新納米載藥系統成功用於惡性腫瘤治療

近日，國際著名學術期刊ACS nano和Biomaterials相繼報導了中科院理化技術研究所研製的新型納米載藥系統在惡性腫瘤治療及其生物安全性評價方面取得的新突破。

化療藥物在殺傷腫瘤細胞的同時，也將正常細胞一同殺滅，是一種「玉石俱焚」的癌症治療方法。納米藥物載體可以增強藥物的抗腫瘤效果，並且降低藥物引起的毒副作用，大大減輕病人痛苦，延長生存期，為腫瘤治療帶來新的機遇。無機納米材料是生物醫學領域的後起之秀，具有獨特的理化性質、特殊的結構及高穩定性，可以克服有機納米材料的功能單一，可控性差等硬傷，在藥物輸送、醫學成像等方面顯示出巨大的應用前景。不過，對於將來的臨床轉化，無機納米材料的生物安全性一直是人們擔憂的問題。如果不能有效代謝出體外，會在體內不斷蓄積而產生毒性，甚至產生血管堵塞等嚴重後果。納米介孔二氧化矽做為生物相容性優異的無機納米材料的卓越代表，被公認是一種極具潛力的藥物傳遞載體，已經被廣泛用於磁性納米顆粒，量子點等功能材料的包覆以降低毒性、提高穩定性。開發在體內具有良好穩定性，高效低毒、產量高並可代謝的介孔二氧化矽藥物載體材料用於惡性腫瘤的治療一直是該領域研究的難點。一旦這種藥物載體材料開發成功，將為癌症病人恢復健康、走向新生帶來曙光。

理化技術研究所唐芳瓊研究員帶領的納米可控制備與應用研究室創新研製出高產量，可精確控制顆粒尺寸、外殼厚度、內部空腔大小，具有中空和介孔結構的「夾心二氧化矽」（Adv. Mater. 2009, 21, 3804-3807）後，一直潛心研究，根據腫瘤治療的需求，設計可與藥物相配伍的新型藥物載體材料夾心二氧化矽。該夾心二氧化矽裝載多烯紫杉醇的載藥量遠高於國際上同類納米藥物載體。夾心二氧化矽裝載多烯紫杉醇治療肝癌的抑瘤率提高到72%，顯著高於多烯紫杉醇靜脈注射劑多西他賽57%的抑瘤率。同時，研究發現，夾心二氧化矽裝載多烯紫杉醇能顯著降低多西他賽的肝臟毒副作用。

此外，研究人員對夾心介孔二氧化矽經靜脈給藥的急性和長期毒性作用進行了系統評價後發現，夾心二氧化矽對小鼠的致死性毒性極低，LD50大於1000mg/kg，遠高於國際同類報導數據（<300mg/kg）。夾心二氧化矽的靶器官主要為肝臟和脾臟，並可以逐漸從這些器官代謝出去。這一結果有效證明了夾心二氧化矽的生物安全性，為其在生物醫學領域的應用掃平障礙。

這種新型夾心二氧化矽納米載藥系統治療惡性腫瘤安全高效，為無機納米藥物載體的設計和生物安全性研究提供了新的思路，有望為惡性腫瘤的治療帶來新的生機。相關工作已獲得國家發明專利授權。

該研究得到國家科技部「863」項目和國家自然科學基金的大力支持。（生物谷Bioon.com）

生物谷推薦英文摘要1：

ACS Nano DOI: 10.1021/nn100918a

In Vivo Delivery of Silica Nanorattle Encapsulated Docetaxel for Liver Cancer Therapy with Low Toxicity and High Efficacy
Linlin Li?, Fangqiong Tang?*, Huiyu Liu?, Tianlong Liu?, Nanjing Hao?, Dong Chen?*, Xu Teng§, and Junqi He§

Mesoporous silica nanomaterial is one of the most promising candidates as drug carrier for cancer therapy. Herein, in vitro and in vivo study of silica nanorattle (SN) with mesoporous and rattle-type structure as a drug delivery system was first reported. Hydrophobic antitumor drug docetaxel (Dtxl) was loaded into the PEGylated silica nanorattle (SN-PEG) with a diameter of 125 nm via electrostatic absorption. In human liver cancer cell Hep-G2, the half-maximum inhibiting concentration (IC50) of silica nanorattle encapsulated docetaxel (SN-PEG-Dtxl) was only 7% of that of free Dtxl at 72 h. In vivo toxicity assessment showed that both nanocarrier of silica nanorattle (40 mg/kg, single dose) and SN-PEG-Dtxl (20 mg/kg of Dtxl, three doses) had low systematic toxicity in healthy ICR mice. The SN-PEG-Dtxl (20 mg/kg, intravenously) showed greater antitumor activity with about 15% enhanced tumor inhibition rate compared with Taxotere on the marine hepatocarcinoma 22 subcutaneous model. The results prove that the SN-PEG-Dtxl has low toxicity and high therapy efficacy, which provides convincing evidence for the silica nanorattle as a promising candidate for a drug delivery system.

生物谷推薦英文摘要2：

Biomaterials doi:10.1016/j.biomaterials.2010.10.035

Single and repeated dose toxicity of mesoporous hollow silica nanoparticles in intravenously exposed mice
Tianlong Liua, Linlin Lia, Xu Tengb, Xinglu Huanga, Huiyu Liua, Dong Chena, Jun Rena, Junqi Heb and Fangqiong Tanga, ,

a Laboratory of Controllable Preparation and Application of Nanomaterials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, No.2 Beiyitiao Zhongguancun, Beijing 100190, China
b Department of Biochemistry and Molecular, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China

Mesoporous hollow silica nanoparticles (MHSNs) are emerging as one of the new and promising nanomaterials for biomedical applications, but the biocompatibility of MHSNs in vivo has received little attention. In the present study, the systematic single and repeated dose toxicity, biodistribution and clearance of MHSNs in vivo were demonstrated after intravenous injection in mice. For single dose toxicity, lethal dose 50 (LD50) of 110 nm MHSNs was higher than 1000 mg/kg. Further repeated dose toxicity studies indicated no death was observed when mice were exposed to MHSNs at 20, 40 and 80 mg/kg by continuous intravenous administration for 14 days. These results suggest low toxicity of MHSNs when intravenous injection at single dose or repeated administrations. ICP–OES and TEM results show that the MHSNs mainly accumulate in mononuclear phagocytic cells in liver and spleen. In addition, these particles could be excreted from the body and the entire clearance time of the particles should be over 4 weeks. These findings would be useful for future development of nanotechnology-based drug delivery system and other biomedical applications.