Biomaterials:药物所甘勇组双阳离子型核壳脂质体纳米粒(DLCS-NP)研究取得进展

眼部疾病的常用治疗方式是局部给以药物溶液（例如滴眼液），这些传统剂型占据市售制剂的90%左右。然而，眼部的生理屏障以及候选药物的低溶解性为眼部给药系统的发展带来许多难题。

最近，各种旨在提高难溶性药物生物利用度的眼部给药方式大量出现。上海药物所甘勇课题组专题综述了这些眼部给药方式，包括水凝胶、聚合物胶束、纳米混悬液和脂质纳米载体等。同时，深入阐述了脂质纳米载体，包括乳液、脂质体、立方液晶、囊泡等，为眼部药物传递提供许多优势，比如提高难溶性药物的生物利用度、靶向给药、控制药物释放以及降低全身副作用等。(相关工作主要由甘莉、王静完成：Drug Discovery Today, in press.)

依据脂质体纳米粒作为眼用载体的独特优势，甘勇课题组设计研究了一种新型双阳离子型核壳脂质体纳米粒(DLCS-NP)。采用薄膜分散水化-挤膜法，直接将旋干的脂质膜与分散的壳聚糖纳米粒(CS-NP)混悬液水化，自组装形成核壳结构的阴离子脂质体纳米粒(LCS-NP)，随后利用阳离子N-[1-(2,3-二油酰基) ]-N,N,N-三甲酰丙烷甲基硫酸盐与磷脂双分子层的亲和作用，在LCS-NP表面形成正电荷磷脂修饰层，形成DLCS-NP。该具有独特双阳离子型核壳脂质体纳米粒，能够显著延长载体角膜滞留时间，提高细胞摄取量，并具有一定的溶酶体逃逸能力，取得了理想的体内外眼表基因转染效果，为眼表疾病的基因治疗开辟了新途径。(相关工作主要由蒋敏、甘莉完成：Biomaterials, 2012, 33: 7621-7630.)

该项研究取得了上海市自然科学基金 (No.11ZR1444700)、国家自然科学基金资助项目(No.81102387)、国家科技重大专项“重大新药创制” (No.2009ZX09301-01) 和国家重点基础研究发展计划 (No.2009CB930300)的资助。

与纳米粒相关的拓展阅读： 

• JACS：纳米粒子标记肿瘤细胞
• Sci Transl Med：RNA纳米粒子纳米粒子缩小小鼠卵巢肿瘤
• Blood Can J：纳米粒子治疗多发性骨髓瘤
• 雷帕霉素纳米粒因穿透力强节省药量
• Nat Med：黄金纳米粒子提升肿瘤手术切除精准度 更多信息请点击：有关纳米粒更多资讯

Cationic core-shell liponanoparticles for ocular gene delivery.
Abstract
To achieve enhanced gene transfection efficiency with ocular eye-drop therapy, a cationic core-shell liponanoparticle (DLCS-NP) was designed by enveloping the plasmid-laden chitosan nanoparticle (CS-NP) into a cationic lipid shell. The cellular uptake of DLCS-NP was up to 1.25-fold and 5-fold higher than that of CS-NP and lipid-coated chitosan nanoparticles (LCS-NP), respectively. Further endocytosis inhibition investigation discovered that facilitated by the cationic outer lipid layer, several other distinct pathways (besides clathrin-mediated endocytosis) were involved in the endocytosis of DLCS-NP. Endolysosome trafficking experiment verified that cationic lipid coating could facilitate the endolysosome escape of DLCS-NP. Consequently, using enhanced green fluorescence protein (EGFP) as a reporter gene, DLCS-NP-treated human conjunctival epithelial cells exhibited 3.1- and 3.5-fold more intense EGFP expression than that of LCS-NP and CS-NP, respectively. Finally, in vivo transfection experiments on rabbits revealed that EGFP expression exhibited 2.52-fold increase in DLCS-NP group than that of CS-NP group. In summary, this type of cationic core-shell liponanoparticle, possessing multiple functions including better DNA protecting effect, superior cellular uptake efficiency, utilization of multiple endocytic pathways, and endolysosome escaping ability, may represent a promising strategy for ocular gene delivery.