【科研動態(tài)】生命學(xué)院楊祥良教授與李子福教授課題組在腫瘤血管靶向智能納米藥物取得系列成果
（通訊員 陳佶棠）8月21日，國際頂級化學(xué)綜合期刊Accounts of Chemical Research (化學(xué)研究述評) (影響因子21.661) 在線發(fā)表了我校生命學(xué)院國家納米藥物工程技術(shù)研究中心楊祥良教授和李子福教授課題組的綜述論文，題目為《腫瘤血管靶向智能納米藥物》 (Smart Nanotherapeutic Targeting of Tumor Vasculature)，標(biāo)志該課題組及合作團隊在腫瘤血管靶向智能納米藥物取得系列成果。
高度紊亂的血管系統(tǒng)是惡性實體腫瘤的共性特征，腫瘤血管靶向治療已成為腫瘤治療領(lǐng)域的重要組成部分，多種腫瘤血管靶向藥物也應(yīng)運而生，有些（如貝伐珠單抗）已經(jīng)獲批上市。然而，目前用于腫瘤血管靶向治療的小分子或抗體藥物面臨療效低、毒副作用大等臨床挑戰(zhàn)。與小分子和抗體藥物相比，智能納米藥物具備以下優(yōu)勢：第一，利用靶向配體分子（如多肽和抗體）對納米藥物的表面進行功能化修飾，納米藥物能夠精確地靶向腫瘤血管內(nèi)皮細胞，從而減少脫靶效應(yīng)，提高抗腫瘤效果；其次，納米載體可以同時攜帶多種抗腫瘤藥物，實現(xiàn)時/空間精準同步抗腫瘤綜合治療；第三，可以將治療藥物和分子影像對比劑整合到一個納米載體，實現(xiàn)腫瘤血管的診療一體化；第四，納米藥物可以實現(xiàn)腫瘤微環(huán)境刺激響應(yīng)智能釋藥，定點清除腫瘤。因此，使用智能納米藥物靶向腫瘤血管治療前景廣闊。
該綜述論文基于生命學(xué)院楊祥良教授團隊和國家納米科學(xué)中心聶廣軍教授團隊的前期工作，提出看似矛盾實則不矛盾的腫瘤血管堵與疏的調(diào)控策略。堵的目的是為了切斷腫瘤細胞營養(yǎng)與氧氣的供給，疏的目的是為了提高抗腫瘤藥物的遞送效率與療效。楊祥良教授團隊研制出一種溫敏納米凝膠實現(xiàn)肝癌高效與特異性栓塞，并提出使用高壓氧治療降低腫瘤血液黏度、增強血流灌注、克服腫瘤力學(xué)微環(huán)境屏障、提高納米藥物遞送效率和抗腫瘤療效。在腫瘤血管堵的調(diào)控策略方面，聶廣軍教授團隊首次構(gòu)筑出裝載凝血酶的DNA納米機器人實現(xiàn)腫瘤部位超選擇性原位血栓生成、掐斷腫瘤細胞營養(yǎng)與氧氣的供給，發(fā)展了腫瘤部位酸響應(yīng)納米藥物摧毀腫瘤補給血管。在腫瘤血管疏的調(diào)控策略方面，聶廣軍教授團隊研制出腫瘤微環(huán)境高表達基質(zhì)金屬蛋白酶響應(yīng)納米藥物選擇性清除腫瘤相關(guān)血小板、提高腫瘤血管通透性與抗腫瘤藥物瘤內(nèi)富集量，構(gòu)建了腫瘤部位酸響應(yīng)納米藥物遞送小干擾RNA敲除腫瘤血管上皮細胞關(guān)鍵蛋白、使腫瘤血管正?；＿@6種腫瘤血管調(diào)控策略都取得極為顯著的抗腫瘤療效。
經(jīng)導(dǎo)管動脈栓塞（TAE）是一種在醫(yī)學(xué)影像設(shè)備的引導(dǎo)下，通過導(dǎo)管選擇性地將栓塞劑注入靶動脈，以阻斷靶動脈進行腫瘤治療的技術(shù)。TAE被認為是一種革命性的腫瘤治療方法，其療效迅速，并發(fā)癥發(fā)生率低，且易于與其它治療方法結(jié)合。例如，TAE與化療藥物的結(jié)合，也被稱為經(jīng)導(dǎo)管動脈化療栓塞（TACE），是不可切除肝細胞癌（HCC）一線姑息療法的金標(biāo)準治療方案。但是，目前TAE和TACE臨床療效嚴重受限于血管栓塞劑。臨床上廣泛使用的固體栓塞劑（包括明膠海綿、聚乙烯醇微顆粒、海藻酸鈣微球）和液體栓塞劑（包括無水酒精和碘油）都有明顯的缺點：固體栓塞劑具備較好的栓塞性，可以栓塞腫瘤大血管但很難同時實現(xiàn)末梢血管栓塞；液體栓塞劑具備較好的流動性，可以栓塞腫瘤末梢血管但面臨栓塞強度較低的問題。這些栓塞劑無法同時兼顧栓塞性和流動性，栓塞不足常引起腫瘤血管再通和腫瘤內(nèi)血液循環(huán)，最終導(dǎo)致腫瘤的復(fù)發(fā)和轉(zhuǎn)移。受血液凝固級聯(lián)反應(yīng)的啟發(fā)，楊祥良教授和趙彥兵教授課題組與華中科技大學(xué)附屬協(xié)和醫(yī)院鄭傳勝教授合作2011年基于聚（N-異丙基丙烯酰胺-甲基丙烯酸丁酯）（PIB）研發(fā)了一種智能納米凝膠。該納米凝膠展示出獨特的溫度觸發(fā)的溶膠-凝膠相轉(zhuǎn)變過程，可實現(xiàn)肝癌大血管和末梢血管永久性同步栓塞。這種新型血管栓塞劑PIB納米凝膠有效的解決了介入治療流動性和栓塞性的矛盾。團隊研制擁有自主知識產(chǎn)權(quán)、效果顯著優(yōu)于現(xiàn)有國內(nèi)外產(chǎn)品的新型肝癌介入栓塞材料，近10年在Advanced Functional Materials，Theranostics，Journal of Controlled Release等高水平雜志上發(fā)表論文近20篇。更重要的是，該團隊掌握核心材料的小試、中試及放大生產(chǎn)的工藝研究、驗證及質(zhì)量控制的關(guān)鍵技術(shù)，有望打破我國肝癌介入治療嚴重依賴進口碘油的卡脖子現(xiàn)狀。
為促進侵襲與轉(zhuǎn)移，腫瘤發(fā)展出一種獨特的血管新生模式，通過在已有的毛細血管上萌芽形成新的血管。這些新生血管迂曲、滲漏，結(jié)構(gòu)完整性差，內(nèi)皮細胞間隙大，平滑肌細胞缺失，周細胞和基底膜覆蓋不全。與正常的血管系統(tǒng)不同，腫瘤血管中的血流并不總是沿著固定的、單向的軌跡流動；并非所有的血管都灌注良好，血流可能在短時間內(nèi)通過同一根血管走不同的路徑，甚至在相反的方向流動。腫瘤血管結(jié)構(gòu)和功能性異常導(dǎo)致蛇形血流和灌注不良，形成一種獨特的微環(huán)境（腫瘤微環(huán)境；TME），表現(xiàn)為乏氧、高凝和免疫抑制。楊祥良教授和李子福教授課題組巧妙的利用臨床常用的高壓氧治療降低腫瘤血管中血液黏度、提高血流灌注、改善腫瘤微環(huán)境、顯著增強納米藥物抗腫瘤療效，相關(guān)研究工作發(fā)表在Advanced Science。
化學(xué)研究述評上的論文主要是闡述自己在某一方面的系統(tǒng)性工作。李子福教授為該論文第一作者，楊祥良教授為共同通訊作者，共同通訊作者還包括國家納米科學(xué)中心李素萍教授和聶廣軍教授。華中科技大學(xué)為第一作者單位。該論文得到了國家重點研究計劃項目，國家自然科學(xué)基金以及華中科技大學(xué)學(xué)術(shù)前沿青年團隊的資助。
論文鏈接：https://pubs.acs.org/doi/10.1021/acs.accounts.9b00283
(Correspondent Jitang Chen) On August 21st, a review paper entitled “Smart Nanotherapeutic Targeting of Tumor Vasculature” has been published on Accounts of Chemical Research (American Chemical Society). This review 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, symbolizing this research team and the collaborative research team have accomplished a series of achievements in leveraging smart nanotherapeutics modulating tumor vasculature.
Highly chaotic vascular system is a common feature of malignant solid tumors. Tumor vascular targeting therapy has therefore become an important part of cancer therapy. Various tumor vascular targeting drugs have emerged, with some, for instance bevacizumab, being approved for clinical practice. Nonetheless, the existing small molecule- or antibody-based drugs for tumor vessel targeted therapy do not well satisfy clinical application criteria such as favorable tumor accumulation and low toxicity. In contrast, nanotherapeutics display attractive properties for improving drug therapeutic efficacy or revolutionizing currently vascular targeting strategies. First, by functionalizing the surfaces of nanotherapeutics with targeting ligand molecules (e.g., peptides, aptamers and antibodies), nanotherapeutics can precisely target and bind tumor endothelial cells, thus reducing adverse, off-target effects and improving antitumor efficacy. Second, nanocarriers can simultaneously carry multiple therapeutic agents to affect combined therapy, precisely synchronizing both the temporal and spatial antitumor attack. Third, nanotherapeutics can integrate therapeutic drugs with molecular imaging agents into a single platform to achieve theranostics in tumor vessels. Forth, smart nanotherapeutics can achieve triggered drug release in response to tumor microenvironment stimuli. Therefore, the use of smart nanotherapeutics targeting tumor vasculature has broad prospects.
Based on previous work of Professor Xiangliang Yang and Professor Guangjun Nie from National Center for Nanoscience and Technology of China, this review paper proposes seemingly contradictory strategies for the regulation of tumor vasculature: blocking and dredging. The purpose of blocking is to cut off the supply of nutrition and oxygen to cancer cells, whereas the aim of dredging is to improve the delivery efficiency and efficacy of antitumor drugs. The team of Professor Xiangliang Yang developed a smart polymeric nanogel for permanent and peripheral embolization of liver tumors and leveraged hyperbaric oxygen (HBO) therapy to decrease the viscosity and promote tumor perfusion of a nanomedicine. To selectively block tumor blood supply and starve the tumor to death, the team of Professor Guangjun Nie developed a thrombin loaded DNA nanorobots and tumor acidity responsive nanoparticle. In addition, this team constructed a hybrid nanoparticle to selectively deplete tumor associated platelets and prepared tumor acidity responsive nanotherapeutics to correct tumor vasculature abnormalities, for the purpose of enhanced tumor vessel permeability. These six strategies have all achieved remarkable anti-tumor effects.
Transcatheter arterial embolization (TAE) is a technique of selectively injecting embolic agents through a catheter to a target artery under the guidance of medical imaging devices to obstruct the target artery for cancer therapy. Considered a revolutionary treatment, TAE produces rapid effects, while incurring a low incidence of complications, and is easy to combine with other therapies. For instance, the combination of TAE with chemotherapeutic drugs, also known as transcatheter arterial chemoembolization (TACE), the gold standard, first-line palliative therapy for unresectable hepatocellular carcinoma (HCC) which was shown to have the largest concentration case in Asia. However, the clinical efficacy of TAE and TACE is severely limited by vascular embolic agents. A wide range of solid and liquid embolic agents are used clinically for TAE/TACE against HCC, including gelatin sponges, polyvinyl alcohol (PVA) particles, calcium alginate microspheres, absolute alcohol and Lipiodol. However, all these materials suffer from overt shortcomings. Insufficient embolization often induces vascular recanalization and collateral circulation in the tumor, ultimately leading to tumor recurrence and metastasis. Inspired by the changes in blood from a liquid state to a solid-like gel state in the conversion of soluble fibrinogen into crosslinked fibrin clots, the team of Professor Xiangliang Yang and Professor Yanbing Zhao, together with Professor Chuansheng Zheng from Union Hospital of Huazhong University of Science and Technology, developed a smart poly (N-isopropylacrylamide-co-butyl methylacrylate) (PIB) nanogel, which displays an intriguing temperature-triggered sol-gel phase transition, for permanent and peripheral embolization of liver tumors. This novel blood-vessel-embolic PIB nanogel largely resolves the dilemma of flowability and embolization in TAE/TACE therapy. The team has developed a novel type of interventional embolic material, with independent intellectual property rights, being superior to the existing products at home and abroad. In recent 10 years, nearly 20 papers have been published by this team in top peer-reviewed journals, such as Advanced Functional Materials, Theranostics, Journal of Controlled Release, to name a few. More importantly, the team has developed the key technologies of small-scale, pilot-scale and enlarged production of core materials, such as process research, verification and quality control.
For progression and metastasis to occur, tumors develop a unique neovascularization paradigm, in which new blood vessels form by sprouting on pre-existing capillaries1. The newly formed vessels are tortuous and leaky, with a lack of structural integrity, containing large gaps between endothelial cells, missing smooth muscle cells, and exhibiting incomplete coverage by pericytes and basement membrane. Unlike normal vasculature, the blood flow in tumors does not always follow a constant, unidirectional track; not all vessels are perfused well, and the blood flow may take varied paths and even flow in opposed directions via the same vessel over a short period of time. The structural and functional vessel abnormalities contribute to a prothrombotic state, serpentine blood flow, and poor perfusion, thereby shaping a distinctive microenvironment (tumor microenvironment; TME) generally characterized by hypoxia, hypercoagulation and immunosuppression. The research team of Professor Yang Xiangliang and Professor Li Zifu skillfully leveraged the commonly used hyperbaric oxygen therapy in clinic to reduce blood viscosity, improve blood perfusion, modulate tumor hypoxia and mechano-microenvironment, and significantly boost the anti-tumor efficacy of nanomedicine Doxil. The related research work was published in Advanced Science.
Review papers on the Accounts of Chemical Research mainly expound the systematic work of oneself in one aspect. Professor Zifu Li is the first author of this review paper, Professor Xiangliang Yang is the corresponding author, and the corresponding authors also include Professor Suping Li and Professor Guangjun Nie from National Center for Nanoscience and Technology of China. The first author affiliation is Huazhong University of Science and Technology. This review paper is supported by grants from the National Key Research and Development Program of China, National Science Foundation of China, and the Program for HUST Academic Frontier Youth Team.
The paper link: https://pubs.acs.org/doi/10.1021/acs.accounts.9b00283
The paper citation: Zifu Li, Chunzhi Di, Suping Li, Xiangliang Yang, Guangjun Nie. Smart Nanotherapeutic Targeting of Tumor Vasculature. Accounts of Chemical Research (2019), DOI: 10.1021/acs.accounts.9b00283
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