Battogtokh Gantumur, Ko Young Tag
College of Pharmacy, Gachon University , Incheon, South Korea 406-799.
Mol Pharm. 2014 Mar 3;11(3):904-12. doi: 10.1021/mp400579h. Epub 2014 Jan 29.
In spite of the great potential of nucleic acids as therapeutic agents, the clinical application of nucleic acid therapeutics requires the development of effective systemic delivery strategies. In an effort to develop effective nucleic acid delivery systems suitable for clinical application, we previously reported a self-assembling micelle-like nanoparticle that was based on phospholipid-polyethylenimine conjugates, i.e., "micelle-like nanoparticles" (MNPs). In this study, we aimed to improve the system by enhancing the efficiency of intracellular delivery of the payload via pH-responsive detachment of the monolayer envelope and release of the nucleic acid therapeutics upon reaching the target tissues with an acidic pH, e.g., tumors. The acid-cleavable phospholipid-polyethylenimine conjugate was synthesized via hydrazone bond, and acid-cleavable MNPs were then prepared and characterized as before. We evaluated the acid-cleavable MNP construct for in vitro and in vivo nucleic acid delivery efficiency using cultured tumor cells and tumor-bearing mice. The acid-cleavable nanocarrier showed an enhanced cellular delivery at pH 6.5 as compared to pH 7.4, whereas the noncleavable nanocarrier did not show any differences. Tail vein injections also led to enhanced intracellular uptake of the acid-cleavable nanocarrier compared to the noncleavable nanocarrier into tumor cells of tumor-bearing mice although no significant difference was observed in total tumor accumulation.
尽管核酸作为治疗剂具有巨大潜力，但核酸疗法的临床应用需要开发有效的全身给药策略。为了开发适用于临床应用的有效核酸递送系统，我们之前报道了一种基于磷脂 - 聚乙烯亚胺共轭物的自组装胶束状纳米颗粒，即“胶束状纳米颗粒”（MNPs）。在本研究中，我们旨在通过增强单层包膜的pH响应性脱离以及在到达酸性pH值的靶组织（如肿瘤）时释放核酸治疗剂来提高细胞内递送有效载荷的效率，从而改进该系统。通过腙键合成了酸可裂解的磷脂 - 聚乙烯亚胺共轭物，然后制备了酸可裂解的MNPs并如前所述进行表征。我们使用培养的肿瘤细胞和荷瘤小鼠评估了酸可裂解的MNP构建体的体外和体内核酸递送效率。与pH 7.4相比，酸可裂解的纳米载体在pH 6.5时显示出增强的细胞递送，而非可裂解的纳米载体没有显示出任何差异。尾静脉注射也导致酸可裂解的纳米载体与非可裂解的纳米载体相比，在荷瘤小鼠的肿瘤细胞中细胞内摄取增强，尽管在总肿瘤积累中未观察到显著差异。
