AbstractMild photothermal therapy (PTT) has attracted attention for effectively avoiding the severe side effects associated with high‐temperature tumor ablation. However, its progress is hindered by the limited availability of high‐performance photothermal agents (PTAs) and the thermoresistance of cancer cells induced by heat shock reactions. Herein, this work proposes a new strategy to expand the library of high‐performance organic small‐molecule PTAs and utilize it to construct a multifunctional nano‐theranostic platform. By incorporating additional acceptors and appropriate π‐bridges, a diketopyrrolopyrrole‐based dye BDB is developed, which exhibits strong absorption and bright fluorescence emission in the near‐infrared (NIR) region. Subsequently, BDB is co‐coated with the heat shock protein (HSP) inhibitor tanespimycin (17‐AAG) using the functional amphiphilic polymers DSPE‐Hyd‐PEG2000‐cRGD to form an all‐in‐one nanoplatform BAG NPs. As a result, BAG NPs can precisely target tumor tissue, guide the treatment process in real‐time through NIR‐II fluorescence/photoacoustic/photothermal imaging, and release 17‐AAG on demand to enhance mild PTT. Additionally, the mild PTT has been demonstrated to induce immunogenic cell death (ICD) and activate a systemic anti‐tumor immune response, thereby suppressing both primary and distant tumors. Overall, this study presents a multifunctional nanoplatform designed for precise mild PTT combined with immunotherapy for effective tumor treatment.

2024-06-01·Journal of Gastrointestinal Oncology

Identifying drug candidates for pancreatic ductal adenocarcinoma based on integrative multiomics analysis

Article

作者: Li, Dingyang ; Gao, Zhiqiang ; Wang, Zhengfeng ; Dang, Xiaowei ; Wu, Yang ; Guo, Huahu ; Qiao, Shishi ; Ge, Penglei ; Wang, Weiwei ; Yang, Huayu

BackgroundDue to a lack of early diagnosis methods and effective drugs, pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. DNA methylation, transcriptome expression and gene copy number variation (CNV) have critical relationships with development and progression of various diseases. The purpose of the study was to screen reliable early diagnostic biomarkers and potential drugs based on integrative multiomics analysis.MethodsWe used methylation, transcriptome and CNV profiles to build a diagnostic model for PDAC. The protein expression of three model-related genes were externally validated using PDAC samples. Then, potential therapeutic drugs for PDAC were identified by interaction information related to existing drugs and genes.ResultsFour significant differentially methylated regions (DMRs) were selected from 589 common DMRs to build a high-performance diagnostic model for PDAC. Then, four hub genes, PHF12, FXYD3, PRKCB and ZNF582, were obtained. The external validation results showed that PHF12, FXYD3 and PRKCB protein expression levels were all upregulated in tumor tissues compared with adjacent normal tissues (P<0.05). Promising candidate drugs with activity against PDAC were screened and repurposed through gene expression analysis of online datasets. The five drugs, including topotecan, PD-0325901, panobinostat, paclitaxel and 17-AAG, with the highest activity among 27 PDAC cell lines were filtered.ConclusionsOverall, the diagnostic model built based on four significant DMRs could accurately distinguish tumor and normal tissues. The five drug candidates might be repurposed as promising therapeutics for particular PDAC patients.

2024-01-01·Ophthalmic Research

Inhibition of Heat Shock Protein 90 Lowered Intraocular Pressure without Affecting the Production of Aqueous Humor in Rabbits

作者: Naito, Akira ; Takahashi, Yuji ; Arakawa, Reijiro ; Otsuka, Tomohiro

Introduction: Heat shock protein (Hsp) 90 is one of the most abundant proteins in unstressed cells and regulates stability and functional maintenance of client proteins. In ocular tissue, Hsp90 is widely expressed in the cornea and retina and has multiple roles in these tissues. The expression of HSPs was induced in the retinas of glaucomatous patients and laser-induced glaucoma in monkey while their mechanisms remain to be elucidated. For this reason, we tried to elucidate the role of Hsp90 in intraocular pressure (IOP) regulation in rabbits. Methods: IOP was measured by a pneumatonometer before and after intracameral injection of Hsp90 inhibitors. The aqueous flow rate was measured by fluorophotometry. Trans-epithelial electrical resistance was measured in primary human trabecular meshwork cells. Results: 17-AAG, a specific Hsp90 inhibitor, significantly lowered IOP at concentrations of more than 30 μ<sc>m</sc> in normotensive rabbits. Other Hsp90 inhibitors also significantly lowered IOP in normotensive rabbits at a dose of 100 μ<sc>m</sc>. No reduction of aqueous humor production was observed by injection of 17-AAG in rabbits. Topical administration of pilocarpine tended to attenuate the IOP-lowering effects induced by the Hsp90 inhibitor. No reduction of trans-epithelial electrical resistance was observed by inhibition of Hsp90 in culture cells. Conclusions: These results indicated that intraocular Hsp90 regulates IOP, and the inhibition of Hsp90 by Hsp90 inhibitor decreases IOP without affecting aqueous humor production in rabbits. Further research in elucidating the mechanism of Hsp90 inhibitors will result in a better understanding of the role of Hsp90 in the regulation of IOP.

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KEGG	Wiki	ATC	Drug Bank
-	17-AAG	-	DB05134

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适应症	最高研发状态	国家/地区	公司	日期
葡萄膜黑色素瘤	临床前	加拿大	McGill University	2014-04-01
高血压	临床前	瑞士	University of Lausanne	2010-11-16
神经系统变性病	临床前	日本	Nagoya University Graduate School of Medicine	2005-10-01