AIEgen-based theranostic system: targeted imaging of cancer cells and adjuvant amplification of antitumor efficacy of paclitaxel.
ABSTRACT: Photosensitizers are generally treated as key components for photodynamic therapy. In contrast, we herein report an aggregation-induced emission luminogen (AIEgen)-based photosensitizer (TPE-Py-FFGYSA) that can serve as a non-toxic adjuvant to amplify the antitumor efficacy of paclitaxel, a well-known anticancer drug, with a synergistic effect of "0 + 1 > 1". Besides the adjuvant function, TPE-Py-FFGYSA can selectively light up EphA2 protein clusters overexpressed in cancer cells in a fluorescence turn-on mode, by taking advantage of the specific YSA peptide (YSAYPDSVPMMS)-EphA2 protein interaction. The simple incorporation of FFG as a self-assembly-aided unit between AIEgen (TPE-Py) and YSA significantly enhances the fluorescent signal output of TPE-Py when imaging EphA2 clusters in live cancer cells. Cytotoxicity and western blot studies reveal that the reactive oxygen species (ROS) generated by TPE-Py-FFGYSA upon exposure to light do not kill cancer cells, but instead provide an intracellular oxidative environment to help paclitaxel have much better efficacy. This study thus not only extends the application scope of photosensitizers, but also offers a unique theranostic system with the combination of diagnostic imaging and adjuvant antitumor therapy.
Project description:Nanoparticle drug delivery system (NDDS) is quite different from the widely studied traditional chemotherapy which suffers from drug resistance and side effect. NDDS offers the straightforward solution to the chemotherapy problem and provides an opportunity to monitor the drug delivery process in real time. In this vein, we developed one NDDS, namely Py-TPE/siRNA@PMP, to relieve resistance and side effects during chemotherapy against ovarian cancer. The Py-TPE/siRNA@PMP is a multifunctional polymeric nanoparticle contained several parts as follows: (1) a nanoparticle (NP) self-assembled by reduction-sensitive paclitaxel polymeric prodrug (PMP); (2) the glutathione (GSH)-responsive release of paclitaxel (PTX) for the suppression of ovarian cancer cells; (3) the P-glycoprotein (P-gp) siRNA for restoring the sensitivity of chemo-resistant tumor cells to chemotherapy; (4) the positively charged aggregation-induced emission fluorogen (AIEgen) Py-TPE for tumor imaging and promoting encapsulation of siRNA into the nanoparticle. <b>Methods</b>: The Py-TPE/siRNA@PMP nanoparticles were prepared by self-assembly method and characterized by the UV-Vis absorption spectra, zeta potentials, TEM image, stability assay and hydrodynamic size distributions. The combinational therapeutic effects of Py-TPE/siRNA@PMP on overcoming chemotherapy resistance were explored both <i>in vitro</i> and <i>in vivo.</i> <b>Result</b>: The Py-TPE/siRNA@PMP exhibited an average hydrodynamic size with a good stability. Meanwhile they gave rise to the remarkable chemotoxicity performances <i>in vitro</i> and suppressed the tumors growth in both SKOV-3/PTX (PTX resistance) subcutaneous and intraperitoneal metastasis tumor models. The investigations on ovarian cancer patient-derived xenografts (PDX) model revealed that Py-TPE/siRNA@PMP was able to effectively overcome their chemo-resistance with minimal side effects. <b>Conclusion:</b> Our findings demonstrated the Py-TPE/siRNA@PMP as a promising agent for the highly efficient treatment of PTX-resistant cells and overcoming the shortage of chemotherapy in ovarian cancer.
Project description:Stimuli-responsive functional gels have shown significant potential for application in biosensing and drug release systems. In this study, aggregation-induced emission luminogen (AIEgen)-functionalized, diselenide-crosslinked polymer gels were synthesized via free radical copolymerization. A series of polymer gels with different crosslink densities or tetraphenylethylene (TPE) contents were synthesized. The diselenide crosslinker in the gels could be fragmented in the presence of H2O2 or dithiothreitol (DTT) due to its redox-responsive property. Thus, the TPE-containing polymer chains were released into the aqueous solution. As a result, the aqueous solution exhibited enhanced fluorescence emission due to the strong hydrophobicity of TPE. The degradation of polymer gels and fluorescence enhancement in an aqueous solution under different H2O2 or DTT concentrations were studied. Furthermore, the polymer gels could be used as drug carriers, suggesting a visual drug release process under the action of external redox agents. The AIEgen-functionalized, diselenide-crosslinked polymer gels hold great potential in the biomedical area for biosensing and controlled drug delivery.
Project description:The design and synthesis of three-dimensional covalent organic frameworks (3D COFs) have still been considered as a big challenge. Here we report the design and synthesis of an AIEgen-based 3D COF (3D-TPE-COF), with a high surface area (1084?m2?g-1). According to powder X-ray diffraction and continuous rotation electron diffraction analyses, 3D-TPE-COF is identified to adopt a seven-fold interpenetrated pts topology. Interestingly, 3D-TPE-COF emits yellow fluorescence upon excitation, with a photoluminescence quantum yield of 20%. Moreover, by simply coating 3D-TPE-COF onto a commercial blue light-emitting diode (LED), a prototype white LED (WLED) under continuously driving without degradation for 1200?h was demonstrated. The present work suggests the possibility of using COF materials for stable WLEDs, which will greatly inspire us to design and synthesize fluorescent 3D COFs and facilitate the development of COF-based WLEDs in future.
Project description:YSA is an EphA2-targeting peptide that effectively delivers anticancer agents to prostate cancer tumors. Here, we report on how we increased the drug-like properties of this delivery system.By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide. We describe the details of the synthesis of YNH and dYNH paclitaxel conjugates (YNH-PTX and dYNH-PTX) and their characterization in cells and in vivo.dYNH-PTX showed improved stability in mouse serum and significantly reduced tumor size in a prostate cancer xenograft model and also reduced tumor vasculature in a syngeneic orthotopic allograft mouse model of renal cancer compared with vehicle or paclitaxel treatments.This study reveals that targeting EphA2 with dYNH drug conjugates could represent an effective way to deliver anticancer agents to a variety of tumor types.
Project description:Furan-cored AIEgen namely tetraphenylethylene-furan (TPE-F) is developed by diyne cyclization and its fluorescent and chemical properties are investigated and compared with its thiophene analogue. Results show that furan is superior to thiophene in terms of fluorescence, chromism, and charge transport. The mechanism of chromism of TPE-F is investigated and its efficient solid-state photoluminescence and good charge-transporting property enable it to serve as light-emitting material for the construction of electroluminescence devices with excellent performance. This work not only demonstrates an efficient strategy for constructing furan-cored AIEgens but also indicates that they are promising as advanced optoelectronic materials.
Project description:Articulated structures of naphthalene-based donor (D)-acceptor (A) type dipolar dye and aggregation-induced emission luminogen (AIEgen) based on tetraphenylethylene (TPE) were synthesized, and their photophysical properties were analyzed for the first time. There are many fluorophore backbones, which have dipolar structure and AIEgen. However, there has been neither property analysis nor research that closely articulates DA and AIE through non-conjugation linker. We have therefore prepared two representative fluorophores; DA-AIE series (DA-AIE-M and DA-AIE-D), and characterized their UV/vis absorption and emission properties with quantum chemical calculations. In addition, we utilized the unique photophysical properties of DA-AIE-D for monitoring a trace of dimethyl sulfoxide (DMSO) in aqueous media, including real water samples.
Project description:EphA2 overexpression has been associated with metastasis in multiple cancer types, including melanomas and ovarian, prostate, lung, and breast cancers. We have recently proposed the development of peptide-drug conjugates (PDCs) using agonistic EphA2-targeting agents, such as the YSA peptide or its optimized version, 123B9. Although our studies indicated that YSA- and 123B9-drug conjugates can selectively deliver cytotoxic drugs to cancer cells in vivo, the relatively low cellular agonistic activities (i.e., the high micromolar concentrations required) of the agents toward the EphA2 receptor remained a limiting factor to the further development of these PDCs in the clinic. Here, we report that a dimeric version of 123B9 can induce receptor activation at nanomolar concentrations. Furthermore, we demonstrated that the conjugation of dimeric 123B9 with paclitaxel is very effective at targeting circulating tumor cells and inhibiting lung metastasis in breast-cancer models. These studies represent an important step toward the development of effective EphA2-targeting PDCs.
Project description:Lysosomes are involved in a multitude of cellular processes and their dysfunction is associated with various diseases. They are the most acidic organelles (pH 3.8-6.6, size 0.1-1.2 ?m) with the highest viscosity (47-190 cP at 25 °C) in the cell. Because of their acidity, pH dependent non-AIE active fluorescent lysosomal probes have been developed that rely on protonation inhibited photoinduced electron transfer (PET). In this work, an acidic pH independent lysosome targetable piperazine-TPE (PIP-TPE) AIEgen has been designed with unique photophysical properties making it a suitable probe for quantifying viscosity. In a non-aggregated state PIP-TPE shows deep-blue emission as opposed to its yellowish-green emission in the bulk. It possesses high specificity for lysosomes with negligible cytotoxicity and good tracing ability due to its better photostability compared to LysoTracker Red. In contrast to most known lysosome probes that rely solely on PET, restriction of intramolecular motion (RIM) due to the larger viscosity inside the lysosomes is the mechanism responsible for PIP-TPE's fluorescence. PIP-TPE's high selectivity is attributed to its unique molecular design that features piperazine fragments providing a perfect balance between lipophilicity and polarity.
Project description:The EphA2 receptor tyrosine kinase has emerged as a promising new therapeutic target in cancer because of its high level of expression in tumors. EphA2-specific antibodies have been used to deliver drugs and toxins to tumor cells, leading to inhibition of tumor growth and metastatic dissemination. We previously identified two related peptides, YSA and SWL, that selectively bind to the ligand-binding domain of EphA2 but not other Eph receptors and could therefore be useful as selective targeting agents. Here we characterize the two peptides and a series of derivatives. On the basis of systematic amino acid replacements, only five YSA residues appear to be critical for high-affinity receptor binding. Furthermore, a peptide comprising only the first five residues of YSA retains selectivity for EphA2. Similar to ephrin-A1, the physiological ligand for EphA2, both YSA and SWL activate EphA2 and inhibit downstream oncogenic signaling pathways in PC3 cancer cells. The two peptides and derivatives are quite stable in conditioned cell culture medium and show promise for delivering drugs and imaging agents to EphA2-expressing tumors.
Project description:The EPH receptor A2 (EphA2) tyrosine kinase plays an important role in a plethora of biological and disease processes, ranging from angiogenesis and cancer to inflammation and parasitic infections. EphA2 is therefore considered an important drug target. Two short peptides previously identified by phage display, named YSA and SWL, are widely used as EphA2-targeting agents owing to their high specificity for this receptor. However, these peptides have only modest (micromolar) potency. Lack of structural information on the binding interactions of YSA and SWL with the extracellular EphA2 ligand-binding domain (LBD) has for many years precluded structure-guided improvements. We now report the high-resolution (1.53-2.20 Å) crystal structures of the YSA peptide and several of its improved derivatives in complex with the EphA2 LBD, disclosing that YSA targets the ephrin-binding pocket of EphA2 and mimics binding features of the ephrin-A ligands. The structural information obtained enabled iterative peptide modifications conferring low nanomolar potency. Furthermore, contacts observed in the crystal structures shed light on how C-terminal features can convert YSA derivatives from antagonists to agonists that likely bivalently interact with two EphA2 molecules to promote receptor oligomerization, autophosphorylation, and downstream signaling. Consistent with this model, quantitative FRET measurements in live cells revealed that the peptide agonists promote the formation of EphA2 oligomeric assemblies. Our findings now enable rational strategies to differentially modify EphA2 signaling toward desired outcomes by using appropriately engineered peptides. Such peptides could be used as research tools to interrogate EphA2 function and to develop pharmacological leads.