Yin Chunyang, Wang Shunhao, Ren Quanzhong, Shen Xinming, Chen Xiaodong, Liu Yajun, Liu Sijin
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China.
School of Aerospace Engineering, Beijing Institute of Technology, Beijing 100081, China.
Sci Bull (Beijing). 2019 May 30;64(10):679-689. doi: 10.1016/j.scib.2019.04.017. Epub 2019 Apr 11.
Since most cancer nanomedicine relies on the enhanced permeability and retention (EPR) effect to eradicate tumors, strategies that are able to promote nanoparticle (NP) delivery and extravasation are presupposed to elevate the EPR effect for more effective cancer therapeutics. However, nanothermotherapeutics still suffers from limited drug delivery into tumor sites, for even though numerous efforts have been made to enhance the selective tumor targeting of NPs. In this study, we uncovered that radial extracorporeal shock wave therapy (rESWT), an important approach in physical therapy that has been overlooked in cancer treatment in the past, can largely improve the EPR-dependent tumor uptake of NPs. We here defined the optimal low dosage and desirable combinatory manner for rESWT in driving NP accumulation towards tumors. Two underlying biophysical mechanisms responsible for the rESWT-enhanced EPR effect were proposed. On one hand, rESWT-conducted compressive and tensile forces could relieve high intra-tumoral pressure; on the other hand, rESWT-induced cavitation bubbles could directly distend and disrupt tumor blood vessels. All these together synergistically promoted vessel vasodilation, tumor perfusion and NP extravasation. Further experiments revealed that the combinatory therapeutics between rESWT and nanothermotherapeutics greatly improved the tumor-killing efficacy. Thus, our findings open a new path to improve EPR-mediated drug delivery with the assistance of rESWT.
由于大多数癌症纳米药物依靠增强的渗透与滞留（EPR）效应来根除肿瘤，因此能够促进纳米颗粒（NP）递送和外渗的策略被认为可以提高EPR效应，从而实现更有效的癌症治疗。然而，纳米热疗法在将药物递送至肿瘤部位方面仍存在局限，即便已经付出诸多努力来增强纳米颗粒对肿瘤的选择性靶向。在本研究中，我们发现，以往在癌症治疗中被忽视的一种重要物理治疗方法——径向体外冲击波疗法（rESWT），可在很大程度上提高纳米颗粒基于EPR的肿瘤摄取。我们在此确定了rESWT促使纳米颗粒向肿瘤积聚的最佳低剂量和理想组合方式。提出了两种导致rESWT增强EPR效应的潜在生物物理机制。一方面，rESWT产生的压缩力和拉伸力可缓解肿瘤内的高压；另一方面，rESWT诱导的空化气泡可直接扩张并破坏肿瘤血管。所有这些共同协同促进血管舒张、肿瘤灌注和纳米颗粒外渗。进一步实验表明，rESWT与纳米热疗法的联合治疗极大地提高了肿瘤杀伤效果。因此，我们的研究结果为借助rESWT改善EPR介导的药物递送开辟了一条新途径。
