Department of Urology, the First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Medical University, Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, 230022, P. R. China.
School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, 510006, P. R. China.
Small. 2023 Jun;19(22):e2207077. doi: 10.1002/smll.202207077. Epub 2023 Mar 1.
Therapeutic efficacy for prostate cancer is highly restricted by insufficient drug accumulation and the resistance to apoptosis and immunogenic cell death (ICD). Although enhanced permeability and retention (EPR) effect of magnetic nanomaterials could benefit from external magnetic field, it falls off rapidly with increased distance from magnet surface. Considering the deep location of prostate in pelvis, the improvement of EPR effect by external magnetic field is limited. In addition, apoptosis resistance and cGAS-STING pathway inhibition-related immunotherapy resistance are major obstacles to conventional therapy. Herein, the magnetic PEGylated manganese-zinc ferrite nanocrystals (PMZFNs) are designed. Instead of providing external magnet, micromagnets into tumor tissues are intratumorally implanted to actively attract and retain intravenously-injected PMZFNs. As a result, PMZFNs accumulate in prostate cancer with high efficacy, depending on the established internal magnetic field, which subsequently elicit potent ferroptosis and the activation of cGAS-STING pathway. Ferroptosis not only directly suppresses prostate cancer but also triggers burst release of cancer-associated antigens and consequently initiates ICD against prostate cancer, where activated cGAS-STING pathway further amplifies the efficacy of ICD by generating interferon-β. Collectively, the intratumorally implanted micromagnets confer a durable EPR effect of PMZFNs, which eventually achieve the synergetic tumoricidal efficacy with negligible systemic toxicity.
治疗前列腺癌的疗效受到药物蓄积不足和对细胞凋亡和免疫原性细胞死亡（ICD）的抵抗的高度限制。尽管磁性纳米材料的增强渗透和保留（EPR）效应可以受益于外部磁场，但随着距磁体表面的距离增加，其迅速下降。考虑到前列腺在骨盆中的深位置，外部磁场对 EPR 效应的改善是有限的。此外，凋亡抵抗和 cGAS-STING 通路抑制相关的免疫治疗抵抗是常规治疗的主要障碍。在此，设计了磁性聚乙二醇化锰锌铁氧体纳米晶体（PMZFNs）。而不是提供外部磁铁，将微磁铁植入肿瘤组织中，以主动吸引和保留静脉内注射的 PMZFNs。结果，PMZFNs 依靠建立的内部磁场，高效地积聚在前列腺癌中，随后引发强烈的铁死亡和 cGAS-STING 通路的激活。铁死亡不仅直接抑制前列腺癌，还引发癌相关抗原的爆发释放，从而引发针对前列腺癌的 ICD，其中激活的 cGAS-STING 通路通过产生干扰素-β进一步放大 ICD 的疗效。总之，植入肿瘤内的微磁铁赋予了 PMZFNs 持久的 EPR 效应，最终实现了协同的肿瘤杀伤疗效，而系统毒性可忽略不计。
