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

Abstract

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 model. In the cancer-transplant model that simultaneously bears tumour xenografts and skin allografts, SRNPs not only effectively inhibited tumour growth but also attenuated allograft damage.

Interpretation: The nanotherapy presented here had enhanced efficacy against tumours and maintained satisfactory immunosuppressive activity and thus has great potential to improve the survival outcomes of patients with a high risk of tumour recurrence following OT.

Funding: This work was supported by the National Natural Science Foundation of China (32171368 and 31671019), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Zhejiang Province Preeminence Youth Fund (LR19H160002), and the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c).

Keywords: Hepatocellular carcinoma; Nanotherapeutic strategy; Organ transplantation; Tumour recurrence.