Hyaluronidase To Enhance Nanoparticle-Based Photodynamic Tumor Therapy
Hyaluronidase To Enhance Nanoparticle-Based Photodynamic Tumor Therapy
复制标题
透明质酸酶增强基于纳米颗粒的光动力肿瘤治疗
DOI：
10.1021/acs.nanolett.6b00068
复制
发表时间：
2016-04-01
期刊：
影响因子：
10.8
通讯作者：
Liu, Zhuang
中科院分区：
文献类型：
--
作者：
Gong, Hua;Chao, Yu;Liu, Zhuang
光动力疗法（PDT）被认为是一种安全和选择性的方法来治疗各种癌症以及非肿瘤性疾病。然而，由于在PDT过程中需要氧气，缺氧的肿瘤微环境在很大程度上限制了PDT治疗肿瘤的功效，特别是那些具有相对较大尺寸的肿瘤。为此，我们发现，透明质酸酶（HAase），它打破透明质酸，细胞外基质（ECM）在肿瘤中的主要成分，将能够提高疗效的纳米粒子为基础的PDT在体内癌症治疗。结果发现，HAase的给药将导致肿瘤血管密度和有效血管面积增加，导致肿瘤内灌注增加。结果，由于改善的“增强渗透性和保留”（EPR）效应，与氯e6共价连接的纳米胶束（NM-Ce 6）的肿瘤摄取将增加约2倍，同时肿瘤氧合水平也显示出显著增加，有效缓解了肿瘤内的缺氧状态。这些效应结合在一起，在极大地提高由纳米颗粒递送的PDT的功效方面提供了显著的益处。利用HAase从原发肿瘤到其引流前哨淋巴结（SLN）的有效迁移，我们进一步证明了这种策略将有助于通过基于纳米颗粒的PDT治疗转移性淋巴结。最后，在全身注射修饰的HAase后，也观察到NM-Ce 6的增强EPR效应和肿瘤的缺氧状态的改善，证明其具有临床转化的潜力。因此，我们的工作提出了一个新的概念，通过调节肿瘤微环境来提高纳米药物的疗效。
Photodynamic therapy (PDT) is considered as a safe and selective way to treat a wide range of cancers as well as nononcological disorders. However, as oxygen is required in the process of PDT, the hypoxic tumor microenvironment has largely limited the efficacy of PDT to treat tumors especially those with relatively large sizes. To this end, we uncover that hyaluronidase (HAase), which breaks down hyaluronan, a major component of extracellular matrix (ECM) in tumors, would be able to enhance the efficacy of nanopartide-based PDT for in vivo cancer treatment. It is found that the administration of HAase would lead to the increase of tumor vessel densities and effective vascular areas, resulting in increased perfusion inside the tumor. As a result, the tumor uptake of nanomicelles covalently linked with chlorine e6 (NM-Ce6) would be increased by similar to 2 folds due to the improved "enhanced permeability and retention" (EPR) effect, while the tumor oxygenation level also shows a remarkable increase, effectively relieving the hypoxia state inside the tumor. Those effects taken together offer significant benefits in greatly improving the efficacy of PDT delivered by nanoparticles. Taking advantage of the effective migration of HAase from the primary tumor to its drainage sentinel lymph nodes (SLNs), we further demonstrate that this strategy would be helpful to the treatment of metastatic lymph nodes by nanoparticle-based PDT. Lastly, both enhanced EPR effect of NM-Ce6 and relieved hypoxia state of tumor are also observed after systemic injection of modified HAase, proving its potential for clinical translation. Therefore, our work presents a new concept to improve the efficacy of nanomedicine by modulating the tumor microenvironment.