Background: Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) and its over expression in tumor tissues contributes to the increase of interstitial fluid pressure (IFP) and hinders the penetration of nanoparticles into solid tumors.
Materials and Methods: We here reported a tumoral microenvironment responsive multistage drug delivery system (NPs-EPI/HAase) which was formed layer by layer via electrostatic interaction with epirubicin (EPI)-loaded PEG-b-poly(2-(diisopropylamino)ethyl methacrylate)-b-poly(2-guanidinoethylmethacrylate) (mPEG-PDPA-PG, PEDG) micelles (NPs-EPI) and hyaluronidase (HAase). In this paper, we focused on the hyaluronidase-combined nanoparticles (NPs-EPI/HAase) for tumor penetration in tumor spheroid and solid tumor models in vitro and in vivo.
Results: Our results showed that NPs-EPI/HAase effectively degrade the HA in ECM and facilitate deep penetration of NPs-EPI into solid tumor. Moreover, NPs-EPI mainly employed clathrin-mediated and macropinocytosis-mediated endocytic pathways for cellular uptake and were subsequently directed to the lysosomes for further drug release triggered by proton sponge effect. Compared with NPs-EPI, the HAase coating group showed an enhanced tumoral drug delivery efficacy and inhibition of tumor growth.
Conclusion: Overall, our studies demonstrated that coating nanoparticles with HAase can provide a simple but efficient strategy for nano-drug carriers to enhance solid tumor penetration and chemotherapeutic efficacy.



中文翻译：

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透明质酸酶结合多级纳米颗粒对实体瘤穿透和抗肿瘤作用的机制研究。

背景：透明质酸（HA）是细胞外基质（ECM）的主要成分，其在肿瘤组织中的过度表达有助于增加间质液压力（IFP）并阻碍纳米颗粒向实体瘤的渗透。
材料和方法：我们在此报道了一种肿瘤微环境响应性多阶段药物递送系统（NPs-EPI/HAase），该系统通过与表柔比星（EPI）负载的PEG-b-聚（2-（二异丙基氨基）乙基）的静电相互作用逐层形成。甲基丙烯酸酯）-b-聚（2-胍基乙基甲基丙烯酸酯）（mPEG-PDPA-PG，PEDG）胶束（NPs-EPI）和透明质酸酶（HAase）。在本文中，我们重点研究了透明质酸酶组合纳米粒子 (NPs-EPI/HAase) 在体外和体内肿瘤球体和实体瘤模型中的肿瘤穿透。
结果：我们的结果表明，NPs-EPI/HAase 可有效降解 ECM 中的 HA，促进 NPs-EPI 深入实体瘤。此外，NPs-EPI 主要采用网格蛋白介导和巨胞饮作用介导的内吞途径进行细胞摄取，随后被引导至溶酶体以进一步释放由质子海绵效应触发的药物。与 NPs-EPI 相比，HAase 涂层组表现出增强的肿瘤药物递送功效和抑制肿瘤生长。
结论：总体而言，我们的研究表明，用 HAase 包覆纳米颗粒可以为纳米药物载体提供一种简单而有效的策略，以增强实体瘤的穿透性和化疗效果。