Medical Laboratory Center, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, People's Republic of China.
Nanotechnology. 2013 Sep 20;24(37):375101. doi: 10.1088/0957-4484/24/37/375101. Epub 2013 Aug 21.
The nontoxic, targeted and effective delivery of nucleic acid drugs remains an important challenge for clinical development. Here, we describe a novel negative lipidoid nanoparticle delivery system, providing entrapment-based transfection agents for local delivery of siRNA to the colorectal cancer focus. The delivery system was synthesized with lipidoid material 98N12-5(1), mPEG2000-C12/C14 glyceride and cholesterol at a desired molar ratio to realize the anionic surface charge of particles, which could alleviate to a larger degree the inflammatory response and immune stimulation of the organism, embodying dramatic biocompatibility. In particular, mPEG2000-C12/C14 glyceride was selected to ameliorate the stability of the delivery system and protection of nucleic acids by extending the tail length of the carbons, crucial also to neutralize the positive charge of 98N12-5(1) to form a resultant anionic particle. In vivo experiments revealed that a particle size of 90 nm perfectly realized a passive target in a size-dependent manner and did not affect the function of the liver and kidneys by a local delivery method, enema. We clarified that the uptake of negative lipidoid nanoparticles internalized through a lipid raft endocytotic pathway with low cytotoxicity, strong biocompatibility and high efficacy. This study suggests that negative lipidoid nanoparticles with enema delivery constitute, uniquely and appropriately, a local anti-colorectal cancer nucleic acid drug delivery platform, and the application of similar modes may be feasible in other therapeutic settings.
核酸药物的非毒性、靶向性和有效性递送仍然是临床开发的一个重要挑战。在这里，我们描述了一种新型的负脂质纳米粒子递药系统，为局部递送 siRNA 到结直肠癌病灶提供了基于包埋的转染试剂。该递药系统由脂质材料 98N12-5(1)、mPEG2000-C12/C14 甘油酯和胆固醇以所需摩尔比合成，实现了粒子的阴离子表面电荷，这可以在更大程度上减轻机体的炎症反应和免疫刺激，体现出显著的生物相容性。特别是，选择 mPEG2000-C12/C14 甘油酯来延长碳原子的尾巴长度，从而改善递药系统的稳定性和核酸的保护，这对于中和 98N12-5(1)的正电荷以形成带负电荷的粒子也是至关重要的。体内实验表明，90nm 的粒径通过尺寸依赖性的被动靶向方式完美地实现了被动靶向，并且通过局部给药方法（灌肠）不会影响肝脏和肾脏的功能。我们阐明了通过脂筏内吞途径内化的负脂质纳米粒子具有低细胞毒性、强生物相容性和高效性。这项研究表明，具有灌肠给药的负脂质纳米粒子独特且适宜地构成了局部抗结直肠癌核酸药物递送平台，类似模式的应用在其他治疗环境中可能是可行的。
