All authors of the paper are from HKBU: (Left to right, sitting) Professor Cai Zongwei, Professor Michel A Van Hove; (left to right, standing) Dr Zhao Rundong, Kwan Chak-shing and Dr Ken Leung Cham-fai.


論文的所有作者均來自浸大:(左起,坐) 蔡宗葦教授、Michel A Van Hove教授,(左起,站立) 趙潤東博士、關擇誠和梁湛輝博士。

Chemical structure of the molecular machines


分子機器的化學結構

Date: 07 Feb 2018 (Wednesday)

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HKBU’s world-first breakthrough in macromolecular machines for actively controlled cancer drug delivery

浸大學者研製世界首創大分子機器 能主動控制治癌標靶藥物釋放

Hong Kong Baptist University (HKBU) scholars demonstrated the design and synthesis of a smart globular macromolecular machine vehicle for actively controlled cancer drug delivery, which would enhance the drug’s efficacy. This world-first breakthrough gives insight to targeted therapy drugs such as Chlorambucil in the treatment of leukemia. The paper entitled “Higher-Generation Type III-B Rotaxane Dendrimers with Controlling Particle Size in Three-Dimensional Molecular Switching” was published in renowned journal Nature Communications (DOI: 10.1038/s41467-018-02902-z).

All authors of the paper are from HKBU Faculty of Science. The team comprises HKBU scholars in Chemistry and Physics: Associate Professor Dr Ken Leung Cham-fai, Founding Kwok Yat Wai Endowed Chair of Environmental and Biological Analysis Professor Cai Zongwei and PhD student Kwan Chak-shing of the Department of Chemistry; Head of Department of Physics Chair Professor Michel A Van Hove and Postdoctoral Fellow Dr Zhao Rundong.

The team reported on a series of novel hyperbranched macromolecules with at most 15 mechanical bonds at the branching unit: mechanical bonds are a novel and exciting class of non-covalent bonds similar to familiar chains and hooks, for example. These macromolecules can induce an overall extension-contraction molecular motion via collective and controllable molecular back-and-forth shuttling, providing the ability to encapsulate drug molecules and release them actively by acidic stimuli.

Dr Ken Leung, who led the research, said that in current leukemia treatment, drugs are delivered to kill leukemia cells that may be present in the blood and bone marrow. The amount of drugs released to kill the free-floating cancer cells cannot be effectively controlled, however. He said the 15 mechanical bonds resemble 15 mechanical arms that actively control the delivery and suitable amount of drugs released to targeted cancer cells.

Dr Leung added that this smart material combines molecular machines and dendrimers with a new breakthrough in synthesis as well as controlled and active drug release. With its complexity and size, this synthetic molecule resembles a small virus. Due to the relatively low toxicity of this smart globular molecular vehicle, it can also serve as a potential ideal long-term drug delivery molecular machine submerged in the human body. The molecular masses of these new macromolecules were characterised by mass spectrometry, and their chemical structures and physical properties were also verified with supercomputer simulations.

Kwan Chak-shing, who completed the synthesis of macromolecules, said, “I am delighted that HKBU has all I need to complete this challenging task. The syntheses of macromolecular machines are complicated whereas the intermediate compounds require the formation of mechanical bonds followed by careful purification and characterisation. I look forward to seeing more creative research work done in HKBU.”

Molecular machines are assembled with their molecular counterparts that are responsive to specific stimuli (input) and produce mechanical movements (output). Rotaxane dendrimers are molecular interlocked molecules that combine hyperbranched macromolecules with molecular machines. Among various types of rotaxane dendrimer, type III-B possesses the most complicated molecular structure and exhibits the largest extension-contraction properties. The breakthrough in the synthesis and the control of particle size of higher-generation rotaxane dendrimers could give scientists an insight to develop more sophisticated molecular machines to be applied in functional materials and nanotechnology, such as the delivery of drugs or biomolecules.

This research is mainly funded by the Area of Excellence Scheme of the University Grants Committee of Hong Kong, a Collaborative Research Fund of the Hong Kong Research Grants Council, and the HKBU Institute of Creativity which is supported by the Hung Hin Shiu Charitable Foundation.

香港浸會大學的學者設計和合成出一種創新的智能球狀分子機器載體,能主動控制藥物釋放和份量,可大幅提升標靶藥物的治療效率。這是全球首次突破性的研究,有望為日後使用血癌藥物如苯丁酸氮芥等標靶治療提供更佳效果。團隊的研究論文「Higher-Generation Type III-B Rotaxane Dendrimers with Controlling Particle Size in Three-Dimensional Molecular Switching」已刊登於著名學術期刊《自然-通訊》(DOI: 10.1038/s41467-018-02902-z)。

論文的所有作者均來自浸大理學院,包括:化學系副教授梁湛輝博士、郭一葦環境與生物分析講座教授蔡宗葦教授和博士生關擇誠,以及物理系系主任Michel A Van Hove教授和博士後研究員趙潤東博士。

團隊發表了一系列具有最多15個分子機械鍵的新型樹狀大分子。這種大分子可以通過可控的分子機器集體誘導整個球體結構的伸縮,並能包封藥物分子,通過癌細胞物質刺激,主動釋放標靶藥物。

主導這個研究項目的梁湛輝博士表示,目前的血癌治療法是透過輸送藥物,殺死可能存在於血液和骨髓中的血癌細胞。但是,現時的方法不能有效地控制釋放殺死自由浮動的癌細胞的藥物劑量。他說,15個機械鍵結構類似15個機械臂,預期在進入人體後,能主動控制標靶癌細胞的藥物釋放和份量,提升治療效率。

梁博士補充說,這種智能材料將分子機器和樹狀分子結合在一起,在合成、控制和主動放藥方面取得了新的突破。這類合成分子的複雜性和大小,近似於一個小型病毒。由於這種智能球狀分子載體的細胞毒性相對較低,因此可以作為日後長期潛伏人體的理想藥物釋放分子機器。新大分子的分子質量已利用質譜儀表徵分析,其中的化學結構和物理特性也通過超級電腦群模擬驗證。

完成分子合成的博士生關擇誠說:「我很高興在浸大完成這個富挑戰性的研究工作。大分子機器的合成並不容易,中間體化合物需要機械鍵的合成,然後仔細純化和表徵分析。我期望在浸大創造更多新分子和研究具創意的項目。」

分子機器是由分子部件裝配組成,可以對特定的刺激(輸入)產生機械運動(輸出)的物體。輪烷樹狀分子是一種把樹狀大分子的性質結合到分子機器上的新型分子互鎖結構。在各種輪烷樹狀分子中,第三B類型輪烷樹狀分子擁有最為複雜的分子結構以及最具潛在應用價值。在人工合成以及控制輪烷樹狀物粒子大小上的重大突破,有助科學家日後發展更為複雜的分子機器,並應用於功能材料及納米科技,例如藥物或生物分子的遞送之中。

研究項目主要由大學教育資助委員會研究資助局卓越學科領域計劃、合作研究基金及孔憲紹慈善基金支持的浸大創意研究院資助。
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