Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
University of Chinese Academy of Sciences, NO.19A Yuquan Road, 100049, Beijing, China.
Nat Commun. 2018 Jul 4;9(1):2607. doi: 10.1038/s41467-018-05061-3.
To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.
为了最佳地穿透生物水凝胶，如黏液和肿瘤间质基质，纳米颗粒（NPs）需要具有通常会阻止细胞摄取的物理化学性质，从而导致药物递送效率低下。在这里，我们证明了具有中等刚性的（聚（乳酸-共-乙醇酸）（PLGA）核）-（脂质壳）NPs 与一些合成的黏液穿透颗粒（MPPs）相比，在通过黏液时显示出增强的扩散性，从而实现了优于其软质和硬质对应物的黏膜和肿瘤穿透能力。口服半弹性 NPs 可有效地克服多个肠道屏障，与 Dox 溶液相比，阿霉素（Dox）的生物利用度增加了 8 倍（高达 8 倍）。分子动力学模拟和超分辨率显微镜揭示，半弹性 NPs 变形为椭圆形，这使得旋转促进穿透成为可能。相比之下，刚性 NPs 不能变形，而过于柔软的 NPs 则受到与水凝胶网络相互作用的阻碍。改变颗粒的刚性可以提高基于 NP 的药物的疗效，并且可以适用于其他屏障。
