Engineering PLGA nano-based systems through understanding the influence of nanoparticle properties and cell-penetrating peptides for cochlear drug delivery
Engineering PLGA nano-based systems through understanding the influence of nanoparticle properties and cell-penetrating peptides for cochlear drug delivery
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通过了解纳米颗粒特性和细胞穿透肽对耳蜗药物输送的影响，设计基于 PLGA 纳米的系统
DOI：
10.1016/j.ijpharm.2017.08.084
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发表时间：
2017-10-30
影响因子：
5.8
通讯作者：
Chen, Gang
中科院分区：
文献类型：
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作者：
Cai, Hui;Liang, Zhongping;Chen, Gang
聚乳酸-羟基乙酸共聚物（PLGA）纳米粒（NPs）和渗透促进剂的性质对NPs通过圆窗膜（RWM）的内耳给药起着决定性的作用。因此，设计了具有各种粒径和表面化学的基于PLGA的纳米系统以及与作为渗透增强剂的细胞穿透肽（CPP）组合的那些系统，以探索它们对体内耳蜗药物递送的影响。首先，我们通过近红外荧光成像证明了NP的性质决定了NP耳蜗进入的程度。尺寸为150和300 nm的纳米颗粒比80 nm的纳米颗粒具有更快的进入。在0.5 h时，在未改性的和用壳聚糖（CS）、泊洛沙姆407（P407）和甲氧基聚乙二醇改性的NP中，CS-PLGA-NP（正表面电荷）最快地将有效载荷携带到耳蜗，而P407-PLGA-NP（表面亲水性）在24 h时显示出在耳蜗中的最大分布。与其他CPP（达特、穿透素和聚（精氨酸）8）相比，低分子量鱼精蛋白（LMWP）在HEI-OCi细胞和耳蜗进入中执行显著增强的NP细胞摄取。更重要的是，具有优化性质的NP和CPP可以组合以改善RWM渗透。我们首次证实，P407-PLGA-NP（平均直径：100-200 nm）和LMWP的组合提供了NP进入Corti器官和血管纹的协同增强，而不诱导耳蜗组织和RWM的病理改变。综上所述，我们提出了一种有效的基于PLGA纳米的策略，用于增强药物递送到内耳组织，该策略结合了亲水性分子修饰的NP和CPP，最终为上级内耳治疗开辟了一条途径。
The properties of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and penetration enhancers play a deciding role in the inner ear drug delivery of NPs across the round window membrane (RWM). Thus, PLGA nano-based systems with a variety of particle sizes and surface chemistries and those combined with cell-penetrating peptides (CPPs) as penetration enhancers were devised to explore their impact on the cochlear drug delivery in vivo. First, we demonstrated that the properties of NPs dictated the extent of NP cochlear entry by near-infrared fluorescence imaging. NPs with the sizes of 150 and 300 nm had faster entry than that of 80 nn NPs. At 0.5 h, among the NPs unmodified and modified with chitosan (CS), poloxamer 407 (P407) and methoxy polyethylene glycol, CS-PLGA-NPs (positive surface charge) carried payload to the cochlea fastest, whereas P407-PLGA-NPs (surface hydrophilicity) showed the greatest distribution in the cochlea at 24 h. Compared to other CPPs (TAT, penetratin and poly(arginine) 8), low molecular weight protamine (LMWP) performed an outstanding enhanced NP cellular uptake in HEI-OCi cells and cochlear entry. More importantly, NPs with optimized properties and CPPs may be combined to improve RWM penetration. For the first time, we confirmed that the combination of P407-PLGA-NPs (mean diameter: 100-200 nm) and LMWP provided a synergistic enhancement in NP entry to the organ of Corti and stria vascularis without inducing pathological alteration of cochlear tissues and RWM. Taken together, we propose an effective PLGA nano-based strategy for enhanced drug delivery to the inner ear tissues that combines hydrophilic molecule-modified NPs and CPPs, ultimately opening an avenue for superior inner ear therapy.