Drug nanocarriers that have long been expected to revolutionize cancer therapy have yet to achieve the significant clinical success. Therefore, it remains controversial to pursue a complex drug nanocarrier that lacks clinical relevance. Herein, we developed an easily-synthesized anti-tumor drug that actively seeks the acidic tumor microenvironment while ignoring the normal tissue without the aid of additional carriers. This called “carrier-free” drug (CFD) is capable of switching its morphology from the unstructured solution to the spherical structure in response to tumor acidity. CFDs were the water-soluble zwitterionic unimers to prevent the non-specific distribution in the circulation, whereas they spontaneously formed into the particles tending to accumulation in tumor. CFD overloading in tumor cells caused the lysosomal dysfunction and autophagy blockage, thereby triggered the cell death. All the in vitro and in vivo data demonstrated the tumor-acidity-selective cytotoxicity of CFD. This facile strategy to create a self-delivering anticancer drug may cast a new light on the development of cancer therapy.

长期以来人们期望药物纳米载体将彻底改变癌症治疗方法，但尚未取得重大的临床成功。因此，寻找缺乏临床相关性的复杂药物纳米载体仍存在争议。本文中，我们开发了一种易于合成的抗肿瘤药物，该药物在不依赖其他组织的情况下，主动寻找酸性肿瘤微环境，而忽略了正常组织。这种称为“无载体”的药物（CFD）能够响应于肿瘤的酸度将其形态从非结构化溶液转变为球形结构。CFD是水溶性两性离子单体，可防止循环中非特异性分布，而它们自发地形成趋于在肿瘤中蓄积的颗粒。肿瘤细胞中的CFD超载导致了溶酶体功能障碍和自噬阻滞，从而触发了细胞死亡。所有的体外和体内数据都证明了CFD对肿瘤酸性的选择性细胞毒性。这种创建自递送抗癌药物的简便策略可能会为癌症治疗的发展开辟新的亮点。