Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Biomaterials. 2014 Aug;35(26):7488-500. doi: 10.1016/j.biomaterials.2014.05.020. Epub 2014 Jun 3.
The development of a stable vehicle with low toxicity, high cellular internalization, efficient endosomal escape, and optimal drug release profile is a key bottleneck in nanomedicine. To overcome all these problems, we have developed a successful layer-by-layer method to covalently conjugate polyethyleneimine (PEI) and poly(methyl vinyl ether-co-maleic acid) (PMVE-MA) copolymer on the surface of undecylenic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs), forming a bilayer zwitterionic nanocomposite containing free positive charge groups of hyper-branched PEI disguised by the PMVE-MA polymer. The surface smoothness, charge and hydrophilicity of the developed NPs considerably improved the colloidal and plasma stabilities via enhanced suspensibility and charge repulsion. Furthermore, despite the surface negative charge of the bilayer polymer-conjugated NPs, the cellular trafficking and endosomal escape were significantly increased in both MDA-MB-231 and MCF-7 breast cancer cells. Remarkably, we also showed that the conjugation of surface free amine groups of the highly toxic UnTHCPSi-PEI (Un-P) NPs to the carboxylic groups of PMVE-MA renders acceptable safety features to the system and preserves the endosomal escape properties via proton sponge mechanism of the free available amine groups located inside the hyper-branched PEI layer. Moreover, the double layer protection not only controlled the aggregation of the NPs and reduced the toxicity, but also sustained the drug release of an anticancer drug, methotrexate, with further improved cytotoxicity profile of the drug-loaded particles. These results provide a proof-of-concept evidence that such zwitterionic polymer-based PSi nanocomposites can be extensively used as a promising candidate for cytosolic drug delivery.
开发一种具有低毒性、高细胞内化效率、高效的内涵体逃逸能力和最佳药物释放特性的稳定载体是纳米医学的一个关键瓶颈。为了克服所有这些问题，我们开发了一种成功的层层方法，将聚乙烯亚胺（PEI）和聚（甲基乙烯基醚-共-马来酸）（PMVE-MA）共聚物共价偶联到十一烯酸功能化热烃化多孔硅纳米粒子（UnTHCPSi NPs）表面，形成含有游离正电荷的双层两性离子纳米复合材料组 hyper-branched PEI 的正电荷基团被 PMVE-MA 聚合物掩盖。开发的 NPs 的表面光滑度、电荷和亲水性通过增强悬浮性和电荷排斥极大地提高了胶体和等离子体稳定性。此外，尽管双层聚合物偶联 NPs 的表面带负电荷，但在 MDA-MB-231 和 MCF-7 乳腺癌细胞中，细胞内转运和内涵体逃逸都显著增加。值得注意的是，我们还表明，将高度毒性的 UnTHCPSi-PEI（Un-P）NPs 表面游离胺基团与 PMVE-MA 的羧基缀合，可使该系统具有可接受的安全性特征，并通过游离可用胺基团的质子海绵机制保留内涵体逃逸特性位于 hyper-branched PEI 层内部。此外，双层保护不仅控制了 NPs 的聚集并降低了毒性，而且还维持了抗癌药物甲氨蝶呤的药物释放，并进一步提高了载药颗粒的细胞毒性特征。这些结果提供了一个概念验证证据，即这种两性离子聚合物基 PSi 纳米复合材料可广泛用作细胞溶质药物递送的有前途的候选物。
