Yue Hu,Anchen Fu,Zhaoyi Miao,Xiaojing Zhang,Tianlin Wang,An Kang,Jinjun Shan,Dong Zhu,Wei Li
Although ligand fishing has been shown to be an efficient technique for the identification of bioactive components from complex mixtures such as natural products , it cannot be applied to biomedical image processing. Herein, a specific fluorescent ligand fishing combined with in situ imaging approach is presented for the identification of heat shock protein 90 (Hsp 90) inhibitors from complex matrixes, Curcuma longa L. , using N-terminus immobilized Hsp 90α functionalized InP/ZnS quantum dots embedded mesoporous nanoparticles ( i.e. Hsp 90α (NT)-FQDNs) as extraction sorbents and fluorescent tracer. The fished ligands were identified by liquid chromatography time-of-flight/mass spectrometry (LC-TOF/MS) and gas chromatography-mass spectrometry (GC-MS). Moreover, in situ imaging by confocal laser scanning microscopy (CLSM) was applied for evaluating the effect of fished-ligands on bioactivity-induced apoptosis morphologically in HeLa cells. MTT assay verified the bioactivity of the ligands and molecular docking results further provided convincing information to verify the feasible binding mode between ligands and protein. Twelve ligands as potential Hsp 90 inhibitors were ultimately fished and identified from Curcuma longa L. crude extracts. The proposed approach based on Hsp 90α functionalized nanocomposites is superior in the combination of highly specific screening efficiency and concurrent visual in situ imaging, which could have great promise for the development of other plant-derived Hsp 90 inhibitors, and providing a rapid and reliable platform for discovering biologically active molecules in natural products.
Blockade of heat shock protein 90 (HSP90) expression in multimodal synergistic therapy has a great prospect for cancer treatment. Nanomaterials combined with bioinformatic analysis provides accurate guidance for the design of anti-HSP90 nanomedicines. Herein, a NIR-II-responsive nanoplatform was developed under bioinformatics guided to effectly inhibit HSP90 for enhanced synergistic mild-photothermal chemotherapy without any notable tissue damage. The nanoplatforms were assembled from NIR-II-responsive gold nanobipyramids (GNBs) combined with curcumin (Cur) via hydrophobic-hydrophobic interactions and hydrogen bonds. On the basis of drug discovery and network pharmacology, we found that Cur has impressive anti-HSP90 capability and analyzed its therapeutic mechanism against NSCLC. Under the irradiation of NIR-II light, the obtained GNBs-Cur blocked the expression of HPS90 and inhibited related antiapoptotic pathways, thus enhancing the mild PTT of GNBs under 1064 nm laser irradiation. Meanwhile, Cur served as chemotherapeutic agents to induce apoptosis in tumor cells. In vivo photoacoustic imaging-guided, GNBs-Cur achieved effective tumor elimination through mild-photothermal chemotherapy without systemic toxicity. Overall, this work provides a new therapeutic modality paradigm for potential NSCLC treatment on the basis of synergistic therapies.
In an attempt to attain synergistic therapeutic benefits and address various intrinsic limitations of the highly efficient black phosphorus quantum dots (BPQDs), we fabricated poly( L -lactide)-poly(ethylene glycol)-poly( L -lactide) triblock copolymer (PLLA-PEG-PLLA)-based nanocomposites co-loaded with BPQDs and gambogic acid (GA) using the supercritical carbon dioxide (SC-CO 2 ) technology to achieve photoacoustic (PA) imaging-guided synergistic chemo-photothermal therapy. On the one hand, BPQDs displayed near-infrared (NIR)-induced hyperthermia through the high photothermal conversion efficiency. On the other hand, the NIR-responsive release of GA facilitated early apoptosis through specific binding to stress-induced overexpression of heat shock protein (HSP)-90 for combating thermoresistant tumor cells. GA significantly promoted the photothermal therapy (PTT) efficiency by enhancing both early and late apoptosis of BPQDs. Moreover, the encapsulation of BPQDs in the polymer significantly improved their chemical as well as photothermal stabilities. Our findings suggested that these nanocomposites fabricated using the eco-friendly supercritical fluid (SCF) technology provided good protection to the biodegradable BPQDs, offering a great potential towards cancer ablation through augmented synergistic effects.
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