加利车霉素是一种有效的、不依赖于细胞周期的烯二炔抗生素，可结合和切割 DNA。毒性导致其以靶向形式使用，作为被批准用于治疗液体肿瘤的抗体药物缀合物。我们使用还原的加利车霉素将其与 pH 低插入肽 (pHLIP) 膜插入端的单个半胱氨酸残基结合，该肽将成像和治疗剂靶向肿瘤。二硫键的细胞质还原释放出加利车霉素，随后发生激活、DNA 结合和链断裂。我们研究了 pHLIP-加利车霉素与脂质体和细胞膜的相互作用，并证明该药物在高度增殖的癌细胞和非增殖性免疫细胞（例如极化的 M2 巨噬细胞）中均表现出细胞毒活性。在体内，该药物可有效抑制小鼠肿瘤生长，且无毒性迹象。生物分布研究证实了肿瘤靶向，且药物在器官和组织中没有积累。在肿瘤块和肿瘤间质界面内发现了该试剂。肿瘤治疗导致肿瘤核心内 CD206 M2 肿瘤相关巨噬细胞的消耗。 pHLIP-加利车霉素可作为治疗实体瘤的有效疗法。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Calicheamicin is a potent, cell-cycle independent enediyne antibiotic that binds and cleaves DNA. Toxicity has led to its use in a targeted form, as an antibody-drug conjugate approved for the treatment of liquid tumors. We used a reduced calicheamicin to conjugate it to a single cysteine residue at the membrane-inserting end of a pH Low Insertion Peptide (pHLIP) that targets imaging and therapeutic agents to tumors. The cytoplasmic reduction of the disulfide releases the calicheamicin, and activation, DNA binding, and strand scission ensue. We studied the interaction of pHLIP-calicheamicin with liposomal and cellular membranes and demonstrated that the agent exhibits cytotoxic activity both in highly proliferative cancer cells and in non-proliferative immune cells, such as polarized M2 macrophages. In vivo, the agent was effective in inhibiting tumor growth in mice with no signs of toxicity. Biodistribution studies confirmed tumor targeting with no accumulation of the agent in organs and tissues. The agent was found within the tumor mass and tumor-stroma interface. Treatment of tumors led to the depletion of CD206+ M2- tumor-associated macrophages within the tumor core. pHLIP-calicheamicin could be pursued as an effective therapeutic for the treatment of solid tumors.Copyright © 2024 Elsevier B.V. All rights reserved.