新纳米载药系统成功用于恶性肿瘤治疗

近日，国际著名学术期刊ACS nano和Biomaterials相继报道了中科院理化技术研究所研制的新型纳米载药系统在恶性肿瘤治疗及其生物安全性评价方面取得的新突破。

化疗药物在杀伤肿瘤细胞的同时，也将正常细胞一同杀灭，是一种“玉石俱焚”的癌症治疗方法。纳米药物载体可以增强药物的抗肿瘤效果，并且降低药物引起的毒副作用，大大减轻病人痛苦，延长生存期，为肿瘤治疗带来新的机遇。无机纳米材料是生物医学领域的后起之秀，具有独特的理化性质、特殊的结构及高稳定性，可以克服有机纳米材料的功能单一，可控性差等硬伤，在药物输送、医学成像等方面显示出巨大的应用前景。不过，对于将来的临床转化，无机纳米材料的生物安全性一直是人们担忧的问题。如果不能有效代谢出体外，会在体内不断蓄积而产生毒性，甚至产生血管堵塞等严重后果。纳米介孔二氧化硅做为生物相容性优异的无机纳米材料的卓越代表，被公认是一种极具潜力的药物传递载体，已经被广泛用于磁性纳米颗粒，量子点等功能材料的包覆以降低毒性、提高稳定性。开发在体内具有良好稳定性，高效低毒、产量高并可代谢的介孔二氧化硅药物载体材料用于恶性肿瘤的治疗一直是该领域研究的难点。一旦这种药物载体材料开发成功，将为癌症病人恢复健康、走向新生带来曙光。

理化技术研究所唐芳琼研究员带领的纳米可控制备与应用研究室创新研制出高产量，可精确控制颗粒尺寸、外壳厚度、内部空腔大小，具有中空和介孔结构的 “夹心二氧化硅”（Adv. Mater. 2009, 21, 3804-3807）后，一直潜心研究，根据肿瘤治疗的需求，设计可与药物相配伍的新型药物载体材料夹心二氧化硅。该夹心二氧化硅装载多烯紫杉醇的载药量远高于国际上同类纳米药物载体。夹心二氧化硅装载多烯紫杉醇治疗肝癌的抑瘤率提高到72%，显着高于多烯紫杉醇静脉注射剂多西他赛57%的抑瘤率。同时，研究发现，夹心二氧化硅装载多烯紫杉醇能显着降低多西他赛的肝脏毒副作用。

此外，研究人员对夹心介孔二氧化硅经静脉给药的急性和长期毒性作用进行了系统评价后发现，夹心二氧化硅对小鼠的致死性毒性极低，LD50大于 1000mg/kg，远高于国际同类报道数据（<300mg/kg）。夹心二氧化硅的靶器官主要为肝脏和脾脏，并可以逐渐从这些器官代谢出去。这一结果有效证明了夹心二氧化硅的生物安全性，为其在生物医学领域的应用扫平障碍。

这种新型夹心二氧化硅纳米载药系统治疗恶性肿瘤安全高效，为无机纳米药物载体的设计和生物安全性研究提供了新的思路，有望为恶性肿瘤的治疗带来新的生机。相关工作已获得国家发明专利授权。

该研究得到国家科技部“863”项目和国家自然科学基金的大力支持。（生物谷Bioon.com）

生物谷推荐英文摘要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.

生物谷推荐英文摘要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.