Rahmat Deni, Müller Christiane, Barthelmes Jan, Shahnaz Gul, Martien Ronny, Bernkop-Schnürch Andreas
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria.
Department of Pharmaceutics, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia.
Eur J Pharm Biopharm. 2013 Feb;83(2):149-55. doi: 10.1016/j.ejpb.2012.10.008. Epub 2012 Nov 10.
Within this study, HEC-cysteamine nanoparticles with free thiol groups in the range of 117-1548 μmol/g were designed and characterized. Nanoparticles were generated via ionic gelation of the cationic polymer with tripolyphosphate (TPP) followed by covalent crosslinking via disulfide bond formation using H2O2 as oxidant. The mean diameter of the particles was in the range of 270-360 nm, and zeta potential was determined to be +4 to +10 mV. Nanoparticles were evaluated in terms of mucoadhesive, permeation enhancing, and biocompatible properties as well as biodegradability. The particles remained attached to porcine intestinal mucosa up to 70% after 3h of incubation. The more nanoparticles were oxidized; however, the less were their mucoadhesive properties. Nanoparticles applied in a concentration of 0.5% (m/v) with the highest content of free thiol groups improved the transport of fluorescein isothiocyanate dextran 4 (FD4) across Caco-2 cell monolayer 3.94-fold in comparison with control (buffer). In addition, the transport of FD4 was even 1.84-fold enhanced in the presence of 0.5% (m/v) nanoparticles with the lowest free thiol group content. The higher the disulfide bond content within nanoparticles was, to a lower degree nanoparticles were hydrolyzed by cellulase. None of these nanoparticles showed pronounced cytotoxicity. Accordingly, HEC-cysteamine could be a promising excipient for nanoparticulate delivery systems for poorly absorbed drugs.
在本研究中，设计并表征了游离巯基含量在117 - 1548 μmol/g范围内的HEC - 半胱胺纳米颗粒。通过阳离子聚合物与三聚磷酸钠（TPP）的离子凝胶化反应生成纳米颗粒，随后以H2O2作为氧化剂通过二硫键形成进行共价交联。颗粒的平均直径在270 - 360 nm范围内，zeta电位测定为 +4至 +10 mV。对纳米颗粒的粘膜粘附性、渗透增强性、生物相容性以及生物降解性进行了评估。孵育3小时后，颗粒在猪肠粘膜上的附着率高达70%。然而，纳米颗粒被氧化得越多，其粘膜粘附性能就越弱。以0.5%（m/v）浓度应用且游离巯基含量最高的纳米颗粒，与对照（缓冲液）相比，使异硫氰酸荧光素葡聚糖4（FD4）跨Caco - 2细胞单层的转运提高了3.94倍。此外，在游离巯基含量最低的0.5%（m/v）纳米颗粒存在下，FD4的转运甚至提高了1.84倍。纳米颗粒中二硫键含量越高，其被纤维素酶水解的程度越低。这些纳米颗粒均未表现出明显的细胞毒性。因此，HEC - 半胱胺可能是用于难吸收药物的纳米颗粒递送系统的一种有前景的辅料。
