Department of Pharmaceutics, Key Lab of State Natural Medicine, China Pharmaceutical University, Nanjing 210009, PR China.
Int J Pharm. 2012 Oct 15;436(1-2):248-57. doi: 10.1016/j.ijpharm.2012.06.040. Epub 2012 Jun 23.
By inserting L-arginine lauril ester (AL) into nanostructure lipid carriers (NLCs) and then coating with bovine serum albumin (BSA), pH-sensitive membranolytic and lysosomolytic nanocarriers (BSA-AL-NLCs) were developed. Hemolysis assay demonstrated the pH-sensitive biomembrane disruptional capability of AL and BSA-AL-NLCs. BSA-AL-NLCs did not disrupt biomembrane at pH 7.4 even at high concentration, exhibited ideal feasibility as lysosomolytic drug delivery nanoparticles without cytotoxicity. Confocal Laser Scanning Microscope (CLSM) images confirmed the lysosomolytic capability of BSA-AL-NLCs after internalized into MCF-7 (human breast cancer cell) via endosome-lysosome path in vitro. Paclitaxel (PTX) loaded BSA-AL-NLCs displayed pH-dependent release in vitro. In MCF-7 viability test with MTT assays, both the blank NLCs did not exhibit cellular toxicity. Of particular interest, the in vitro cell experiments demonstrated that the anti-tumor effect of PTX-loaded BSA-AL-NLCs was preferable to BSA-NLCs, even comparable with PTX solution, which indicated that AL served to facilitate lysosomal escape of BSA-AL-NLCs so as to improve the anti-cancer effect. Biodistribution and anti-cancer activity in vivo confirmed the improved tumor targeting and anti-cancer efficacy of BSA-AL-NLCs. The study suggested that the simple and small molecule of AL may render more nanocarriers lysosomolytic capability with lower cytotoxicity, as well as improved therapeutic index of loaded active agents.
通过将 L-精氨酸月桂酸酯（AL）插入纳米结构脂质载体（NLC）中，然后用牛血清白蛋白（BSA）进行涂层，开发了 pH 敏感的膜溶胀和溶酶体溶胀纳米载体（BSA-AL-NLC）。溶血试验证明了 AL 和 BSA-AL-NLC 的 pH 敏感生物膜破坏能力。即使在高浓度下，BSA-AL-NLC 在 pH 7.4 时也不会破坏生物膜，表现出作为溶酶体释药纳米颗粒的理想可行性，没有细胞毒性。共聚焦激光扫描显微镜（CLSM）图像证实了 BSA-AL-NLC 在通过内体-溶酶体途径内化到 MCF-7（人乳腺癌细胞）后体外溶酶体的能力。紫杉醇（PTX）负载的 BSA-AL-NLC 显示出体外 pH 依赖性释放。在 MCF-7 细胞活力测定的 MTT 试验中，空白 NLC 均未显示出细胞毒性。特别有趣的是，体外细胞实验表明，载紫杉醇的 BSA-AL-NLC 的抗肿瘤作用优于 BSA-NLC，甚至与紫杉醇溶液相当，这表明 AL 有助于促进 BSA-AL-NLC 的溶酶体逃逸，从而提高抗癌效果。体内分布和抗癌活性证实了 BSA-AL-NLC 的改善的肿瘤靶向和抗癌功效。该研究表明，简单的小分子 AL 可能使更多的纳米载体具有更低的细胞毒性的溶酶体溶胀能力，以及改善负载活性物质的治疗指数。
