【科研動態(tài)】楊祥良教授與李子福教授課題組在腫瘤微環(huán)境刺激可激活的診療一體化納米藥物方面取得新進展
（通訊員 陳佶棠）7月25日，美國化學(xué)會旗下納米領(lǐng)域權(quán)威期刊《納米快報》（Nano Letters）刊發(fā)了華中科技大學(xué)生命科學(xué)與技術(shù)學(xué)院、國家納米藥物工程技術(shù)研究中心楊祥良教授與李子福教授課題組題為《一種谷胱甘肽刺激可激活的診療一體化納米藥物用于腫瘤的雙模成像以及化療光熱綜合治療》（“A Simple Glutathione-Responsive Turn-on Theranostic Nanoparticle for Dual-Modal Imaging and Chemo-Photothermal Combination Therapy”）的研究論文。
腫瘤微環(huán)境刺激可激活的診療一體化納米藥物在精準(zhǔn)納米醫(yī)藥中地位十分重要，它們具有信噪比高、背景干擾小等優(yōu)點，為腫瘤的治療以及多模式成像診斷提供了一種便捷手段。然而，復(fù)雜的成分以及制備工藝嚴重阻礙了腫瘤微環(huán)境刺激可激活診療一體化納米藥物的臨床轉(zhuǎn)化。本文報道了一種簡單的谷胱甘肽刺激可激活的診療一體化納米藥物用于腫瘤的雙模成像以及化療光熱綜合治療。基于簡單的一步透析法制備出只有兩種組分（羥乙基淀粉-紫杉醇偶聯(lián)物，HES-SS-PTX，和近紅外熒光分子DiR）的診療一體化納米藥物（DHP），巧妙的利用了熒光分子DiR聚集誘導(dǎo)淬滅（ACQ效應(yīng)）實現(xiàn)腫瘤細胞微環(huán)境響應(yīng)刺激激活。DiR被包裹在HES-SS-PTX形成的疏水核內(nèi)，DiR分子的熒光因為聚集而淬滅（ACQ效應(yīng)）。一旦DHP被腫瘤細胞攝取，HES-SS-PTX的二硫鍵可被腫瘤細胞內(nèi)GSH裂解，導(dǎo)致偶聯(lián)的PTX和包載的DiR同步釋放。釋放的PTX可以發(fā)揮其殺腫瘤作用，而DiR會吸附到鄰近的內(nèi)體/溶酶體膜上并恢復(fù)其熒光。因此，DHP可以通過DiR的熒光恢復(fù)來監(jiān)測PTX的釋放以及治療效果。DHP還可作為光聲活體成像的對比劑，實現(xiàn)對腫瘤深部血管中DHP滲透到腫瘤組織的監(jiān)控。此外，DHP不僅是一種良好的熒光/光聲雙模式成像對比劑，同時還能通過化療光熱綜合治療有效的抑制腫瘤生長。更重要的是，監(jiān)測PTX的釋放和治療效果、活體雙模成像以及光熱治療不是由多種成分實現(xiàn)，而是由單一組分DiR完成，從而極大的簡化了DHP的組分和制備工藝。谷胱甘肽刺激可激活的診療一體化納米藥物DHP設(shè)計原理巧妙、成分簡單、制備方法簡便，具有很高的臨床轉(zhuǎn)化潛力。這項研究為推進腫瘤微環(huán)境刺激可激活的診療一體化納米藥物的臨床轉(zhuǎn)化提供了新思路。
華中科技大學(xué)生命學(xué)院博士生李憶卉、碩士生吳毓昕以及博士生陳佶棠為該論文的共同第一作者。生命學(xué)院2015級本科生李世友、張蒙蒙、崔黃陳、李甜甜參與了該項研究。生命學(xué)院楊祥良教授和李子福教授為論文通訊作者。該研究得到國家重點研究計劃（2018YFA0208900，2015CB931802），國家自然科學(xué)基金(31700867, 81627901)，以及華中科技大學(xué)學(xué)術(shù)前沿青年團隊（2018QYTD01）的資助。
羥乙基淀粉（HES）是臨床上最常用的血漿擴容劑，它們是一類經(jīng)羥乙基化取代的支鏈淀粉，具有良好的水溶性、生物相容性和生物可降解性。楊祥良教授團隊自2002年開始研究羥乙基淀粉制備與生產(chǎn)工藝，已獲得4個品種（HES 130/0.4原料與制劑以及HES 200/0.5原料與制劑）藥物生產(chǎn)許可證，孵化武漢華科大生命科技有限公司專門生產(chǎn)HES原材料（年產(chǎn)逾百噸），相關(guān)技術(shù)成果獲得湖北省科技進步一等獎，發(fā)展的相關(guān)技術(shù)申報中國發(fā)明專利14項，其中已授權(quán)3項。在中分子量HES系列原料藥及制劑產(chǎn)業(yè)化基礎(chǔ)上，對標(biāo)納米藥物研究領(lǐng)域的金標(biāo)準(zhǔn)PEG化策略（PEGylation），進一步研發(fā)了基于HES的抗腫瘤納米藥物，楊祥良教授、李子福教授課題組以及萬影教授近三年來發(fā)展了多種藥物偶聯(lián)和包載的HES化策略（HESylation），取得一系列突出成果，在影響因子6分以上雜志發(fā)表論文總共11篇，1篇Journal of Controlled Release (2018, 275, 67-77), 4篇ACS Appl. Mater. Interfaces (2016, 8, 30833-30844; 2017, 9, 19125-19230; 2017, 9, 42225-42238; 2017, 9, 10481-10493), 4篇Nanoscale (2018, 10, 10514-10527; 2018, 10, 17265-17274; 2019, 11, 6217-6227; 2019, 11, 6384-6393), 1篇Chemical Engineering Journal (2018, 349, 129-145), 以及1篇Cancers (2019, 11, 207)。楊祥良教授團隊在羥乙基淀粉方向上已經(jīng)形成獨具特色產(chǎn)學(xué)研緊密結(jié)合的發(fā)展模式。
(Reporter Jitang Chen) On July 25th, a research entitled “A Simple Glutathione-Responsive Turn-on Theranostic Nanoparticle for Dual-Modal Imaging and Chemo-Photothermal Combination Therapy” has been published on Nano Letters (American Chemical Society). This work is contributed by the team of Prof. Xiangliang Yang and Prof. Zifu Li from College of Life Science & Technology, HUST and National Engineering Research Center for Nanomedicine.
Tumor microenvironment stimuli activatable theranostic nanoparticles are highly pursued for precise nanomedicine. The theranostic systems have the advantages of a higher signal-to-noise (S/N) ratio and lower background interference, providing a convenient means to simultaneously exert therapeutic effects and realize multimodal imaging for diagnosis. Nonetheless, the multiple components complicate the preparation process and impede the clinical translation. Herein, based on DiR and HES-SS-PTX, this work reported a novel and simple glutathione-responsive turn-on theranostic nanoparticle, DHP, for dual-modal imaging and combination therapy. DHP is prepared with a simple one-step dialysis method. Due to the high concentration in a limited space of the hydrophobic core, the ?uorescence of DiR was signi?cantly quenched by the ACQ e?ect. Nonetheless, once DHP is internalized by cancer cells, the disul?de bond of HES- SS-PTX can be cleaved by endogenous GSH, leading to the simultaneous release of conjugated PTX and loaded DiR. The released PTX could exert its therapeutic e?ect, while DiR could adsorb onto nearby endosomes/lysosomes membranes and regain its fluorescence. Thus, DHP could monitor the release and therapeutic effect of PTX through the fluorescence recovery of DiR. DHP can also be used as an in vivo probe for both fluorescent and photoacoustic imaging and at the same time achieves a potent antitumor efficacy through chemo-photothermal combination therapy. Importantly, monitoring PTX release and therapeutic action, dual-modal imaging, and photothermal therapy is not achieved from various constituents but realized with single component DiR, thereby greatly simplifying the components and preparations of theranostic nanoparticles. The GSH-responsive turn-on theranostic DHP, prepared with simple components and preparation method, possesses a great clinical translation potential.
PhD candidate YiHui Li, master student Yuxin Wu, PhD candidate Jitang Chen from College of Life Science & Technology, HUST contributed equally to this work. Shiyou Li, MengMeng Zhang, Huangchen Cui, Tiantian Li (undergraduates enrolled in 2015, College of Life Science & Technology, HUST) participated in this work. Prof. Zifu Li and Prof. Xiangliang Yang from College of Life Science & Technology, HUST are corresponding authors. This work was ?nancially supported by grants from National Key Research and Development Program of China (2018YFA0208900), National Basic Research Program of China (2015CB931802), National Science Foundation of China (31700867 and 81627901), and Program for HUST Academic Frontier Youth Team (2018QYTD01).
Derived from waxy maize, which contains more than 95% of amylopectin, hydroxyethyl starch (HES) is therefore highly water soluble with good biocompatibility and biodegradability and has wide clinical use as plasma volume expander. The team of Prof. Xiangliang Yang has been studying the preparation and preparation process of HES since 2002 and has obtained four drug production licenses (raw materials and formulation of HES 130/0.4 and HES 200/0.5). They establish Wuhan HUST Life Science & Technology Co., Ltd., to specialize in producing raw materials of HES (annual output exceeds 100 tons). Based on the HES related technologies, they have won the First Prize for Scientific and Technological Progress in Hubei Province and applied for fourteen Chinese invention patents with three granted. They further develop HES related antitumor nanomedicine. Prof. Xiangliang Yang, Prof. Zifu Li and Prof. Ying Wan have developed several nanoparticles based on HESylation strategy and make a series of outstanding achievements during the past three years. They have published eleven papers in journals with impact factors over 6. Journal of Controlled Release (2018, 275, 67-77), ACS Appl. Mater. Interfaces (2016, 8, 30833-30844; 2017, 9, 19125-19230; 2017, 9, 42225-42238; 2017, 9, 10481-10493), Nanoscale (2018, 10, 10514-10527; 2018, 10, 17265-17274; 2019, 11, 6217-6227; 2019, 11, 6384-6393), Chemical Engineering Journal (2018, 349, 129-145), and Cancers (2019, 11, 207). In the field of HES, the team of Prof. Xiangliang Yang has formed a unique development model with close integration of research and development.
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