Overcoming the Reticuloendothelial System Barrier to Drug Delivery with a "Don't-Eat-Us" Strategy
Overcoming the Reticuloendothelial System Barrier to Drug Delivery with a "Don't-Eat-Us" Strategy
复制标题
通过“不吃我们”策略克服网状内皮系统药物输送障碍
DOI：
10.1021/acsnano.9b05679
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发表时间：
2019-11-01
期刊：
影响因子：
17.1
通讯作者：
Li, Chong
中科院分区：
文献类型：
--
作者：
Tang, Yixuan;Wang, Xiaoyou;Li, Chong
长期以来，克服网状内皮系统（RES）一直是纳米颗粒作为药物载体面临的重大挑战。用聚乙二醇修饰纳米颗粒有助于它们避免被巨噬细胞清除，同时也抑制它们被靶细胞内化。为了克服这个悖论，我们利用“不吃我们”策略开发了一种 RES 特定的阻止系统。首先，设计了 CD47 衍生的抗酶肽配体并将其放置在脂质体上（D-自肽标记脂质体，DSL）。主线给药后，DSL 迅速吸附到肝吞噬细胞膜（包括库普弗细胞和肝窦内皮细胞的膜）上，形成持久的掩模，包围细胞膜，从而减少吞噬细胞与随后注射的纳米颗粒之间的相互作用。与空白常规脂质体（CL）相比，DSL以低得多的剂量阻断RES，并且作用持续时间更长，极大地延长了随后注射的纳米颗粒的消除半衰期。 DSL 的这种“不吃我们”策略在针对隐球菌性脑膜炎模型的大脑靶向递送上得到了进一步验证，与 CL 相比，显着增强了靶向递送系统的大脑积累，并且模型药物两性霉素 B 的治疗效果更佳。我们的研究展示了一种通过掩蔽吞噬细胞表面来阻断 RES 的策略，以延长纳米颗粒的循环时间，而无需过度修饰，并说明了其在增强纳米颗粒递送方面的效用。
Overcoming the reticuloendothelial system (RES) has long been a vital challenge to nanoparticles as drug carriers. Modification of nanoparticles with polyethylene glycol helps them avoid clearance by macrophages but also suppresses their internalization by target cells. To overcome this paradox, we developed an RES-specific blocking system utilizing a "don't-eat-us" strategy. First, a CD47-derived, enzyme-resistant peptide ligand was designed and placed on liposomes (D-self-peptide-labeled liposome, DSL). After mainline administration, DSL was quickly adsorbed onto hepatic phagocyte membranes (including those of Kupffer cells and liver sinusoidal endothelial cells), forming a long-lasting mask that enclosed the cell membranes and thus reducing interactions between phagocytes and subsequently injected nanoparticles. Compared with blank conventional liposomes (CL), DSL blocked the RES at a much lower dose, and the effect was sustained for a much longer time, highly prolonging the elimination half-life of the subsequently injected nanoparticles. This "don't-eat-us" strategy by DSL was further verified on the brain-targeted delivery against a cryptococcal meningitis model, providing dramatically enhanced brain accumulation of the targeted delivery system and superior therapeutic outcome of model drug Amphotericin B compared with CL. Our study demonstrates a strategy that blocks the RES by masking phagocyte surfaces to prolong nanoparticle circulation time without excess modification and illustrates its utility in enhancing nanoparticle delivery.