The design of innovative anticancer chemotherapies with superior antitumor efficacy and reduced toxicity continues to be a challenging endeavor. Recently, the success of Adcetris^® and Kadcyla^® made antibody-drug conjugates (ADCs) serious contenders to reach the envied status of Paul Ehrlich's “magic bullet”. However, ADCs classically target overexpressed and internalizing antigens at the surface of cancer cells, and in solid tumors are associated with poor tumor penetration, insufficient targeting in heterogeneous tumors, and appearance of several resistance mechanisms. In this context, alternative non-internalizing ADCs and prodrugs have been developed to circumvent these limitations, in which the drug can be selectively released by an extracellular stimulus in the tumor microenvironment. Each strategy and method of activation will be discussed as potential alternatives to internalizing ADCs for cancer therapy.

具有优异的抗肿瘤功效和降低的毒性的创新抗癌化学疗法的设计仍是一项艰巨的努力。近日，Adcetris成功^®和Kadcyla ^®使抗体-药物结合物（ADC）成为重要竞争者，从而达到了保罗·埃里希（Paul Ehrlich）的“魔术子弹”令人羡慕的地位。但是，ADC传统上将癌细胞表面的抗原过度表达和内在化，而在实体瘤中，肿瘤的渗透性差，在异质性肿瘤中的靶向不足以及多种耐药机制的出现都与之相关。在这种情况下，已经开发了替代性的非内在化ADC和前药来规避这些局限性，在这些局限性中，可以通过肿瘤微环境中的细胞外刺激选择性地释放药物。将讨论每种激活策略和方法，作为将ADC内在化用于癌症治疗的潜在替代方法。