Evaluation of the anti-tumor effect of gambogic acid loaded macrophage membranes nanoparticles combined with radiotherapy and anti-PD-1mAb in the colorectal cancer with liver metastasis model

Abstract

Background

The prognosis of patients with colorectal liver metastasis (CRLM) is poor. The 5-year survival rate of those who cannot be treated by surgery is less than 5 %, thus, the management of patients with CRLM remains a significant challenge. Based on the anti-tumor activity of traditional Chinese medicine monomer and the local immune activation caused by low dose radiotherapy combined with immune checkpoint inhibitors, we jointly applied it to explore the tumor inhibitory effect and the change of local immune microenvironment in liver metastasis model.

Methods

We engineered biomimetic nanoparticles through macrophage membrane encapsulation of gambogic acid (GA)-loaded PLGA cores, employing a double emulsion-solvent evaporation method to fabricate M-PLGA@GA nanoparticles. In tumor-bearing mice with surgically induced colorectal liver metastasis via hemisplenectomy, therapeutic efficacy was evaluated through intratumoral administration of M-PLGA@GA combined with triple-modality therapy: low-dose radiotherapy (LDRT; 5 Gy), anti-programmed cell death protein 1 monoclonal antibody (anti-PD-1 mAb; 200 μg), and nanoparticle delivery. This combinatorial approach leveraged spatial-temporal control of tumor microenvironment modulation.

Results

The nanoparticles augmented the targeted delivery ability of drugs to tumor cells and in vivo circulation duration, coupled with improved aqueous solubility of the encapsulated therapeutic agent, all while preserving its therapeutic potency. The radiotherapy notably augments the population of Dendritic cells (DCs) and bolsters the presentation of antigens to the tumor cells. Moreover, the administration of GA induces modifications in the tumor's immune microenvironment and escalates the fraction of CD8+ T cells. Within the context of the mouse CRLM model, the amalgamation of M-PLGA@GA with low-dose radiotherapy and immunotherapy markedly attenuates the pace of tumor proliferation and extends the survival of mice.

Conclusions

Our findings propose that a novel therapeutic regimen combining radiotherapy, immunotherapy, and Nanoparticle gambogic acid can effectively impede tumor progression in the mouse model of CRLM. Therefore, our study provides novel insights into the role of combined antitumor therapy on innate and adaptive antitumor immunity modulation for CRLM.