Biomacromolecules. 2018 Jul 9;19(7):3030-3039. doi: 10.1021/acs.biomac.8b00589. Epub 2018 Jun 22.
Current drug delivery systems are hampered by poor delivery to tumors, in part reflecting poor encapsulation stability of nanocarriers. Although nanocarriers such as polymeric micelles have high colloidal stability and do not aggregate or precipitate in bulk solution, nanocarriers with low encapsulation stability can lose their cargo during circulation in blood due to interactions with blood cells, cellular membranes, serum proteins, and other biomacromolecules. The resulting premature drug release from carriers limits the therapeutic efficacy at target sites. Herein, we report a simple and robust technique to improve encapsulation stability of drug delivery systems. Specifically, we show that installation of disulfide cross-linked noncovalent polymer gatekeepers onto mesoporous silica nanoparticles with a high loading capacity for hydrophobic drugs enhances in vivo therapeutic efficacy by preventing premature release of cargo. Subsequent release of drug cargos was triggered by cleavage of disulfide cross-linking by glutathione, leading to improved antitumor activity of doxoroubicin in mice. These findings provide novel insights into the development of nanocarriers with high encapsulation stability and improved in vivo therapeutic efficacy.
目前的药物传递系统受到向肿瘤传递效果差的限制，部分原因是纳米载体的封装稳定性差。尽管纳米载体（如聚合物胶束）具有高胶体稳定性，在大量溶液中不会聚集或沉淀，但由于与血细胞、细胞膜、血清蛋白和其他生物大分子相互作用，封装稳定性低的纳米载体在血液循环中可能会丢失其货物。载体中药物的过早释放会限制在靶部位的治疗效果。在这里，我们报告了一种简单而强大的技术来提高药物传递系统的封装稳定性。具体来说，我们表明，将二硫键交联的非共价聚合物门控器安装到具有高疏水性药物载药能力的介孔硅纳米颗粒上，通过防止货物过早释放，提高了体内治疗效果。随后，谷胱甘肽通过裂解二硫键触发药物货物的释放，从而提高了小鼠体内多柔比星的抗肿瘤活性。这些发现为开发具有高封装稳定性和改善体内治疗效果的纳米载体提供了新的思路。
