Professor Zhang Ge (centre), Dr Li Fangfei (right) and Dr Lu Jun share the significant research findings


張戈教授 (中)、李芳菲博士 (右) 與魯軍博士分享團隊的研究成果

Comparison of the therapeutic effect between nucleolin aptamer-paclitaxel conjugate and other types


「核仁素適配子──紫杉醇偶合物」對比其他組別的抗腫瘤效果

Date: 14 Dec 2017 (Thursday)

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HKBU Chinese medicine scholars develop new generation of tumour-specific aptamer-drug conjugate to treat cancer

浸大中醫學者世界首創新一代智慧型腫瘤靶向化合物 有助癌症標靶治療 減低副作用

The toxic nature of chemotherapy poses a great challenge to clinical treatment of cancer. A team of scholars from the School of Chinese Medicine (SCM) devoted their efforts to the development of a new generation of smart anti-cancer drug molecules. The tumour-specific aptamer-drug conjugate they developed performs well in the treatment of tumours and reduces possible toxic side-effects. The team has submitted a patent application to China for the molecules and the research findings were recently published in the internationally renowned academic journal Nature Communications.

The research team is led by Dean of SCM Professor Lyu Aiping together with Director of the Technology Development Division and Associate Director of the Teaching and Research Division of SCM Professor Zhang Ge. Other researchers include SCM’s Research Assistant Professor Dr Li Fangfei, Post-doctoral Research Fellow Dr Lu Jun, Post-doctoral Research Fellow Dr Liu Jin, Post-doctoral Research Fellow Dr Liang Chao, and the research team of Dr Zhang Baoting of the School of Chinese Medicine, The Chinese University of Hong Kong.

Professor Lyu explained that since chemotherapy drugs could not distinguish cancer cells from normal cells, both are damaged during treatment. This not only limits the therapeutic effect of chemotherapy drugs but also creates certain side-effects on patients. To address this problem, the research team connected a tumor-targeting aptamer with a plant-derived cytotoxic drug to form a novel tumor-specific aptamer-drug conjugate.

Aptamers are single strand oligonucleotides that could form 3D structures and bind to specific cell types or proteins. They have been widely used for targeted drug delivery of small molecules and siRNAs due to their advantages, such as good water solubility, low immunogenicity, high permeability and stability.

To date, nucleolin aptamer has been proven safe and tumor specific. By conjugating nucleolin aptamer with a first-line chemotherapy drug paclitaxel into one molecule, the aptamer could improve both water solubility and tumor-targeting ability of the conjugated paclitaxel. By enhancing the delivery of drugs via body fluid to the different parts of the human body, the therapeutic effect is therefore strengthened.

Professor Zhang Ge said the research team developed a nucleolin aptamer-paclitaxel conjugate with good water solubility. An enzyme-sensitive linker was utilised to connect the aptamer and paclitaxel. The linker remained stable in the circulation, and broke inside tumor cells and released paclitaxel for action. The results showed that the conjugate exhibited excellent antitumor activity and decreased toxicity in the experiments using a mouse model.

The research paper entitled “A water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer” was recently published in the internationally renowned academic journal Nature Communications (https://www.nature.com/articles/s41467-017-01565-6).

In addition to the paper publication, one of the research members recently won the First Prize for related research in the Fifteenth “Challenge Cup” National College Students’ Extracurricular Academic Science and Technology Works Contest held in Shanghai University. Last year, a team of five HKBU undergraduate students also won the Gold Project Award for a study in the same field in the 2016 International Bio-molecular Design Competition held in San Francisco, USA.

Some of the experiments of this research project were conducted in the Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research of SCM.

腫瘤化療藥物對人體所產生的有毒副作用,是癌症臨床治療的一大嚴峻挑戰,香港浸會大學中醫藥學院研究團隊利用具靶向癌細胞的適配子,加上具有高細胞毒活性的天然產物,形成新一代的智慧型腫瘤靶向化合物,有助腫瘤治療並減低毒副作用。團隊已為新化合物申請中國專利,而研究結果亦已刊登於著名國際學術期刊《自然-通訊》。

研究團隊由浸大中醫藥學院院長呂愛平教授與技術開發部主任兼教學科研部副主任張戈教授率領,團員包括研究助理教授李芳菲博士和三名博士後研究學人魯軍博士、劉進博士和梁超博士,以及香港中文大學中醫學院張保亭教授團隊。

呂教授表示,由於化療藥物無法分辨正常細胞和癌細胞,所以在化療過程中,癌細胞和正常細胞都被破壞,既限制了化療藥物的藥效,也為病者帶來副作用。研究團隊利用能識別並靶向癌細胞的適配子,連結源於草藥而能殺死癌細胞的天然產物,形成新的腫瘤靶向化合物──「適配子-藥物偶合物」。

適配子(Aptamer)是一類具有三維結構的單鏈寡核苷酸,可以與特定的細胞與靶分子結合。由於它具有高水溶性、低免疫反應、較強的細胞穿透和穩定性,已被廣泛應用於小分子或核酸藥物的靶向遞送。

目前,核仁素適配子已被證實是安全而具備癌細胞識別能力。通過將能識別癌細胞的核仁素適配子與目前治療癌症的一線藥物「紫杉醇」結合形成一個分子,不僅可以賦予紫杉醇的靶向性,還可以顯著改善紫杉醇的水溶性,增加藥物經人體體液傳送的能力,加強治療效果。

張戈教授說,研究團隊開發了具有高水溶性的「核仁素適配子──紫杉醇偶合物」,其中連接適配子和紫杉醇的連接鍵採用癌細胞酶敏感鍵,也就是此連接鍵可以在循環系統中保持穩定,在癌細胞中可以斷裂並釋放細胞毒藥物紫杉醇。研究結果顯示,此偶合物在小鼠腫瘤移植模型中可以靶向聚集在腫瘤組織,抑制腫瘤細胞,同時降低了紫杉醇的毒副作用,例如血液毒性和神經毒性。

團隊的最新研究論文「高水溶性的核仁素適配子紫杉醇偶合物靶向治療卵巢癌」近日刊登於著名國際學術期刊《自然-通訊》(https://www.nature.com/articles/s41467-017-01565-6)。

除發表研究論文外,研究團隊成員憑與該研究有關的論文,最近榮獲在上海大學舉行的第15屆「挑戰杯」全國大學生課外學術科技作品競賽一等獎。去年,五名浸大本科生亦憑與這項研究有關的項目,在美國三藩市舉行的2016年國際生物分子設計比賽中贏得金獎。

是項研究的部分實驗於學院的岑堯寬岑碧泉紀念癌症炎症研究中心進行。