Stimuli-responsive hydrogel microspheres encapsulated with tumor-cell-derived microparticles for malignant ascites treatment

Tumor-cell-derived microparticles (TMPs) have been recognized as chemotherapeutic drug carriers and immunomodulators for anti-tumor therapy. Research in the clinical application of TMPs has been devoted to developing an effective delivery formulation that could enhance their therapeutic effects. Here, we propose thermal-responsive agarose hydrogel microspheres (MTX-TMPs@MSs) with encapsulation of Methotrexate (MTX)-packaging TMPs (MTX-TMPs) and black phosphorus quantum dots (BPQDs) by microfluidic technology for synergistic treatment of malignant ascites. The laden MTX-TMPs, separated from apoptotic tumor cells, could target tumor cells for the delivery of chemotherapy drugs and modulate the tumor immune microenvironment. Under near-infrared (NIR) induced thermal stimulation, MTX-TMPs could be controllably released from the low-melting-point agarose matrix hydrogel microspheres for chemotherapy (CHT) and immunotherapy (IMT). In addition, benefiting from photothermal therapy (PTT)-induced tumor immunogenic death, the anti-tumor immune response triggered by MTX-TMPs was further enhanced. Based on these features, the MTX-TMPs@MSs could remarkably eliminate tumor cells in vitro and obviously suppress tumor growth in vivo through synergistic PTT, CHT, and IMT. Therefore, it is envisaged that this TMPs-integrated microcarrier will have promising applications in clinical tumor therapy.

Statement of Significance

Primary liver cancer ranks third among the causes of cancer deaths globally, with hepatocellular carcinoma (HCC) being the most common type. In particular, patients with advanced HCC accompanied by malignant ascites, a common complication, indicate tumor metastasis and a poor prognosis. In this paper, we developed stimuli-responsive hydrogel microspheres from microfluidics for the delivery of methotrexate (MTX)-loaded tumor-cell-derived microparticles (MTX-TMPs) for synergistic chemotherapy, photothermal therapy, and immunotherapy. The release of MTX-TMPs from hydrogel microspheres could be on-demand controlled through BPQDs-mediated photothermal stimulus. On the other hand, BPQDs-mediated mild hyperthermia cooperatesss with MTX-TMPs-induced chemotherapy could participate in remodeling the tumor immunosuppressive microenvironment. Thus, the prepared microcarrier system holds great promise for tumor therapy.