. , These aggregation-induced emission luminogens (AIEgens) would undoubtedly be satisfactory candidates for PDT. Therefore, the development of biomarker-responsive AIE fluorescent probes ac...…”