Greindl Melanie, Bernkop-Schnürch Andreas
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 52, Josef-Möller-Haus, 6020 Innsbruck, Austria.
Pharm Res. 2006 Sep;23(9):2183-9. doi: 10.1007/s11095-006-9087-1. Epub 2006 Aug 9.
To develop a novel method for the preparation of thiolated polyacrylic acid nanoparticles via ionic gelation.
In a first step nanoparticles were generated by ionotropic gelation of polyacrylic acid (PAA) of three different molecular weights (100, 240 and 450 kDa) and various cations including Ca2+, Mg2+, Zn2+, Al3+ and Fe3+. Via in vitro characterization of the particles (particle size, size distribution and zeta potential) the optimal preparation conditions were established. Taking into consideration, that thiolated polyacrylic acid (PAA-Cys) displays higher mucoadhesive and permeation enhancing properties than unmodified PAA, PAA-Cys nanoparticles were produced in the same manner with Ca2+, as the most promising results concerning particle size and stability of particles could be achieved with this ionic crosslinker. The nanoparticles were stabilized via the formation of inter- and intrachain disulfide bonds within these particles due to oxidation with H2O2. Ca2+ was removed proximately by the addition of EDTA and exhaustive dialysis.
Using the preparation method described above PAA-Cys nanoparticles of a mean diameter of about 220 nm (PAA(100)-Cys), 250 nm (PAA(240)-Cys) and 295 nm (PAA(450)-Cys) can be generated. In comparison to PAA nanoparticles ionically crosslinked with Ca2+, the removal of the crosslinker Ca2+ from PAA-Cys particles led to a nearly three-fold decrease in the zeta potential, from about -7 up to -20 mV. Apart from this advantage, covalently crosslinked PAA-Cys nanoparticles were more firm as they remained stable when incubated in hydrochloride solution, whereas ionically crosslinked particles dissolved at pH lower than 5.
This novel nanoparticulate delivery system seems to be a promising vehicle for the administration of therapeutic proteins, genes and antigens via mucosal membranes.
开发一种通过离子凝胶法制备巯基化聚丙烯酸纳米颗粒的新方法。
第一步，通过三种不同分子量（100、240和450 kDa）的聚丙烯酸（PAA）与包括Ca2+、Mg2+、Zn2+、Al3+和Fe3+在内的各种阳离子进行离子凝胶化反应生成纳米颗粒。通过对颗粒进行体外表征（粒径、粒径分布和zeta电位）确定最佳制备条件。考虑到巯基化聚丙烯酸（PAA-Cys）比未修饰的PAA表现出更高的粘膜粘附性和渗透增强特性，采用相同方法以Ca2+制备PAA-Cys纳米颗粒，因为使用这种离子交联剂在粒径和颗粒稳定性方面可获得最有前景的结果。通过用H2O2氧化，纳米颗粒通过在这些颗粒内形成链间和链内二硫键而得以稳定。通过添加EDTA和彻底透析近似去除Ca2+。
使用上述制备方法可生成平均直径约为220 nm（PAA(100)-Cys）、250 nm（PAA(240)-Cys）和295 nm（PAA(450)-Cys）的PAA-Cys纳米颗粒。与用Ca2+进行离子交联的PAA纳米颗粒相比，从PAA-Cys颗粒中去除交联剂Ca2+导致zeta电位下降近三倍，从约-7 mV降至-20 mV。除此之外，共价交联的PAA-Cys纳米颗粒更稳定，因为它们在盐酸溶液中孵育时保持稳定，而离子交联颗粒在pH低于5时溶解。
这种新型纳米颗粒递送系统似乎是通过粘膜给药治疗性蛋白质、基因和抗原的一种有前景的载体。
