A nanotherapeutic strategy that engages cytotoxic and immunosuppressive activities for the treatment of cancer recurrence following organ transplantation

作者：Zhentao Yang, Haiyang Xie, Jianqin Wan, Yuchen Wang, Liang Zhang, Ke Zhou, Hong Tang, Wentao Zhao, Hangxiang Wang, Penghong Song, Shusen Zheng · 发表于：EBioMedicine · 年份：2023 · DOI：10.1016/j.ebiom.2023.104594 · 被引用次数：7 · 研究领域：Nanoplatforms for cancer theranostics、Cancer Research and Treatments、Immunotherapy and Immune Responses

BACKGROUND: Long-term treatment with immunosuppressants is necessary to attenuate allograft rejection following organ transplantation (OT). Consequently, the overall survival of OT recipients with malignancies has been substantially compromised by tumour recurrence. Rapamycin (RAPA) is a clinically approved immunosuppressive agent with antitumour activity that is considered beneficial in preventing posttransplant tumour recurrence. However, the clinical outcome of RAPA is impeded by acquired drug resistance and its poor oral bioavailability. METHODS: A nanotherapeutic strategy was developed by supramolecular assembly of RAPA into a polymer cytotoxic 7-ethyl-10-hydroxycamptothecin (SN38) prodrug nanoparticle (termed SRNP) for simultaneous codelivery of cytotoxic/immunosuppressive agents. Cell-based experiments were used to evaluate the cytotoxicity of SRNPs against hepatocellular carcinoma (HCC). The therapeutic efficacy of SRNPs was evaluated in multiple preclinical models including an orthotopic HCC mouse model, an orthotopic liver transplantation (OLT) rat model and a clinically relevant cancer-transplant model to examine its antitumour and immunosuppressive activity. FINDINGS: The combination of SN38 with RAPA resulted in synergetic effects against HCC cells and alleviated RAPA resistance by abrogating Akt/mTOR signalling activation. SRNPs exhibited potent antitumour efficiency in the orthotopic HCC model while substantially prolonging the survival of allografts in the OLT...