National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, 430074, Wuhan, P. R. China.
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 430074, Wuhan, P. R. China.
Nat Commun. 2023 Mar 15;14(1):1437. doi: 10.1038/s41467-023-37150-3.
Nanomedicine has been developed for cancer therapy over several decades, while rapid clearance from blood circulation by reticuloendothelial system (RES) severely limits nanomedicine antitumour efficacy. We design a series of nanogels with distinctive stiffness and investigate how nanogel mechanical properties could be leveraged to overcome RES. Stiff nanogels are injected preferentially to abrogate uptake capacity of macrophages and temporarily block RES, relying on inhibition of clathrin and prolonged liver retention. Afterwards, soft nanogels deliver doxorubicin (DOX) with excellent efficiency, reflected in high tumour accumulation, deep tumour penetration and outstanding antitumour efficacy. In this work, we combine the advantage of stiff nanogels in RES-blockade with the superiority of soft nanogels in drug delivery leads to the optimum tumour inhibition effect, which is defined as mechano-boosting antitumour strategy. Clinical implications of stiffness-dependent RES-blockade are also confirmed by promoting antitumour efficacy of commercialized nanomedicines, such as Doxil and Abraxane.
纳米医学在过去几十年中已经被开发用于癌症治疗，而网状内皮系统（RES）的快速从血液循环中清除严重限制了纳米医学的抗肿瘤疗效。我们设计了一系列具有独特硬度的纳米凝胶，并研究了纳米凝胶的机械性能如何能够被利用来克服 RES。硬纳米凝胶优先注射，以消除巨噬细胞的摄取能力并暂时阻断 RES，这依赖于网格蛋白的抑制和延长的肝脏保留。之后，软纳米凝胶以优异的效率递送阿霉素（DOX），表现为高肿瘤积累、深肿瘤渗透和出色的抗肿瘤疗效。在这项工作中，我们将硬纳米凝胶在 RES 阻断方面的优势与软纳米凝胶在药物传递方面的优势相结合，从而达到最佳的肿瘤抑制效果，这被定义为机械增强抗肿瘤策略。通过促进商业化纳米药物（如 Doxil 和 Abraxane）的抗肿瘤疗效，也证实了基于刚度的 RES 阻断的临床意义。
