Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
J Am Chem Soc. 2023 Aug 23;145(33):18414-18431. doi: 10.1021/jacs.3c04467. Epub 2023 Jul 31.
Lysosomes remain powerful organelles and important targets for cancer therapy because cancer cell proliferation is greatly dependent on effective lysosomal function. Recent studies have shown that lysosomal membrane permeabilization induces cell death and is an effective way to treat cancer by bypassing the classical caspase-dependent apoptotic pathway. However, most lysosome-targeted anticancer drugs have very low selectivity for cancer cells. Here, we show intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. We designed a peptide amphiphile that localizes in the cancer lysosome and undergoes cathepsin B enzyme-instructed supramolecular assembly. This localized assembly induces lysosomal swelling, membrane permeabilization, and damage to the lysosome, which eventually causes caspase-independent apoptotic death of cancer cells without conventional chemotherapeutic drugs. It has specific anticancer effects and is effective against drug-resistant cancers. Moreover, this peptide amphiphile exhibits high tumor targeting when attached to a tumor-targeting ligand and causes significant inhibition of tumor growth both in cancer and drug-resistant cancer xenograft models.
溶酶体仍然是强大的细胞器，也是癌症治疗的重要靶点，因为癌细胞的增殖在很大程度上依赖于有效的溶酶体功能。最近的研究表明，溶酶体膜通透性的诱导细胞死亡是一种有效的治疗癌症的方法，可以绕过经典的 caspase 依赖性细胞凋亡途径。然而，大多数溶酶体靶向抗癌药物对癌细胞的选择性非常低。在这里，我们展示了一种肽两亲体的溶酶体内自组装作为克服这个问题的强大技术。我们设计了一种肽两亲体，它定位于癌细胞的溶酶体中，并经历组织蛋白酶 B 酶指导的超分子组装。这种局部组装诱导溶酶体肿胀、膜通透性和溶酶体损伤，最终导致 caspase 非依赖性的癌细胞凋亡，而无需传统的化疗药物。它具有特异性的抗癌作用，对耐药性癌症有效。此外，当与肿瘤靶向配体结合时，这种肽两亲体表现出高肿瘤靶向性，并在癌症和耐药性癌症异种移植模型中显著抑制肿瘤生长。
