Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy
Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy
复制标题
药效团杂交和纳米级组装发现用于癌症治疗的自我释放溶酶体性新化学实体
DOI：
10.1038/s41467-020-18399-4
复制
发表时间：
2020-09-15
影响因子：
16.6
通讯作者：
Li, Yuanpei
中科院分区：
文献类型：
--
作者：
Ma, Zhao;Li, Jin;Li, Yuanpei
整合药物发现和药物输送领域的独特优势对于药物开发的进步是无价的。在这里，我们提出了一种自我递送的单组分新化学实体纳米药物（ONN）策略，通过将自组装原理纳入药物设计来改善癌症治疗。一种溶酶体性清洁剂（MSDH）和一种自噬抑制剂（Lys05）杂交开发了双氨基喹啉衍生物，可以本质上形成纳米组装体。所选择的BAQ12和BAQ13 onn在诱导溶酶体破坏、溶酶体功能障碍和自噬阻断方面非常有效，其抗增殖活性比临床试验中使用的羟氯喹高30倍。这些单药纳米颗粒在体内表现出优异的药代动力学和毒理学特征和显著的抗肿瘤功效。此外，它们能够包封并将额外的药物递送到肿瘤部位，因此是基于自噬抑制的联合治疗的有希望的药物。鉴于它们的跨学科优势，这些BAQ onn在改善癌症治疗方面具有巨大的潜力。
Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.