Professor Lu Aiping (left) and Dr Zhang Ge (second from right) lead HKBU research team to develop a novel osteoblast-specific delivery system


呂愛平教授 (左) 和張戈博士 (右二) 率領浸大研究團隊成功開發新型成骨細胞特異性遞送系統

Date: 10 Feb 2015 (Tuesday)

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HKBU Chinese medicine scholars’ work on novel osteoblast-specific delivery system is published in Nature Medicine

浸大中醫藥學者開發新型成骨細胞特異性遞送系統 研究論文於《自然─醫學》雜誌發表

The School of Chinese Medicine (SCM) and the Institute for Advancing Translational Medicine in Bone & Joint Diseases (TMBJ) have recently accomplished a significant achievement in targeted therapy for osteoporosis in collaboration with the Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences; and the State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine. The researchers developed a novel aptamer-functionalised delivery system that achieves osteoblast-specific delivery of osteogenic siRNAs to promote bone formation. This new system will drive forward and accelerate the development of targeted therapies for osteoporosis. The result of the research was recently published in premier scientific journal Nature Medicine (http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3791.html).
 
The project was supported by grants from the Ministry of Science and Technology of China, the Natural Science Foundation Council of China, the China Academy of Chinese Medical Sciences, the Research Grants Council of Hong Kong and many other research grants. This interdisciplinary research project conducted by scientists from Hong Kong and Beijing leveraged their respective strengths. The team of Professor Lu Aiping, Dean of SCM, and Director of TMBJ, and Dr Zhang Ge, Deputy Director of TMBJ, selected the targeting ligands, prepared the delivery system and conducted bone bio-imaging analysis. Meanwhile, the team from the Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, led by Professor Lu, carried out all the animal studies. The team of Dr Zhang Lingqiang from State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, provided molecular biology support for all the in vitro studies while Kunshan Industrial Technology Research Institute supplied most of the nucleic acid reagents.
 
After four years of concerted efforts, researchers developed a direct osteoblast-specific aptamer and an aptamer-functionalised delivery system to restore bone mass in osteoporosis animal models.  
 
Professor Lu Aiping said: “Not only can aptamers be used in cell-specific delivery of siRNAs, but they can also play a significant role in new drug discovery. China is rich in Chinese herbal  medicine and natural products, providing a good supply of potential drugs. The studies have revealed the strong potential of developing these resources into effective new drugs to treat tumors, inflammation and infectious diseases as well as osteoporosis. Until this latest modification made on aptamer technology, clinical application of these products was hindered by their poor solubility and high toxicity. Aptamer-modified herbs and natural products show significantly improved solubility. Furthermore, cell-selectivity of aptamers enhances the therapeutic effect of herbs and natural products and also reduces their side effects for non-target cells and organs.” Recently, Professor Lu established a university-enterprise collaborative innovation platform and launched a series of projects for the development of innovative class I drugs (aptamer-drug conjugates) with different enterprises in the Mainland. 
 
Dr Zhang Lingqiang from State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, said: “The continuous development of China’s manned space programme brings with it challenges to the physical fitness of astronauts. Microgravity-induced bone loss is one of the most serious conditions caused by the extreme environment of space. This novel delivery system could be used to prevent bone loss in astronauts and may have significant implications for the development of manned space technology.”
 
The project was developed from another research of Dr Zhang Ge which was published in Nature Medicine in 2012. Under the then study, an oligopeptide-based delivery system was developed to promote bone formation and facilitate the selective-enrichment of osteogenic siRNAs in osteoblasts on bone formation surfaces. However, the complicated human body requires a more accurate and safe delivery system, namely the direct osteoblast-specific delivery system. 
 
Dr Zhang Ge described the previously developed oligopeptide-based delivery system as the first-generation system. He said: “This novel aptamer-based delivery system is an enhanced version of the first-generation system and it is a real osteoblast-specific delivery system at the cellular level.”

中醫藥學院、骨與關節疾病轉化醫學研究所最近與中國中醫科學院中醫臨床基礎醫學研究所和北京軍事醫學科學院蛋白質組學國家重點實驗室等科研機構,在促進骨質疏鬆症轉化治療方面取得突破性成果,成功開發了一種以適配子為靶向配體的新型成骨細胞特異性遞送系統,可以精準地識別具有成骨潛能的小核酸及將這些小核酸遞送往成骨細胞,從而促進骨的形成,推動了骨質疏鬆成骨靶向藥物的開發。研究結果近日在國際著名科學雜誌《自然─醫學》網上發表(http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3791.html)。
 
這項研究獲得中國科技部重大新藥創制、國家自然科學基金委員會、中國中醫科學院、香港研究資助局等京港兩地多項資助。研究由京港等地的研究團隊聯合進行,開展多學科交叉、合作研究。中醫藥學院院長兼骨與關節疾病轉化醫學研究所所長呂愛平教授與副所長張戈博士組成的研究團隊,負責尋找新型成骨細胞靶向配體、遞送系統製備和體內骨組織成像與定量評價。另一方面,呂教授領導的中國中醫科學院中醫臨床基礎醫學研究所的團隊負責動物模型研究,北京軍事醫學科學院蛋白質組學國家重點實驗室張令強研究員的團隊則負責遞送系統的體外評估。此外,昆山市工業技術研究院小核酸生物技術研究所提供了研究所需的所有核酸產物。
 
經過四年的聯合研究,團隊成功篩選了可以直接靶向成骨細胞的靶向配體─核酸適配子,並開發了新型的細胞特異性識別水準的成骨小核酸遞送系統,在動物實驗中,令有骨質疏鬆的動物恢復骨量。
 
呂愛平教授說:「具有細胞特異性靶向的適配子不僅可以用在小核酸的選擇性遞送上,還可以在新藥開發上發揮更大的效用。中國有豐富的中藥和天然產物資源,在篩選具有藥理活性小分子方面具有優勢。是次研究顯示,這些資源有極大的潛能可開發為抗腫瘤、抗炎、抗感染、抗骨質疏鬆等藥物,但由於很多中藥和天然產物的水溶性欠佳及毒性過高,嚴重限制了其臨床應用。適配子技術的發展有望為中藥和天然產物的臨床轉化帶來轉機,經適配子修飾後的中藥成分和天然產物水溶性大大加強,靶向遞送特性既提高了中藥成分和天然產物的治療效果,又降低了對其他非靶細胞、組織和器官的毒性副作用。」由呂教授組建的大學─企業協同創新平台已經與多家內地大型製藥企業啟動了多個適配子修飾的小分子化合物(適配子─藥物偶聯物)的一類創新藥物研發工作。
 
北京軍事醫學科學院蛋白質組學國家重點實驗室的張令強研究員說:「中國載人航天技術正在迅速發展,空間站的建設也在密鑼緊鼓的進行中。然而,在長時間的太空飛行過程中,極端的太空環境會對航天員的身體造成嚴重傷害。其中,航天員在空間微重力環境下丟失骨量是各國共同面對的嚴峻技術難題之一。這次聯合開發的成骨小核酸遞送系統對航天員骨丟失的預防和治療具有十分重要的轉化意義。」
 
這項研究是以張戈博士於2012年在《自然─醫學》雜誌上發表的另一項嶄新設計理念為基礎。張博士率領的研究團隊當時開發了世界上首例以寡肽作為靶向配體的成骨小核酸遞送系統,通過利用寡肽對骨形成表面晶體結構的特異性識別,來實現將小核酸導入富集在骨形成表面的成骨細胞。由於人體內的微環境複雜,因此必須由更加精確和安全的核酸遞送系統,即直接識別成骨細胞來實現特異性遞送。
 
張戈博士說:「如果把2012年開發的寡肽─脂質體看作是第一代小核酸遞送系統,這次開發的適配子─納米顆粒則是第二代小核酸遞送系統,實現了更加直接安全的成骨細胞遞送,是真正意義上的細胞水準小核酸遞送系統。」