Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Department of Oncology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
ACS Nano. 2024 May 28;18(21):13683-13695. doi: 10.1021/acsnano.4c01352. Epub 2024 May 15.
Tumor metastases and reoccurrence are considered the leading causes of cancer-associated deaths. As an emerging therapeutic method, increasing research efforts have been devoted to immunogenic cell death (ICD)-inducing compounds to solve the challenge. The clinically approved chemotherapeutic Pt complexes are not or are only poorly able to trigger ICD. Herein, the axial functionalization of the Pt(II) complex cisplatin with perfluorocarbon chains into ICD-inducing Pt(IV) prodrugs is reported. Strikingly, while the Pt(II) complex as well as the perfluorocarbon ligands did not induce ICD, the Pt(IV) prodrug demonstrated unexpectantly the induction of ICD through accumulation in the endoplasmic reticulum and generation of reactive oxygen species in this organelle. To enhance the pharmacological properties, the compound was encapsulated with human serum albumin into nanoparticles. While selectively accumulating in the tumorous tissue, the nanoparticles demonstrated a strong tumor growth inhibitory effect against osteosarcoma inside a mouse model. tumor vaccine analysis also demonstrated the ability of Pt(IV) to be an ideal ICD inducer. Overall, this study reports on axially perfluorocarbon chain-modified Pt(IV) complexes for ICD induction and chemoimmunotherapy in osteosarcoma.
肿瘤转移和复发被认为是癌症相关死亡的主要原因。作为一种新兴的治疗方法，越来越多的研究致力于寻找能够诱导免疫原性细胞死亡（ICD）的化合物来解决这一挑战。已批准临床使用的铂类化疗药物不能或只能轻微地触发 ICD。在此，报道了将顺铂的 Pt(II) 配合物轴向功能化，用全氟碳链修饰为 ICD 诱导型 Pt(IV) 前药。引人注目的是，虽然 Pt(II) 配合物和全氟碳配体本身不能诱导 ICD，但 Pt(IV) 前药通过在 ER 中积累并在该细胞器中产生活性氧，出人意料地诱导了 ICD。为了增强药理学性质，将该化合物用人血清白蛋白包封成纳米颗粒。在小鼠模型中，纳米颗粒选择性地在肿瘤组织中积累，对骨肉瘤表现出强烈的肿瘤生长抑制作用。肿瘤疫苗分析也表明 Pt(IV) 具有成为理想的 ICD 诱导剂的能力。总的来说，本研究报告了轴向全氟碳链修饰的 Pt(IV) 配合物在骨肉瘤的 ICD 诱导和化学免疫治疗中的应用。
