Wang Lilin, Geng Di, Su Haijia
State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Chaoyang District, Beijing, China.
Beijing University of Chinese Medicine, 11 Beisanhuan East Road, Chaoyang District, Beijing, China.
Colloids Surf B Biointerfaces. 2014 Nov 1;123:395-402. doi: 10.1016/j.colsurfb.2014.09.003. Epub 2014 Sep 15.
Incorporating the pH-sensitivity of octylamine grafted poly aspartic acid (PASP) with the biocompatibility of liposomes, a novel pH sensitive drug delivery system, octylamine-graft-PASP (PASP-g-C8) modified liposomes (OPLPs), was obtained. Since hydrophobic chains have been grafted into PASP backbones, the octylamine chain could act as the "anchor" to implant onto liposomes. The structure of PASP-g-C8, involving long-chain and hydrophobic anchors can significantly enhance the stability of the drug carrier. The shortcoming of single PASP chain modified liposomes (PLPs), that cannot sustain a slow and controlled release especially in a physiological pH solution (resembling normal tissues of pH 7.4) is thus overcome. Drug release experiments were carried out and the result showed that OPLPs sustained a slow and steady release in comparison with PLPs in the physiological pH 7.4 environment. However, OPLPs can provide a fast release in subacid environment (pH 5.0 of resembled tumor tissues). The results of diameter analysis and zeta potential demonstrated that OPLPs presented a larger diameter and higher electronegativity. Furthermore, in the "chain-anchor" structure of PASP-g-C8, the degree of substitution (DS) of the "anchor" is a remarkable factor to alter the pH-sensitivity of OPLPs. The in vitro tumor inhibition and cell toxicity studies revealed that tumor cells treated with OPLPs survived only 35.0% after 48 h whereas normal cells survived 100% in the same condition. The pH sensitive OPLPs are promising tumor targeting drug delivery with high tumor inhibition and insignificant cytotoxicity.
将辛胺接枝聚天冬氨酸（PASP）的pH敏感性与脂质体的生物相容性相结合，得到了一种新型的pH敏感药物递送系统——辛胺接枝PASP（PASP-g-C8）修饰脂质体（OPLPs）。由于疏水链已接枝到PASP主链中，辛胺链可作为“锚”植入脂质体。PASP-g-C8的结构包含长链和疏水锚，可显著提高药物载体的稳定性。从而克服了单链PASP修饰脂质体（PLPs）的缺点，尤其是在生理pH溶液（类似于pH 7.4的正常组织）中不能维持缓慢且可控的释放。进行了药物释放实验，结果表明，在生理pH 7.4环境中，与PLPs相比，OPLPs能维持缓慢且稳定的释放。然而，OPLPs在亚酸性环境（类似于肿瘤组织的pH 5.0）中能实现快速释放。粒径分析和zeta电位结果表明，OPLPs具有更大的粒径和更高的负电性。此外，在PASP-g-C8的“链-锚”结构中，“锚”的取代度（DS）是改变OPLPs pH敏感性的一个显著因素。体外肿瘤抑制和细胞毒性研究表明，用OPLPs处理的肿瘤细胞在48小时后存活率仅为35.0%，而在相同条件下正常细胞存活率为100%。这种pH敏感的OPLPs有望成为具有高肿瘤抑制率和低细胞毒性的肿瘤靶向药物递送系统。
