Nanoparticles (NPs), such as liposomes, effectively evade the severe toxicity of unexpected accumulation and passively shuttle drugs into tumor tissues by enhanced permeability and retention. In the case of non-small cell lung cancer and pancreatic ductal adenocarcinoma, cancer-associated fibroblasts promote the aggregation of a gel-like extracellular matrix that forms a physical barrier in the desmoplastic stroma of the tumor. These stroma are composed of protein networks and glycosaminoglycans (GAGs) that greatly compromise tumor-penetrating performance, leading to insufficient extravasation and tissue penetration of NPs. Moreover, the presence of heparan sulfate (HS) and related proteoglycans on the cell surface and tumor extracellular matrix may serve as molecular targets for NP-mediated drug delivery. Here, a GAG-binding peptide (GBP) with high affinity for HS and high cell-penetrating activity was used to develop an HS-targeting delivery system. Specifically, liposomal doxorubicin (L-DOX) was modified by post-insertion with the GBP. We show that the in vitro uptake of L-DOX in A549 lung adenocarcinoma cells increased by GBP modification. Cellular uptake of GBP-modified L-DOX (L-DOX-GBP) was diminished in the presence of extracellular HS but not in the presence of other GAGs, indicating that the interaction with HS is critical for the cell surface binding of L-DOX-GBP. The cytotoxicity of doxorubicin positively correlated with the molecular composition of GBP. Moreover, GBP modification improved the in vivo distribution and anticancer efficiency of L-DOX, with enhanced desmoplastic targeting and extensive distribution. Taken together, GBP modification may greatly improve the tissue distribution and delivery efficiency of NPs against HS-abundant desmoplastic stroma-associated neoplasm.

中文翻译：

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硫酸乙酰肝素靶向策略可增强脂质体药物的积累并促进肿瘤的深度分布。

纳米颗粒（NPs），例如脂质体，可以有效地规避意外积累的严重毒性，并通过增强的通透性和保留力将药物被动地转运到肿瘤组织中。在非小细胞肺癌和胰腺导管腺癌的情况下，与癌症相关的成纤维细胞促进了凝胶状细胞外基质的聚集，该凝胶状细胞外基质在肿瘤的增生基质中形成了物理屏障。这些基质由蛋白质网络和糖胺聚糖（GAG）组成，它们极大地损害了肿瘤的穿透性能，导致NP的外渗和组织渗透不足。此外，细胞表面和肿瘤细胞外基质上硫酸乙酰肝素（HS）和相关蛋白聚糖的存在可作为NP介导药物递送的分子靶标。这里，具有对HS高亲和力和高细胞穿透活性的GAG结合肽（GBP）用于开发HS靶向递送系统。具体而言，脂质体阿霉素（L-DOX）通过插入后用GBP进行修饰。我们显示，GBP修饰增加了A549肺腺癌细胞中L-DOX的体外摄取。在存在细胞外HS的情况下减少了GBP修饰的L-DOX（L-DOX-GBP）的细胞摄取，但在其他GAG的存在下则没有减少，表明与HS的相互作用对于L-DOX的细胞表面结合至关重要-英镑。阿霉素的细胞毒性与GBP的分子组成呈正相关。此外，GBP修饰改善了L-DOX的体内分布和抗癌效率，并增强了促肿瘤靶向作用和广泛的分布。在一起