Jiang Lingdong, Wu Anbang, Zeng Lingting, Zhou Bin, Zhao Min, Fan Mingjian, Jin Zhaokui, He Qianjun
College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China.
School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, Guangdong, 518060, China.
Adv Healthc Mater. 2025 Mar;14(6):e2404085. doi: 10.1002/adhm.202404085. Epub 2025 Jan 5.
Poor tumor penetration is the major predicament of nanomedicines that limits their anticancer efficacy. The dense extracellular matrix (ECM) in the tumor is one of the major barriers against the deep penetration of nanomedicines. In this work, a slimming/excavating strategy is proposed for enhanced intratumoral penetration based on an acid-disassemblable nanomicelles-assembled nanomedicine and the NO-mediated degradation of ECM. The nanomedicine is constructed by cross-linking nanomicelles, which are self-assembled with two kinds of dendrimers containing phenylboronic acid and lactobionic acid, through borate esterification. In the acidic tumor microenvironment, the pH-sensitive borate ester bonds among the nanomicelles are hydrolyzed, triggering the disassembly of nanomedicine (≈150 nm) into small nanomicelles (≈25 nm). In response to the intratumoral over-expressed glutathione (GSH), the NO donor loaded in the nanomicelles produces NO, which mediates the expression of matrix metalloproteinases for the degradation of ECM in the tumor. By collaboration of the disassembling behavior of nanomedicine with the NO-mediated degradation of ECM, the designed nanomedicine can penetrate a long distance in tumors. The proposed slimming/excavating strategy will provide inspiration for overcoming the challenge of nanomedicines in tumor penetration.
肿瘤穿透性差是纳米药物面临的主要困境，限制了它们的抗癌疗效。肿瘤中致密的细胞外基质（ECM）是纳米药物深度穿透的主要障碍之一。在这项工作中，基于酸可分解的纳米胶束组装纳米药物和NO介导的ECM降解，提出了一种瘦身/挖掘策略以增强肿瘤内穿透性。该纳米药物通过硼酸酯化交联纳米胶束构建而成，这些纳米胶束由两种分别含有苯硼酸和乳糖酸的树枝状大分子自组装而成。在酸性肿瘤微环境中，纳米胶束之间的pH敏感硼酸酯键被水解，促使纳米药物（≈150 nm）分解为小纳米胶束（≈25 nm）。响应肿瘤内过度表达的谷胱甘肽（GSH），负载在纳米胶束中的NO供体产生NO，其介导基质金属蛋白酶的表达以降解肿瘤中的ECM。通过纳米药物的分解行为与NO介导的ECM降解协同作用，设计的纳米药物能够在肿瘤中实现长距离穿透。所提出的瘦身/挖掘策略将为克服纳米药物在肿瘤穿透方面的挑战提供灵感。
