Ginsenoside Rg3 nanoparticles with permeation enhancing based chitosan derivatives were encapsulated with doxorubicin by thermosensitive hydrogel and anti-cancer evaluation of peritumoral hydrogel injection combined with PD-L1 antibody

Background: Combination of chemotherapy and immune checkpoint inhibitor therapy has greatly improved the anticancer effect on multiple malignancies. However, the efficiency on triple-negative breast cancer (TNBC) is limited, since most patients bear cold tumors with low tumor immunogenicity. Doxorubicin (DOX), one of the most effective chemotherapy agents, can induce immunogenic cell death (ICD) and thus initiating immune response.Methods: In this study, to maximize the ICD effect induced by DOX, chitosan and cell-penetrating peptide (R6F3)-modified nanoparticles (PNPs) loaded with ginsenoside Rg3 (Rg3) were fabricated using the self-assembly technique, followed by co-encapsulation with DOX based on thermo-sensitive hydrogel. Orthotopic tumor model and contralateral tumor model were established to observe the antitumor efficacy of the thermo-sensitive hydrogel combined with anti-PD-L1 immunotherapy, besides, the biocompatibility was also evaluated by histopathological.Results: Rg3-PNPs strengthened the immunogenic cell death (ICD) effect induced by DOX. Moreover, the hydrogel co-loading Rg3-PNPs and DOX provoked stronger immune response in originally nonimmunogenic 4T1 tumors than DOX monotherapy. Following combination with PD-L1 blocking, substantial antitumor effect was achieved due to the recruitment of memory T cells and the decline of adaptive PD-L1 enrichment.Conclusion: The hydrogel encapsulating DOX and highly permeable Rg3-PNPs provided an efficient strategy for remodeling immunosuppressive tumor microenvironment and converting immune cold 4T1 into hot tumors.

Automated summary

This study demonstrated that encapsulating doxorubicin (DOX) and highly permeable ginsenoside Rg3 (Rg3)-modified nanoparticles (PNPs) in a thermo-sensitive hydrogel can enhance the immunogenic cell death (ICD) effect induced by DOX and provoke a stronger immune response. This encapsulation strategy remodels the tumor microenvironment, converting originally nonimmunogenic tumors into immunogenic ones.